MH_dev_126

Efficacy and safety of erlotinib HCl , an epidermal growth factor receptor ( P00533 REA / P00533 REA ) tyrosine kinase inhibitor , in patients with advanced ovarian carcinoma : results from a phase II multicenter study . The aim of this single-arm , phase II study was to estimate the tumor response rate and safety profile of erlotinib HCl ( erlotinib , Tarceva , DB00530 SUB ) monotherapy in patients with refractory , recurrent , P00533 REA / P00533 REA - positive epithelial ovarian tumors , who had failed prior taxane and / or platinum-based chemotherapy . Thirty-four patients received 150 mg erlotinib orally once daily for up to 48 weeks or until disease progression or dose-limiting toxicity . Two patients had partial responses , lasting 8 + and 17 weeks , giving an objective response rate of 6 % ( 95 % confidence interval [ CI ] , 0.7- 19.7 % ) . Fifteen patients ( 44 % ) had stable disease , and 17 patients ( 50 % ) had progressive disease . Median overall survival was 8 months ( 95 % CI , 5.7- 12.7 months ) , with a 1 - year survival rate of 35.3 % ( 95 % CI , 19.8- 53.5 % ) . Patients with rash survived significantly longer than those without ( P= 0.009 ) , correlating with rash grade . Erlotinib was generally well tolerated . The most frequent erlotinib-related adverse events were rash ( 68 % ) and diarrhea ( 38 % ) . Erlotinib had marginal activity but was generally well tolerated . The safety profile appears more favorable than typically experienced with standard chemotherapeutic agents , which is encouraging in these heavily pretreated patients . Combination of erlotinib with chemotherapy or other targeted agents should be considered .

Development of the epidermal growth factor receptor inhibitor DB00530 SUB . The epidermal growth factor receptor ( P00533 REA ) is a transmembrane receptor involved in the regulation of a complex array of essential biological processes such as cell proliferation and survival . Dysregulation of the P00533 REA signaling network has been frequently reported in multiple human cancers and has been associated with the processes of tumor development , growth , proliferation , metastasis , and angiogenesis . Inhibition of the P00533 REA was associated with antitumor effects in preclinical models . On the basis of these data , therapeutics targeting the P00533 REA were explored in clinical trials . DB00530 SUB is a small-molecule selective inhibitor of the P00533 REA tyrosine kinase . In preclinical studies , DB00530 SUB inhibited the phosphorylation of the P00533 REA in a dose-dependent and concentration-dependent manner resulting in cell cycle arrest and induction of apoptosis . In in vivo studies , this agent caused tumor growth inhibition and showed synergistic effects when combined with conventional chemotherapy . Subsequent single-agent phase I studies and phase I studies in combination with chemotherapy showed that the agent has a good safety profile and induced tumor growth inhibition in a substantial number of patients with a variety of different solid tumors . Preliminary reports from phase II studies confirmed the excellent tolerability of DB00530 SUB and showed encouraging preliminary activity . Phase III studies have either been completed or are ongoing in several tumor types such as lung cancer and pancreatic cancer . In summary , DB00530 SUB is a novel inhibitor of the P00533 REA tyrosine kinase that has shown promising activity in initial studies and is currently undergoing full development as an anticancer drug .

Tamoxifen enhances erlotinib-induced cytotoxicity through down-regulating AKT-mediated thymidine phosphorylase expression in human non-small-cell lung cancer cells . Tamoxifen is a triphenylethylene nonsteroidal estrogen receptor ( ER ) antagonist used worldwide as an adjuvant hormone therapeutic agent in the treatment of breast cancer . However , the molecular mechanism of tamoxifen-induced cytotoxicity in non-small cell lung cancer ( NSCLC ) cells has not been identified . P19971 REA ( TP ) is an enzyme of the pyrimidine salvage pathway which is upregulated in cancers . In this study , tamoxifen treatment inhibited cell survival in two NSCLC cells , H520 and H1975 . Treatment with tamoxifen decreased TP mRNA and protein levels through AKT inactivation . Furthermore , expression of constitutively active AKT ( AKT-CA ) vectors significantly rescued the decreased TP protein and mRNA levels in tamoxifen-treated NSCLC cells . In contrast , combination treatment with PI3K inhibitors ( LY294002 or wortmannin ) and tamoxifen further decreased the TP expression and cell viability of NSCLC cells . Knocking down TP expression by transfection with small interfering RNA of TP enhanced the cytotoxicity and cell growth inhibition of tamoxifen . Erlotinib ( Tarceva , DB00530 SUB ) , an orally available small molecular inhibitor of epidermal growth factor receptor ( P00533 REA ) tyrosine kinase , is approved for clinical treatment of NSCLC . Compared to a single agent alone , tamoxifen combined with erlotinib resulted in cytotoxicity and cell growth inhibition synergistically in NSCLC cells , accompanied with reduced activation of phospho-AKT and phospho - P27361 REA / 2 , and reduced TP protein levels . These findings may have implications for the rational design of future drug regimens incorporating tamoxifen and erlotinib for the treatment of NSCLC .

Role of nitrative and oxidative DNA damage in inflammation-related carcinogenesis . Chronic inflammation induced by biological , chemical , and physical factors has been found to be associated with the increased risk of cancer in various organs . We revealed that infectious agents including liver fluke , Helicobacter pylori , and human papilloma virus and noninfectious agents such as asbestos fiber induced P35228 REA - dependent formation of 8 - nitroguanine and 8 - oxo - 7 , 8-d ihydro - 2 ' - deoxyguanosine ( 8 - oxodG ) in cancer tissues and precancerous regions . Our results with the colocalization of phosphorylated Q13315 REA and γ - P16104 REA with 8 - oxodG and 8 - nitroguanine in inflammation-related cancer tissues suggest that DNA base damage leads to double-stranded breaks . It is interesting from the aspect of genetic instability . We also demonstrated P05231 REA - modulated P35228 REA expression via P40763 REA and P00533 REA in Epstein-Barr-virus-associated nasopharyngeal carcinoma and found promoter hypermethylation in several tumor suppressor genes . Such epigenetic alteration may occur by controlling the DNA methylation through P05231 REA - mediated JAK / P40763 REA pathways . Collectively , 8 - nitroguanine would be a useful biomarker for predicting the risk of inflammation-related cancers .

Beyond the TRIBUTE trial : integrating P00533 REA / P00533 REA tyrosine kinase inhibitors with chemotherapy in advanced NSCLC . Evaluation of : Herbst RS , Prager D , Hermann R et al . : TRIBUTE : a Phase III trial of erlotinib hydrochloride ( DB00530 SUB ) combined with carboplatin and paclitaxel chemotherapy in advanced non-small cell lung cancer . J . Clin . Oncol . 23 , 5892-5899 ( 2005 ) . Patients diagnosed with advanced non-small cell lung cancer have limited therapeutic options . A large , randomized , controlled trial of the human epidermal growth factor receptor tyrosine-kinase inhibitor , erlotinib ( Tarceva ) , plus standard first-line chemotherapy did not meet its primary end point of improved survival in the overall population , but did reveal a striking survival benefit in a subset of patients who had never smoked . There are a number of possible explanations for the lack of overall benefit , including the use of an unselected patient population , the need for alternatives to concurrent administration , and a postulated pathophysiological interaction between erlotinib and chemotherapy . Ongoing studies investigating alternative schedules and sequences of administration with chemotherapy will help clinicians to determine how agents such as erlotinib can best be combined with standard cytotoxic agents .

Association between severe toxicity of nilotinib and P22309 REA polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : DB04868 MEN is a P11274 REA - P00519 REA kinase inhibitor approved for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia ( CML ) . The P22309 REA ( P22309 REA ) polymorphism P22309 REA * 28 ( * 28 ) / * 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 REA * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 REA . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 REA polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 REA polymorphisms with severe nilotinib-related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 / * 6 or * 6 / * 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 / * 1 or * 1 / * 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 REA polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .

Targeted therapy using novel agents in the treatment of non-small-cell lung cancer . Patients with advanced non-small-cell lung cancer ( NSCLC ) have a poor prognosis and high mortality . The therapeutic improvement caused by the new generation of cytotoxic agents seems to have reached a plateau . The main categories of targeted therapeutics applicable for NSCLC include receptor-targeted therapy , signal transduction or cell-cycle inhibition , angiogenesis inhibitors , gene therapy , and vaccines . Several major classes of agents directed at specific cellular mechanisms exist for the treatment of NSCLC . The anti-epidermal growth factor receptor ( P00533 REA ) group contains trastuzumab and IMC-C 225 , monoclonal antibodies against EGFRs that are overexpressed in many cancers . DB00530 SUB and ZD1839 are inhibitors of P00533 REA tyrosine kinase , a key enzyme of the signaling pathway . Farnesyl transferase inhibitors , such as SCH 66336 , and protein kinase C inhibitors , such as ISIS 3521 , have also shown antitumor activity . Antiangiogenesis agents that have shown promise include TNP - 470 , recombinant endostatin , and angiostatin . Antibodies to vascular endothelial growth factor ( P15692 REA ) also seem to control tumor progression and may prolong survival . LY317615 , an inhibitor of protein kinase Cb , augmented the tumor growth delay produced by cytotoxic drugs . All of these agents are in different phases of clinical testing and have shown encouraging activity as single agents or in combination with chemotherapy drugs . These new agents are more target specific , less toxic , easier to administer , and may lead to enhanced safety and survival for patients with advanced NSCLC .

Therapy with a synthetic retinoid - - ( Ro 10-1670 ) etretin - - increases the cellular retinoic acid-binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 REA ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , DB00459 MEN ( Ro 10-1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 REA levels were not altered during therapy . The results show that P09455 REA and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .

DB04868 MEN and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia . We show that imatinib , nilotinib , and dasatinib possess weak off-target activity against RAF and , therefore , drive paradoxical activation of P15056 REA and CRAF in a DB01367 - dependent manner . Critically , because DB01367 is activated by P11274 REA - P00519 REA , in drug-resistant chronic myeloid leukemia ( CML ) cells , DB01367 activity persists in the presence of these drugs , driving paradoxical activation of P15056 REA , CRAF , MEK , and P29323 REA , and leading to an unexpected dependency on the pathway . Consequently , nilotinib synergizes with MEK inhibitors to kill drug-resistant CML cells and block tumor growth in mice . Thus , we show that imatinib , nilotinib , and dasatinib drive paradoxical RAF / MEK / P29323 REA pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug-resistant CML cells in vitro and in vivo .

Erlotinib : success of a molecularly targeted agent for the treatment of advanced pancreatic cancer . P00533 REA ( P00533 REA ) is overexpressed by several solid tumors , including pancreatic cancer , and has become an important target for novel anticancer pharmacotherapy . Erlotinib ( Tarceva , DB00530 SUB ) is an orally available small-molecule inhibitor of the P00533 REA tyrosine kinase . The addition of erlotinib to gemcitabine has been shown to prolong survival of patients treated for advanced pancreatic cancer in the National Cancer Institute of Canada PA . 3 trial . This survival advantage is small yet noteworthy , in that numerous gemcitabine-containing combinations have failed to show a statistically significant survival advantage over gemcitabine alone . The most frequent toxicities associated with the addition of erlotinib are diarrhea and rash . Erlotinib-induced rash appears to be predictive of outcome . Further clinical studies of erlotinib in the treatment of pancreatic cancer are ongoing .

DB01296 MEN sulfate inhibits P01375 REA and P01579 REA - induced production of P05362 REA in human retinal pigment epithelial cells in vitro . PURPOSE : DB01296 MEN sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine-induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 REA gene upregulated by P01375 REA or P01579 REA , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT-PCR ) . The activation and nuclear translocation of the nuclear factors NF-kappaB and P42224 REA were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 REA and P01579 REA increased the expression of P05362 REA at the mRNA and protein levels in a time - and dose-dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 REA - or P01579 REA - induced expression of P05362 REA in the protein and mRNA level in a dose-dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 REA and phosphorylated P42224 REA in P01579 REA - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 REA gene in ARPE - 19 cell stimulated with P01375 REA or P01579 REA through blockade of NF-kappaB subunit p65 and nuclear translocation of P42224 REA . This study has demonstrated a potentially important property of GS in reducing P05362 REA mediated inflammatory mechanisms in the eye .

Gefitinib ( ' DB00317 ' , ZD1839 ) and new epidermal growth factor receptor inhibitors . The epidermal growth factor receptor ( P00533 REA ) is a promising target for cancer therapy and a number of P00533 REA - targeted agents have been developed . Those most advanced in development are the P00533 REA tyrosine kinase inhibitors gefitinib ( ' DB00317 ' , ZD1839 ) and erlotinib ( ' Tarceva ' , DB00530 SUB ) , and the monoclonal antibody cetuximab ( ' Erbitux ' , IMC-C 225 ) . This review provides a clinical overview of these agents , highlighting their antitumour activities in different tumour types . P00533 REA - targeted agents are generally well tolerated and are not typically associated with the severe adverse events often seen with cytotoxic chemotherapy . Gefitinib is the agent with the most extensive clinical experience , particularly in non-small-cell lung cancer ( NSCLC ) . Recently , gefitinib became the first-approved P00533 REA - targeted agent , for use in patients with previously treated advanced NSCLC in Japan , the USA and other countries . Further studies are required to explore the full potential of these novel agents either as monotherapy or combination therapy .

Dual P00533 REA and P42345 REA targeting in squamous cell carcinoma models , and development of early markers of efficacy . The epidermal growth factor receptor ( P00533 REA ) is a validated target in squamous cell carcinoma ( SCC ) of the head and neck . Most patients , however , do not respond or develop resistance to this agent . P42345 REA ( P42345 REA ) is involved in the pathogenesis of SCC of the head and neck ( SCCHN ) . This study aimed to determine if targeting P42345 REA in combination with P00533 REA is effective in SCC , and to develop early pharmacodynamic markers of efficacy . Two SCC cell lines , one resistant ( HEP 2 ) and one of intermediate susceptibility ( Detroit 562 ) to P00533 REA inhibitors , were xenografted in vivo and treated with an P42345 REA inhibitor ( temsirolimus ) , an P00533 REA inhibitor ( erlotinib ) or a combination of both . DB06287 MEN exerted superior growth arrest in both cell lines than erlotinib . The combined treatment resulted in synergistic antitumor effects in the Detroit 562 cell line . Immunohistochemical assessment of pharmacodynamic effects in fine-needle aspiration ( FNA ) biopsies early after treatment using phospho MAPK , Phospho-P 70 and Ki67 as end points demonstrated pathway abrogation in the Detroit 562 tumours treated with the combination , the only group where regressions were seen . In conclusion , an P42345 REA inhibitor showed antitumor activity in P00533 REA - resistant SCC cell lines . Marked antitumor effects were associated with dual pathway inhibition , which were detected by early FNA biopsies .

Erlotinib ( Tarceva , DB00530 SUB ) antagonizes DB00171 - binding cassette subfamily B member 1 and DB00171 - binding cassette subfamily G member 2 - mediated drug resistance . It has been reported that gefitinib , an epidermal growth factor receptor ( P00533 REA ) tyrosine kinase inhibitor ( TKI ) , has the ability to modulate the function of certain DB00171 - binding cassette ( DB01048 ) transporters and to reverse ABC subfamily B member 1 ( P08183 REA ; P-glycoprotein ) - and ABC subfamily G member 2 ( Q9UNQ0 ; breast cancer resistance protein / mitoxantrone resistance protein ) - mediated multidrug resistance ( MDR ) in cancer cells . However , it is unknown whether other P00533 REA TKIs have effects similar to that of gefitinib . In the present study , we have investigated the interaction of another P00533 REA TKI , erlotinib , with selected ABC drug transporters . Our findings show that erlotinib significantly potentiated the sensitivity of established P08183 REA or Q9UNQ0 substrates and increased the accumulation of paclitaxel or mitoxantrone in P08183 REA - or Q9UNQ0 - overexpressing cells . Furthermore , erlotinib did not significantly alter the sensitivity of non - P08183 REA or non - Q9UNQ0 substrates in all cells and was unable to reverse MRP 1 - mediated MDR and had no effect on the parental cells . However , erlotinib remarkably inhibited the transport of E ( 2 ) 17 beta G and methotrexate by Q9UNQ0 . In addition , the results of ATPase assays show that erlotinib stimulated the ATPase activity of both P08183 REA and Q9UNQ0 . Interestingly , erlotinib slightly inhibited the photolabeling of P08183 REA with [ ( 125 ) I ] iodoarylazidoprazosin ( IAAP ) at high concentration , but it did not inhibit the photolabeling of Q9UNQ0 with IAAP . Overall , we conclude that erlotinib reverses P08183 REA - and Q9UNQ0 - mediated MDR in cancer cells through direct inhibition of the drug efflux function of P08183 REA and Q9UNQ0 . These findings may be useful for cancer combinational therapy with erlotinib in the clinic .

Why the epidermal growth factor receptor ? The rationale for cancer therapy . There is a need for new , selective anticancer agents that differentiate between malignant and nonmalignant cells . The benefits of such agents would include a higher therapeutic index and lower toxicity than conventional therapies . Although expressed in nonmalignant cells , the epidermal growth factor receptor ( P00533 REA ) is highly expressed in a variety of tumors , and its expression correlates with poor response to treatment , disease progression , and poor survival . Evidence for a role for the P00533 REA in the inhibition and pathogenesis of various cancers has led to the rational design and development of agents that selectively target this receptor . Activation of the P00533 REA signaling pathway in cancer cells has been linked with increased cell proliferation , angiogenesis , and metastasis , and decreased apoptosis . Preclinical data show that anti - P00533 REA therapies can inhibit these effects in vitro and in vivo . In addition , preclinical data confirm that many such agents have the potential to increase the effectiveness of current cytotoxic agents . Following accelerated drug development programs , phase III trials are now under way for a number of P00533 REA - targeted therapies , including the monoclonal antibody IMC-C 225 and the P00533 REA - tyrosine kinase inhibitors ZD1839 ( DB00317 ) and DB00530 SUB . Thus , the rationale for P00533 REA - targeted approaches to cancer treatment is apparent and now well established , and there is increasing evidence that they may represent a significant contribution to cancer therapy .

C . elegans vulval development as a model system to study the cancer biology of P00533 REA signaling . Molecular genetic studies of C . elegans vulval development have helped to define an evolutionarily conserved signaling pathway from an P01133 REA - like ligand through P01133 REA - receptor , Ras and Q96HU1 kinase to the nucleus . Further studies have identified novel positive regulators such as Q8IVT5 - 1 and Q09428 REA - 8/ Q5T124 - 2 and negative regulators such as cbl / SLI - 1 . The many negative regulatory proteins might serve to prevent inappropriate signaling , and thus are analogous to tumor suppressor genes .

Anti-epidermal growth factor receptor drugs in cancer therapy . The epidermal growth factor receptor is a cell membrane growth factor receptor that plays a key role in cancer development and progression . P00533 REA - activated signalling pathways control cell proliferation , apoptosis , angiogenesis and metastatic spread in the majority of human epithelial cancers . Targeting the epidermal growth factor receptor represents a valuable molecular approach to cancer therapy . Promising strategies in clinical development include monoclonal antibodies which block ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity which prevent epidermal growth factor receptor autophosphorylation and propagation of downstream intracellular signals . Several anti-epidermal growth factor receptor agents are in clinical development for cancer therapy . Among these , IMC - 225 ( cetuximab ) , a chimeric human-mouse monoclonal IgG 1 antibody , DB00530 SUB ( Tarceva ) and ZD1839 ( DB00317 ) , two small molecule epidermal growth factor receptor-selective tyrosine kinase inhibitors , are currently in Phase II and III development as single agents or in combination with conventional therapies , such as radiotherapy or chemotherapy . Results from Phase I - II trials in advanced cancer demonstrate that these drugs have an acceptable tolerability and an interesting clinical activity in patients with a variety of tumour types .

Potential role for epidermal growth factor receptor inhibitors in combined-modality therapy for non-small-cell lung cancer . There has been a surge of interest in the translation of discoveries in molecular biology into clinically relevant therapies in the field of hematology / oncology . The epidermal growth factor receptor ( P00533 REA ) has been a molecular target of significant interest and investigation , and preclinical and clinical studies support a role for targeted therapy in a variety of cancers , including non-small-cell lung cancer ( NSCLC ) via compounds that specifically inhibit P00533 REA . ZD1839 , IMC-C 225 , and DB00530 SUB are the most clinically developed of these compounds . Interestingly , preclinical studies have demonstrated that P00533 REA inhibitors may have radiation-sensitizing properties , as well as increased cytotoxic activity in combination with chemotherapeutic agents , suggesting a potential role for P00533 REA inhibitors as an adjunct to the current combined-modality approach for therapy of Stage III NSCLC . Therefore , clinical trials have been proposed and initiated to address the issue of determining the impact of the addition of P00533 REA inhibitors to the standard combined-modality regimen ( chemotherapy / radiation therapy + / - surgery ) for Stage III NSCLC . This article reviews preclinical and clinical data supporting the role for P00533 REA inhibitors alone or in combination with chemotherapy / radiation therapy for locally advanced NSCLC . Also , it will provide an overview of ongoing and proposed clinical studies investigating the potential role for P00533 REA inhibitors in Stage III NSCLC .

Erlotinib ( DB00530 SUB ) - induced inhibition of transitional cell carcinoma of bladder cell line growth is enhanced by interferon-alpha . OBJECTIVE : To examine whether erlotinib gives similar results to gefitinib , a small molecule epidermal growth factor receptor ( P00533 REA / P00533 REA ) tyrosine kinase ( TK ) inhibitor that inhibits the growth of human bladder cancer cell lines in vitro , and given that interferon-alpha ( IFNalpha ) promotes an antiproliferative effect of P00533 REA / P00533 REA inhibitors on colon cancer cell lines , to also determine the effects of erlotinib alone or together with INFalpha on bladder cancer cell lines , and whether sensitivity is influenced by P00533 REA / P00533 REA mutation status . MATERIALS AND METHODS : Seven bladder cancer cell lines were characterized for P00533 REA / P00533 REA expression , then treated with erlotinib alone , IFNalpha alone , or IFNalpha plus erlotinib . Cell growth inhibition was assessed by crystal-violet staining and P00533 REA / P00533 REA expression by flow cytometry . Synergy was evaluated using the combination index of Chou and Talalay . DNA from these cell lines in the linear growth phase and from 14 bladder cancer tissue samples were tested for P00533 REA / EGFRTK mutations . RESULTS : Cell-surface P00533 REA / P00533 REA expression was present in all seven bladder cancer cell lines . Both erlotinib and IFNalpha independently were significantly antiproliferative , and combined treatment synergistically enhanced the sensitivity in six of the seven cell lines . No bladder cancer cell lines or tissues tested expressed P00533 REA / EGFRTK mutations . CONCLUSION : Erlotinib inhibits the growth of human bladder cancer cell lines . Enhanced inhibition in the presence of IFNalpha is not determined by the presence of P00533 REA / EGFRTK mutations . This study might have clinical implications for improving the treatment of bladder cancer .

Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 REA and P01375 REA released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 REA and P05231 REA are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 REA were measured in monocyte supernatants . The spontaneous release of P05231 REA or P01375 REA was increased in young athletes when compared to older subjects . The spontaneous release of P01375 REA was increased , but not significantly , by exercise and there was no correlation between the release of P05231 REA and P01375 REA and lung function measured during hypoxemia . DB00668 MEN inhibited the release of P05231 REA or P01375 REA . Correlations were observed between the in vitro release of P05231 REA or P01375 REA and age , VO2max , maximal ventilation and maximal power output of the subjects .

Autocrine signaling via release of DB00171 and activation of Q99572 REA receptor influences motile activity of human lung cancer cells . Extracellular nucleotides , such as DB00171 , are released from cells and play roles in various physiological and pathological processes through activation of P2 receptors . Here , we show that autocrine signaling through release of DB00171 and activation of Q99572 REA receptor influences migration of human lung cancer cells . Release of DB00171 was induced by stimulation with TGF-β 1 , which is a potent inducer of cell migration , in human lung cancer H292 cells , but not in noncancerous BEAS - 2B cells . Treatment of H292 cells with a specific antagonist of Q99572 REA receptor resulted in suppression of TGF-β 1 - induced migration . PC - 9 human lung cancer cells released a large amount of DB00171 under standard cell culture conditions , and Q99572 REA receptor-dependent dye uptake was observed even in the absence of exogenous ligand , suggesting constitutive activation of Q99572 REA receptor in this cell line . PC - 9 cells showed high motile activity , which was inhibited by treatment with ecto-nucleotidase and Q99572 REA receptor antagonists , whereas a Q99572 REA receptor agonist enhanced migration . PC - 9 cells also harbor a constitutively active mutation in epidermal growth factor receptor ( P00533 REA ) . Treatment with P00533 REA tyrosine kinase inhibitor AG1478 suppressed both cell migration and Q99572 REA receptor expression in PC - 9 cells . Compared to control PC - 9 cells , cells treated with Q99572 REA antagonist exhibited broadened lamellipodia around the cell periphery , while AG1478 - treated cells lacked lamellipodia . These results indicate that Q99572 REA - mediated signaling and P00533 REA signaling may regulate migration of PC - 9 cells through distinct mechanisms . We propose that autocrine DB00171 - Q99572 REA signaling is involved in migration of human lung cancer cells through regulation of actin cytoskeleton rearrangement .

DB00530 SUB OSI Pharmaceuticals . DB00530 SUB ( formerly CP - 358774 ) , a quinazoline derivative , is an orally active epidermal growth factor receptor ( P00533 REA ) inhibitor which was originally under joint development by Pfizer and OSI Pharmaceuticals ( formerly Oncogene Science ) for the potential treatment of cancer ( eg , ovarian , non-small cell lung cancer ( NSCLC ) and head and neck ) . It is being evaluated in phase II trials [ 304305 ] , [ 372201 ] . On 8 January 2001 , OSI announced that it had signed an agreement with Roche and Genentech for the global co-development and marketing of DB00530 SUB . The agreement with Genentech covers the United States , that with Roche the rest of the world [ 395371 ] , [ 395526 ] . In June 2000 , OSI gained all development and marketing rights for DB00530 SUB following Pfizer ' s merger with Warner-Lambert [ 371439 ] . In September 2000 , Pfizer transferred the IND dossierfor DB00530 SUB to OSI ahead of the timeline agreed in the June 2000 development and marketing rights agreement [ 383786 ] . The phase II trials will assess DB00530 SUB both as a single agent and in combination with existing chemotherapy regimens [ 347783 ] . Phase III trials are expected to be initiated in 2001 [ 347783 ] . In October 2000 , Lehman Brothers predicted that DB00530 SUB would move into pivotal trials in thefirst half of 2001 and that the drug would be launched in 2003 . The analysts also estimated worldwide sales of US $ 66 million , $ 285 million and $ 461 million in 2003 , 2004 and 2005 , respectively , and peak sales in excess of US $ 500 million [ 395189 ] .

Modulatory effects of heparin and short-length oligosaccharides of heparin on the metastasis and growth of LMD MDA-MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 REA allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 REA . In this study , we determined whether this interaction could be disrupted using short-chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 REA . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 REA ( 71 % inhibition ; P < 0.001 ) . These oligosaccharides also significantly inhibited P48061 REA - induced migration of P61073 REA - expressing LMD MDA-MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , DB06822 MEN . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0.05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0.001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin-derived oligosaccharides in the inhibition of tumour growth and metastases .

Label-free electrochemical measurement of protein tyrosine kinase activity and inhibition based on electro-catalyzed tyrosine signaling . A novel label-free electrochemical method for measuring the activity of protein tyrosine kinases ( PTK ) has been developed . P00533 REA ( P00533 REA ) , a typical PTK associated with a large percentage of all solid tumors , was used as the model kinase . Poly ( glu , tyr ) ( 4:1 ) peptide , as a substrate of P00533 REA , was covalently immobilized on the surface of indium tin oxide ( ITO ) electrode by silane chemistry . The tyrosine ( DB00135 ) residue in the polypeptide served as an electrochemical signal reporter . Its voltammetric current was catalyzed by a dissolved electron mediator Os ( bpy ) ( 3 ) ( 2 + ) ( bpy = 2,2 ' - bipyridine ) for increased sensitivity . Phosphorylation of the DB00135 led to a loss of its electrochemical current , thus providing a sensing mechanism for PTK activity . Experimental conditions for the silanization of ITO surface and immobilization of polypeptide were investigated in details to facilitate the generation of DB00135 electrochemical signal . The proposed biosensor exhibited high sensitivity and excellent stability . The limit of detection for P00533 REA was 1 UmL ( - 1 ) . Furthermore , this biosensor can also be used for quantitative analysis of kinase inhibition . On the basis of the inhibitor concentration dependent electrochemical signal , the half-maximal inhibition value IC ( 50 ) of three P00533 REA inhibitors , PD - 153035 , DB00530 SUB and ZD - 1839 , and their corresponding inhibition constants K ( i ) were estimated , which were in agreement with those obtained from the conventional kinase assay . This electrochemical biosensor can be implemented in an array format for the high throughput assay of in vitro PTK activity and PTK inhibitors screening for practical diagnostic application and drug discovery .

[ Molecular target-based cancer therapy : epidermal growth factor receptor inhibitors ] . Based on recent progress in cancer biology , numerous molecules that contribute to proliferation , invasion , and metastasis of cancer cells have been identified . The epidermal growth factor receptor ( P00533 REA ) , a member of cell membrane receptors , is overexpressed by many tumors , and P00533 REA overexpression correlates with poor prognosis and disease progression . The P00533 REA is an attractive target for novel anticancer therapy . ZD1839 and DB00530 SUB , highly specific P00533 REA tyrosine kinase inhibitors , have shown promising antitumor activity against cisplatin-resistant non-small cell lung cancer in phase I and phase II trials . IMC-C 225 , a monoclonal antibody against P00533 REA , has achieved significant disease control in head and neck cancer and colorectal cancer in combination with anticancer agents . These agents are under evaluation in phase III trials . In conclusion , it is expected that P00533 REA - directed therapies will soon be established as an effective novel treatment for many cancer patients .

Erlotinib in non-small cell lung cancer : a review . Erlotinib ( Tarceva , DB00530 SUB ; Pfizer , Inc . ) is an orally-active , targeted inhibitor of the epidermal growth factor receptor ( P00533 REA / P00533 REA ) , which is part of a key regulatory pathway in cancer . Patients with advanced , incurable non-small cell lung cancer ( NSCLC ) may derive a clinical benefit from first - and second-line chemotherapy , but third-line treatment with available cytotoxic agents is not effective . Remarkably , P00533 REA / P00533 REA antagonists have demonstrated activity as second - and even third-line treatment for this disease . Erlotinib is the first of this novel class of drug to demonstrate a statistically significant and clinically relevant difference in overall survival , progression free survival and time to disease related symptoms ( cough , pain , shortness of breath ) compared with treatment with best supportive care in patients who have failed standard first - or second-line chemotherapy . This paper reviews the pharmacology , preclinical and clinical data to support the use of erlotinib in NSCLC .

Overview of tyrosine kinase inhibitors in clinical breast cancer . Studies of cell models and profiling of clinical breast cancer material to reveal the mechanisms of resistance to anti-oestrogen therapy , and to tamoxifen in particular , have reported that this phenomenon can be associated with increased expression and signalling through erbB Type 1 growth factor receptors , notably the epidermal growth factor receptor ( P00533 REA ) and P04626 REA . Further molecular studies have revealed an intricate interlinking between such growth factor receptor pathways and oestrogen receptor ( ER ) signalling . Inhibition of receptor tyrosine kinase activity involved in the P00533 REA signalling cascade forms the basis for the use of P00533 REA specific tyrosine kinase inhibitors exemplified by gefitinib ( ZD1839 , DB00317 ) and erlotinib ( DB00530 SUB , Tarceva ) . Such agents have proved promising in pre-clinical studies and are currently in clinical trials in breast cancer , where gefitinib has been studied more extensively to date . Here , we present an overview of the current development of gefitinib in clinical breast cancer . This includes results from our clinical breast cancer trial 1839IL / 0057 that demonstrate the efficacy of gefitinib within ER-positive , tamoxifen-resistant patients with locally advanced / metastatic disease , where parallel decreases in P00533 REA signal transduction and the Ki67 ( Q86YT6 ) proliferation marker can be detected as predicted from model system studies . We also consider trials examining combination treatment with gefitinib and anti-hormonal strategies that will begin to address the clinically important question of whether gefitinib can delay / prevent onset of anti-hormone resistance .

Increased expression of cellular retinol-binding protein 1 in laryngeal squamous cell carcinoma . PURPOSE : To investigate the genomic alterations in larynx carcinomas ( LaCa ) tissues and its prognostics values in predicting survival . METHODS : To analyse the aberrations in the genome of LaCa patients , we used array comparative genomic hybridization in 19 human laryngeal tumour samples . DNA samples were also subjected to detect human papillomavirus ( HPV ) sequences by polymerase chain reaction ( PCR ) . Copy number gain was confirmed by real-time PCR . The cellular retinol-binding protein 1 ( P09455 REA - 1 ) gene expression was also confirmed by immunohistochemistry assay on LaCa tissues . To identify prognostic feature , P09455 REA - 1 gene gain was correlated to patient survival . RESULTS : The most common gains were detected for P09455 REA - 1 and P00533 REA genes , while DNA lost in RAF - 1 gene . Immunohistochemistry assay was revealed strong expression of P09455 REA protein in those cases with P09455 REA - 1 gene gain . The P09455 REA - 1 gene gain and its expression correlated significantly with survival ( P = 0.003 ) . Cox regression analysis indicated that P09455 REA - 1 expression level was a factor of survival ( P = 0.008 ) . HPV sequences were detected in 42 % of the samples , and did not show any relationship with specific gene alterations . CONCLUSION : Our data shows that P09455 REA - 1 gene gain can be determined by immunohistochemistry on routinely processed tissue specimens , and could support as a potential novel marker for long-term survival in laryngeal squamous cell carcinoma .

Targeting the P00533 REA pathway for cancer therapy . Clinical studies have shown that HER - 2 / Neu is over-expressed in up to one-third of patients with a variety of cancers , including B-cell acute lymphoblastic leukemia ( B-ALL ) , breast cancer and lung cancer , and that these patients are frequently resistant to conventional chemo-therapies . Additionally , in most patients with multiple myeloma , the malignant cells over-express a number of epidermal growth factor receptors ( P00533 REA ) s and their ligands , HB - P01133 REA and amphiregulin , thus this growth-factor family may be an important aspect in the patho-biology of this disease . These and other , related findings have provided the rationale for the targeting of the components of the P00533 REA signaling pathways for cancer therapy . Below we discuss various aspects of P00533 REA - targeted therapies mainly in hematologic malignancies , lung cancer and breast cancer . Beside novel therapeutic approaches , we also discuss specific side effects associated with the therapeutic inhibition of components of the P00533 REA - pathways . Alongside small inhibitors , such as DB01259 ( DB01259 , GW572016 ) , Gefitinib ( DB00317 , ZD1839 ) , and Erlotinib ( Tarceva , DB00530 SUB ) , a significant part of the review is also dedicated to therapeutic antibodies ( e . g . : DB00072 / Herceptin , DB06366 / DB06366 / rhuMab - 2C4 , Cetuximab / Erbitux / IMC-C 225 , DB01269 / Abenix / DB01269 , and also DB05294 ) . In addition , we summarize , both current therapy development driven by antibody-based targeting of the P00533 REA - dependent signaling pathways , and furthermore , we provide a background on the history and the development of therapeutic antibodies .

Substance P autocrine signaling contributes to persistent P04626 REA activation that drives malignant progression and drug resistance in breast cancer . P00533 REA receptor transmodulation by heterologous G-protein-coupled receptors ( GPCR ) generates functional diversity in signal transduction . Tachykinins are neuropeptides and proinflammatory cytokines that promote cell survival and cancer progression by activating several GPCRs . In this work , we found that the pain-associated tachykinin Substance P ( SP ) contributes to persistent transmodulation of the P00533 REA receptors , P00533 REA and P04626 REA , in breast cancer , acting to enhance malignancy and therapeutic resistance . SP and its high-affinity receptor P25103 REA were highly expressed in P04626 REA ( + ) primary breast tumors ( relative to the luminal and triple-negative subtypes ) and were overall correlated with poor prognosis factors . In breast cancer cell lines and primary cultures derived from breast cancer samples , we found that SP could activate P04626 REA . Conversely , RNA interference-mediated attenuation of P25103 REA , or its chemical inhibition , or suppression of overall GPCR-mediated signaling , all strongly decreased steady-state expression of P00533 REA and P04626 REA , establishing that their basal activity relied upon transdirectional activation by GPCR . Thus , SP exposure affected cellular responses to anti - P00533 REA therapies . Our work reveals an important oncogenic cooperation between P25103 REA and P04626 REA , thereby adding a novel link between inflammation and cancer progression that may be targetable by SP antagonists that have been clinically explored .

Determination of ancestral allele for possible human cancer-associated polymorphisms . To determine ancestral allele in possible cancer-associated polymorphisms , DNA samples from 10 chimpanzees ( Pan troglodytes ) were sequenced for alleles corresponding to 17 polymorphisms : 8 short tandem repeats [ P18510 REA ( alias IL - 1RA ) variable number tandem repeat ( VNTR ) ; P04818 REA ( previously TS ) VNTR ; AR CAG repeat ; dinucleotide repeats of P22309 REA , IGF 1 , P01579 REA ( alias P01579 REA ) , P03372 REA ( alias P03372 REA ) , and P00533 REA ] and 9 single nucleotide polymorphisms ( P03956 REA - 1607 1G / 2G , P08254 REA - 1171 5A / 6A , O15527 REA Ser 326Cys , P05091 REA Gly 487Lys , P04637 REA Arg 72Pro , Q9UNQ0 Gln 141Lys , P16455 REA Leu 84Phe , P04179 REA Ala - 9Val , and P42898 REA Ala 222Val ) . No chimpanzee polymorphism corresponded to human P18510 REA VNTR ; the ancestral allele was a repeat lost in humans . Dinucleotide repeat polymorphisms of IGF 1 , P01579 REA , P03372 REA , and P00533 REA were shared by chimpanzees , but the length of repeats tended to be longer in humans than in chimpanzees . This tendency was particularly evident for IGF 1 . All of the SNPs tested are human-specific nucleotide changes . The ancestral allele 7A was shown to be lost in P08254 REA - 1171 5A / 6A . Thus , all of the possible cancer-associated polymorphisms tested have human-specific alleles , and the ancestral allele is lost in three polymorphisms ( P18510 REA VNTR , P22309 REA CA repeat , and P08254 REA - 1171 5A / 6A ) , suggesting a possible involvement of human-specific alleles in cancer susceptibility .

Interferon-alpha promotes the anti-proliferative effect of Erlotinib ( DB00530 SUB ) on human colon cancer cell lines . Interferon-alpha ( IFNalpha ) treatment is associated with up-regulation of epidermal growth factor receptor ( P00533 REA / P00533 REA ) expression and marked growth inhibition while maintaining the sensitivity of the target colon cancer cells to epidermal growth factor ( Gut 2004 ; 53:123 ) . We aimed to determine the effect of combining IFNalpha and Erlotinib ( an P00533 REA / P00533 REA inhibitor ) on colon cancer cell line growth . Crystal-violet staining and flow cytometry were used to assess cell proliferation and expression of P00533 REA / P00533 REA . IFNalpha pre-treatment followed by a combination of IFNalpha plus Erlotinib significantly enhanced the sensitivity of 7/9 of colon cancer cell lines by 7-43 % . This approach may have clinical implications for improving treatment based on targeting of P00533 REA / P00533 REA .

P04626 REA up-regulates P26447 and several other prometastatic genes in medulloblastoma . Medulloblastoma is frequently disseminated throughout the central nervous system by the time of diagnosis . Conventional therapeutic approaches have not reduced the high mortality associated with metastatic medulloblastoma and little is known regarding the molecular mechanisms that promote tumor invasion . Previously , we reported that overexpression of P04626 REA in medulloblastoma is associated with poor prognosis and metastasis . Here , we demonstrate that P04626 REA overexpression increases the migration of medulloblastoma cells across basement membranes in vitro . Furthermore , using microarray expression profiling , we show that P04626 REA up-regulates the expression of prometastatic genes in medulloblastoma cells . These include P26447 , which was previously shown to promote metastasis of breast cancer . We demonstrate that P26447 is a direct target of P04626 REA signaling in medulloblastoma cells via a pathway involving phosphatidylinositol 3 - kinase , P31749 REA , and extracellular signal-regulated kinase 1/2 and that levels of P04626 REA and P26447 are tightly correlated in samples of primary medulloblastoma . Finally , we show that P04626 REA - dependent medulloblastoma cell invasion in vitro and prometastatic gene expression in vivo can be blocked using the P00533 REA tyrosine kinase inhibitor DB00530 SUB . These data identify an P04626 REA driven prometastatic pathway that may provide a novel target for therapeutic intervention in metastatic medulloblastoma .

Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4 - anilinoquinazoline inhibitor . The crystal structure of the kinase domain from the epidermal growth factor receptor ( EGFRK ) including forty amino acids from the carboxyl-terminal tail has been determined to 2.6- A resolution , both with and without an EGFRK-specific inhibitor currently in Phase III clinical trials as an anti-cancer agent , erlotinib ( DB00530 SUB , CP -358,774 , Tarceva ( TM ) ) . The P00533 REA family members are distinguished from all other known receptor tyrosine kinases in possessing constitutive kinase activity without a phosphorylation event within their kinase domains . Despite its lack of phosphorylation , we find that the EGFRK activation loop adopts a conformation similar to that of the phosphorylated active form of the kinase domain from the insulin receptor . Surprisingly , key residues of a putative dimerization motif lying between the EGFRK domain and carboxyl-terminal substrate docking sites are found in close contact with the kinase domain . Significant intermolecular contacts involving the carboxyl-terminal tail are discussed with respect to receptor oligomerization .

Biologically targeted treatment of non-small-cell lung cancer : focus on epidermal growth factor receptor . The epidermal growth factor receptor ( P00533 REA ) has emerged in recent years as a key target of molecular therapy for solid tumors . The postembryonic role of P00533 REA is normally limited . In cancer , however , abnormal P00533 REA - tyrosine kinase ( TK ) activity plays a central role in many of the processes involved in tumor progression , such as proliferation , angiogenesis , invasiveness , decreased apoptosis , and loss of differentiation . Several different approaches have been taken to inhibit P00533 REA - mediated activity in tumor cells , including monoclonal antibodies directed at the ligand-binding portion of the P00533 REA and small-molecule agents that directly inhibit the intracellular TK domain of P00533 REA . Two of these TK inhibitors , gefitinib and erlotinib ( DB00530 SUB , Tarceva ) , have shown antitumor activity and good tolerability across several tumor types in early dose-finding clinical trials , particularly for non-small-cell lung cancer ( NSCLC ) . In heavily pretreated patients with advanced NSCLC , gefitinib showed clinically significant tumor responses and symptom relief with good tolerability . Based on these results , gefitinib has now been approved for the third-line treatment of advanced NSCLC . The use of gefitinib in standard treatment programs or combined with other molecular targeted agents may substantially improve the outlook for patients with NSCLC or other types of solid tumors

Epithelial growth factor receptor interacting agents . The data reviewed here have further established the promise of anti - P00533 REA - targeted therapies . This statement is supported by the evidence of antitumor activity of the TK inhibitors ZD1839 and DB00530 SUB against several tumor types and by the ability of the monoclonal antibody IMC-C 225 to reverse clinical chemotherapy resistance . These results are further supported by an emerging number of compounds , monoclonal antibodies , and TK inhibitors directed at the P00533 REA that are in clinical development ( see Fig . 2 , Table 1 ) . Among the TK inhibitors , these compounds can be further categorized by their receptor specificity and reversibility of binding . In the case of anti - P00533 REA monoclonal antibodies , compounds in clinical development include chimeric , humanized , and bispecific antibodies . The fundamental observation is that these compounds have shown activity in several tumor types , including NSCL cancer , prostate carcinoma , colorectal carcinoma , ovarian carcinoma , renal cell carcinoma , and head and neck cancers . These findings observed with different agents and in different tumor types validate P00533 REA as a target for cancer therapy . The results of ongoing studies with these agents in diverse indications and tumor types may establish the role of these promising therapies to our current cancer treatments .

P00533 REA tyrosine kinase inhibitors in late stage clinical trials . The epidermal growth factor receptor ( P00533 REA ) is a cell membrane receptor that plays a key role in cancer development and progression . Ligand-activated P00533 REA - dependent signalling is involved in cell proliferation , apoptosis , angiogenesis and metastatic spread . Targeting the P00533 REA , therefore , represents a promising molecular approach in cancer treatment . Several anti - P00533 REA agents are in clinical development . Three drugs are currently in Phase II and III development as single agents , or in combination with other anticancer modalities : IMC - 225 ( cetuximab / Erbitux ; ImClone ) , a chimaeric human-mouse monoclonal IgG ( 1 ) antibody , which blocks ligand binding and functional activation of the P00533 REA ; DB00530 SUB ( erlotinib / Tarceva ; Genentech / OSI / Roch ) and ZD1839 ( gefitinib / DB00317 ; AstraZeneca ) , two small molecule P00533 REA - selective inhibitors of tyrosine kinase enzymatic activity , which prevent P00533 REA autophosphorylation and activation . DB00317 is the first P00533 REA - targeting agent to be registered as an anticancer drug in Japan , in Australia and in the US for the third-line treatment of chemoresistant non-small cell lung cancer ( NSCLC ) patients . This review will focus on the preclinical background and on the results from the first series of clinical trials with these drugs . Furthermore , continuing clinical trials and a series of open clinical issues for the development of optimal strategies of using P00533 REA - targeting agents will be discussed .

A phase II study of erlotinib ( DB00530 SUB ) given in combination with carboplatin in patients with recurrent epithelial ovarian cancer ( NCIC CTG IND . 149 ) . OBJECTIVES : Approximately 50 % of ovarian cancers have elevated levels of epidermal growth factor receptor ( P00533 REA ) which correlates with a poor prognosis . Preclinical evidence suggests that P00533 REA tyrosine kinase inhibitors ( TKIs ) , such as erlotinib ( DB00530 SUB ) , may potentiate the anti-tumour effects of cytotoxic agents , including carboplatin . Blocking P00533 REA could thus potentially reverse drug resistance . The primary objective of the study was to assess the response rate to the addition of erlotinib in patients with recurrent ovarian cancer who were receiving carboplatin . METHODS : Patients enrolled on this study had either local or advanced recurrent ovarian cancer with measurable disease . They may have had up to 2 prior chemotherapy regimens , one of which must have contained platinum , and they must have responded to prior platinum therapy . Patients were stratified by platinum sensitivity and were treated with erlotinib 150 mg daily on a continuous dosing schedule , and carboplatin at an AUC of 5 every 21 days . RESULTS : Fifty patients with recurrent ovarian cancer entered the study , 33 in the platinum-sensitive arm and 17 in the platinum-resistant arm . Of patients evaluable for response , there were 14 partial responses ( PR ) of 30 evaluable for response ( 57 % objective response rate ( ORR ) ) in the platinum-sensitive arm , and 1 PR of 14 evaluable for response ( 7 % ORR ) in the platinum-resistant arm . CONCLUSIONS : The combination of erlotinib and carboplatin was active in patients with platinum-sensitive disease , but not in platinum-resistant disease . The toxicities seen were those expected with carboplatin and erlotinib .

Glioblastoma : synergy of growth promotion between P13501 REA and P25103 REA can be thwarted by blocking P13501 REA with miraviroc , an FDA approved anti-HIV drug and blocking P25103 REA with aprepitant , an FDA approved anti-nausea drug . WHAT IS KNOWN AND BACKGROUND : Two receptor signaling pathways that are commonly active in facilitating glioblastoma growth and invasion - that of P51681 REA and neurokinin ( NK ) - 1R - have small molecule inhibitors that are FDA approved and marketed to treat other conditions . The anti-HIV drug , maraviroc , inhibits human P51681 REA ' s ligand from binding , and hence blocks P51681 REA stimulation . The anti-nausea drug aprepitant blocks DB05875 signaling at P25103 REA . AIMS AND OBJECTIVE : We propose on the basis of molecular insights that a combination of the two drugs is likely to be useful in the treatment of glioblastoma . COMMENT : After stimulation by their respective ligands both P51681 REA and P25103 REA , through intermediaries , phosphorylate and thereby activate P27361 REA / 2 , triggering in turn migratory and mitotic events . Neurokinin - 1R second messenger signaling also happens to serine phosphorylate P51681 REA . Phosphorylated P51681 REA exhibits amplified activity after agonist ligation . Therefore , aprepitant and maraviroc combined treatment is expected to exert synergestic inhibition of growth enhancing signaling in glioblastoma . Inhibiting an amplifier is equivalent to amplifying an inhibitor . Since the two suggested drugs are non-cytotoxic they are envisioned as adjunctive treatments to current standard temozolomide , radiation , and bevacizumab , all to be used after debulking primary resection . WHAT IS NEW AND CONCLUSION : Our analysis makes the case for a well-designed trial of the proposed combination in the treatment of glioblastoma .

Phase II study of erlotinib ( DB00530 SUB ) in patients with metastatic colorectal cancer . Erlotinib ( Tarceva , DB00530 SUB ) , a potent epidermal growth factor receptor tyrosine kinase inhibitor ( P00533 REA ) , was evaluated in a phase II study to assess its activity in patients with metastatic colorectal cancer . In all , 38 patients with metastatic colorectal cancer were treated with erlotinib at a continuous daily oral dose of 150 mg . Radiological evaluation was carried out every 8 weeks and tumour biopsies were performed before treatment and on day 8 . Of 31 evaluable patients , 19 ( 61 % ) had progressive disease and 12 ( 39 % ) had stable disease ( s . d . ) . The median time to progression for those patients having s . d . was 123 days ( range 108-329 days ) . The most common adverse events were rash in 34 patients and diarrhoea in 23 patients . Correlative studies were conducted to investigate the effect of erlotinib on downstream signalling . Tumour tissue correlations were based on usable tissue from eight match paired tumour samples pre - and on therapy , and showed a statistically significant decrease in the median intensity of both pEGFR ( P= 0.008 ) and phospho-extracellular signal-regulated kinase ( P29323 REA ) ( P= 0.008 ) a week after commencement of treatment . No other statistically significant change in tumour markers was observed . Erlotinib was well tolerated with the most common toxicities being rash and diarrhoea . More than one-third of evaluable patients had s . d . for a minimum of 8 weeks . Correlative studies showed a reduction in phosphorylated P00533 REA and P29323 REA in tumour tissue post-treatment .

Rationale for investigation of epidermal growth factor receptor inhibitors in definitive treatment of locally advanced non-small cell lung cancer and head and neck cancer . Designing targeted therapies has become an important field in cancer therapeutics . The epidermal growth factor receptor ( P00533 REA ) is a molecular target that has gained immense attention as preclinical and clinical studies have supported its potential role for therapy of a variety of cancers , including non-small cell lung cancer ( NSCLC ) and head and neck ( HN ) cancer . Several compounds that specifically inhibit P00533 REA have been developed , including ZD1839 , C225 , and DB00530 SUB . Interestingly , studies suggesting a potential role for P00533 REA inhibitors as an adjunct to the current combined-modality approach for therapy of NSCLC and HN cancer have been performed in the preclinical and clinical setting . Therefore , determining the potential of P00533 REA inhibitors to improve the efficacy of standard combined-modality regimens ( chemotherapy / radiation therapy + / - surgery ) for NSCLC and HN cancer patients is of the utmost importance . An overview of the rationale and the ongoing / proposed studies aimed at determining the role for P00533 REA inhibitors in combination with radiation therapy for NSCLC and HN cancer patients will be presented .

P40763 REA signaling is induced by intercellular adhesion in squamous cell carcinoma cells . The signal transducer and activator of transcription - 3 ( P40763 REA ) frequently activated during tumor progression has been linked to enhanced cell growth . In squamous cell carcinoma of the head and neck ( HNSCC ) , P40763 REA signaling has been shown to inhibit apoptosis and induce a more aggressive phenotype through the activation of specific signaling pathways . In the present study , we have examined the potential mechanism by which cell-cell contact initiates P40763 REA activation . Using a panel of HNSCC cell lines , Ca ( + 2 ) - dependent cell-cell adhesion and adherens junction formation in multicellular aggregates triggered phosphorylation of P40763 REA - Y705 and P42224 REA - Y701 . This intercellular adhesion-induced P40763 REA activation was mediated by JAK and Src signaling and partially by P00533 REA signaling . In addition , immunolocalization studies revealed initial formation of phosphorylated P40763 REA - Y705 at nascent P12830 REA cell junctions with eventual translocation to the nucleus in cell aggregates . Adhesion-mediated P35610 REA activation in monolayer and cell aggregate cultures required functional P12830 REA . These results indicate that , in HNSCC cells , cadherin-mediated intercellular adhesion induces P35610 REA signaling that may modulate cell survival and resistance to apoptosis during tumor progression .

Development of the epidermal growth factor receptor inhibitor Tarceva ( DB00530 SUB ) . The epidermal growth factor receptor ( P00533 REA ) is a transmembrane receptor involved in the regulation of a complex array of essential biological processes such as cell proliferation and survival . Dysregulation of P00533 REA signaling network has been frequently reported in multiple human cancers and has been associated with the processes of tumor development , growth , proliferation , metastasis and angiogenesis . Inhibition of the P00533 REA was associated with antitumor effects in preclinical models . On the bases of these data , therapeutics targeting the P00533 REA were explore in clinical trials . Tarceva ( DB00530 SUB , OSI Pharmaceuticals , Uniondale , NY ) is a small molecule selective inhibitor of the P00533 REA tyrosine kinase ( TK ) . In preclinical studies , Tarceva inhibited the phosphorylation of the P00533 REA in a dose and concentration dependent manner resulting in cell cycle arrest and induction of apoptosis . In in vivo studies , the agent caused tumor growth inhibition and shoved synergistic effects when combined with conventional chemotherapy . Subsequent single agent phase I studies and phase I studies in combination with chemotherapy demonstrated that the agent has a good safety profile and induced tumor growth inhibition in a substantial number of patients with a variety of different solid tumor . Preliminary report from phase II studies confirmed the excellent tolerability of Tarceva as well as showed encouraging preliminary activity . Phase III studies have either been completed or are ongoing in several tumor types such as lung cancer and pancreatic cancer . In summary , Tarceva is a novel inhibitor of the P00533 REA TK which has shown promising activity in initial studies and is currently undergoing full development as an anticancer drug .

P48061 REA and [ N33A ] P48061 REA in 5637 and HeLa cells : regulating P00533 REA phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 REA elicited , as expected , downstream signals via both G-protein-dependent and β-arrestin-dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 REA / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 REA triggered no β-arrestin-dependent phosphorylation of P27361 REA / 2 , and signaled via G protein-dependent pathways alone . Both P48061 REA and [ N33A ] P48061 REA , however , generated signals that transinhibited P00533 REA phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 REA / P00533 REA - positive 5637 or HeLa cells with P48061 REA modified the HB - P01133 REA - dependent activation of P00533 REA by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 REA , while preserving P61073 REA - related chemotaxis and P61073 REA internalization , abolished P00533 REA phosphorylation . 3 ) In cells knockdown of β-arrestin 2 , P48061 REA induced a full inhibition of P00533 REA like [ N33A ] P48061 REA in non-silenced cells . 4 ) P00533 REA phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 REA and its structural variant [ N33A ] P48061 REA may transinhibit P00533 REA via G-proteins / calmodulin / calcineurin , but [ N33A ] P48061 REA does not activate β-arrestin-dependent P27361 REA / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 REA may influence the magnitude and the persistence of signaling downstream of P00533 REA in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 REA activates preferentially G-protein-dependent pathways and is an inhibitor of P00533 REA .

A unique structure for epidermal growth factor receptor bound to GW572016 ( DB01259 ) : relationships among protein conformation , inhibitor off-rate , and receptor activity in tumor cells . GW572016 ( DB01259 ) is a tyrosine kinase inhibitor in clinical development for cancer that is a potent dual inhibitor of epidermal growth factor receptor ( P00533 REA , ErbB - 1 ) and ErbB - 2 . We determined the crystal structure of P00533 REA bound to GW572016 . The compound is bound to an inactive-like conformation of P00533 REA that is very different from the active-like structure bound by the selective P00533 REA inhibitor DB00530 SUB ( Tarceva ) described previously . Surprisingly , we found that GW572016 has a very slow off-rate from the purified intracellular domains of P00533 REA and ErbB - 2 compared with DB00530 SUB and another P00533 REA selective inhibitor , ZD - 1839 ( DB00317 ) . Treatment of tumor cells with these inhibitors results in down-regulation of receptor tyrosine phosphorylation . We evaluated the duration of the drug effect after washing away free compound and found that the rate of recovery of receptor phosphorylation in the tumor cells reflected the inhibitor off-rate from the purified intracellular domain . The slow off-rate of GW572016 correlates with a prolonged down-regulation of receptor tyrosine phosphorylation in tumor cells . The differences in the off-rates of these drugs and the ability of GW572016 to inhibit ErbB - 2 can be explained by the enzyme-inhibitor structures .

DB01016 MEN - induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform Q09428 REA but not by expression of SUR 2B or the mutant Q09428 REA ( M1289T ) . Q09428 REA ( Q09428 REA ) is the regulatory subunit of the pancreatic DB00171 - sensitive K + channel ( K ( DB00171 ) channel ) , which is essential for triggering insulin secretion via membrane depolarization . Sulfonylureas , such as glibenclamide and tolbutamide , act as K ( DB00171 ) channel blockers and are widely used in diabetes treatment . These antidiabetic substances are known to induce apoptosis in pancreatic beta-cells or beta-cell lines under certain conditions . However , the precise molecular mechanisms of this sulfonylurea-induced apoptosis are still unidentified . To investigate the role of Q09428 REA in apoptosis induction , we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either Q09428 REA , the smooth muscular isoform SUR 2B , or the mutant Q09428 REA ( M1289T ) at which a single amino acid in transmembrane helix 17 ( TM17 ) was exchanged by the corresponding amino acid of SUR 2 . By analyzing cell detachment , nuclear condensation , DNA fragmentation , and caspase - 3 - like activity , we observed a Q09428 REA - specific enhancement of glibenclamide-induced apoptosis that was not seen in SUR 2B , Q09428 REA ( M1289T ) , or control cells . Coexpression with the pore-forming Kir 6.2 subunit did not significantly alter the apoptotic effect of glibenclamide on Q09428 REA cells . In conclusion , expression of Q09428 REA , but not of SUR 2B or Q09428 REA ( M1289T ) , renders cells more susceptible to glibenclamide-induced apoptosis . Therefore , Q09428 REA as a pancreatic protein could be involved in specific variation of beta-cell mass and might also contribute to the regulation of insulin secretion at this level . According to our results , TM17 is essentially involved in Q09428 REA - mediated apoptosis . This effect does not require the presence of functional Kir 6.2- containing K ( DB00171 ) channels , which points to additional , so far unknown functions of Q09428 REA .

Mutant epidermal growth factor receptor up-regulates molecular effectors of tumor invasion . The gene most commonly altered in human glioblastomas is the epidermalgrowth factor receptor ( P00533 REA ) . We profiled transcripts induced by mutantEGFR to better understand its role in tumor progression . The pattern found suggested enhanced tumor invasion . The highly induced genes included extracellular matrix components , metalloproteases , and a serine protease . We confirmed that mutant P00533 REA did make glioblastoma cells both more motile and invasive using in vitro assays . Furthermore , inhibitors of P00533 REA ( DB00530 SUB and Tyrphostin AG1478 ) selectively down-regulated these molecular effectors in glioblastoma cells , eliminating enhanced invasion .

Inhibition of proliferation , migration , and matrix metalloprotease production in malignant mesothelioma cells by tyrosine kinase inhibitors . The epidermal growth factor receptor ( P00533 REA ) is expressed in a variety of human solid tumors , including malignant mesothelioma . P00533 REA has been implicated in regulation of cell proliferation , survival , angiogenesis , and metastasis , making it an ideal target for drug development . ZD1839 ( gefitinib ) and DB00530 SUB ( erlotinib ) are new , low-molecular-weight , P00533 REA - selective tyrosine kinase ( TK ) inhibitors , whereas DB05424 is a pan - P00533 REA family TK inhibitor . In the present study , we used ZD1839 , DB00530 SUB , and DB05424 and investigated the effect of these drugs on proliferation , migration , and matrix metalloprotease ( MMP ) production in three malignant mesothelioma cell lines ( M14K , ZL34 , and SPC 212 ) . Using [ 3H ] thymidine incorporation , DNA synthesis assay , we found that all three drugs inhibited transforming growth factor-alpha ( TGF-alpha ) - induced cellular proliferation in a dose-dependent manner . In addition , all three drugs induced apoptosis in ZL34 cells as determined by flow cytometry using annexin-V staining . Furthermore , all three drugs inhibited TGF-alpha-induced cell migration ( chemotaxis ) in a dose-dependent manner as determined by Boyden chamber assay . TGF-alpha-induced P14780 REA production was also inhibited in a dose-dependent manner as determined by gelatin zymography in three cell lines tested . In conclusion , our study demonstrates inhibitory effectiveness of P00533 REA - TK inhibitors in malignant mesothelioma cells and suggests that these drugs may be an effective treatment strategy for malignant mesothelioma .

Interstitial lung disease in patients with non-small-cell lung cancer treated with epidermal growth factor receptor inhibitors . Interstitial lung disease ( ILD ) refers to a diverse range of pulmonary fibrotic disorders and may be hard to accurately diagnose , as distinguishing it from other pulmonary diseases can be difficult . Estimations of the incidence in populations are confounded by the complexity of the different forms of the disorder . In addition , ILD is a comorbid disease of lung cancer and is seen after most forms of chemotherapy and radiotherapy for advanced lung cancer . Incidences of > or = 10 % have been reported ; however , whatever the true incidence , both chemotherapy and radiotherapy enhance the risk of developing ILD . ILD has also been reported with the epidermal growth factor receptor ( P00533 REA ) tyrosine kinase inhibitors , including erlotinib ( Tarceva , DB00530 SUB ) and gefitinib ( IRESSA ) . In a large number of gefitinib-treated patients ( n > 185,000 ) an incidence of approx 1 % has been observed ( approx 2 % in Japan ; 0.3 % in the rest of the world ) . Nevertheless , as with other treatments for advanced non-small-cell lung cancer , the clinical benefit outweighs the risk of ILD . In this article , we review the data on ILD with P00533 REA inhibitors and other common lung cancer treatments .

P00533 REA inhibitors , gefitinib and erlotinib ( Tarceva , DB00530 SUB ) , in the treatment of bronchioloalveolar carcinoma .

Inactivation of Akt by the epidermal growth factor receptor inhibitor erlotinib is mediated by HER - 3 in pancreatic and colorectal tumor cell lines and contributes to erlotinib sensitivity . Signaling through the receptor for epidermal growth factor receptor ( P00533 REA ) is frequently deregulated in solid tumors . Erlotinib ( Tarceva , DB00530 SUB , OSI Pharmaceuticals , Inc . , Melville , NY ) is a low molecular weight , orally bioavailable inhibitor of the P00533 REA that has been approved for both non-small cell lung cancer and pancreatic cancers . Previous studies have indicated that sensitivity to P00533 REA antagonists correlated with HER - 3 signaling for non-small cell lung cancer . Herein , we have sought to understand the signaling pathways that mediate erlotinib sensitivity for pancreatic and colorectal cancers . In a panel of 12 pancreatic tumor cell lines , we find that P00533 REA is coexpressed with HER - 3 in all cell lines sensitive to erlotinib but not in insensitive cell lines . Erlotinib can block HER - 3 phosphorylation in these sensitive cell lines , suggesting that HER - 3 is transactivated by P00533 REA . Knockdown of HER - 3 in BxPC 3 , an erlotinib-sensitive pancreatic tumor cell line , results in inhibition of the phosphorylation for both Akt and S6 and is associated with a decrease in cell proliferation and reduced sensitivity to erlotinib . Therefore , P00533 REA transactivation of HER - 3 mediates Akt signaling and can contribute to erlotinib sensitivity for pancreatic tumors . We extended our analysis to a panel of 13 colorectal tumor cell lines and find that , like pancreatic , HER - 3 is coexpressed with P00533 REA in the most erlotinib-sensitive cell lines but not in erlotinib-insensitive cell lines . These studies suggest that HER - 3 could be used as a biomarker to select patients who are most likely to respond to erlotinib therapy .

Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 REA antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double-blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( -13.85 for placebo to -16.17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . DB09048 MENMAX DB09048 MEN was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .

New targeted therapies in gastrointestinal cancers . Despite surgical , radiotherapeutic , and chemotherapeutic advances , a large proportion of gastrointestinal ( GI ) cancers remain incurable . An improved understanding of the molecular pathogenesis of cancer has promulgated the development of novel agents designed to target critical pathways involved in cancer development and progression . The crucial role of the epidermal growth factor receptor ( P00533 REA ) in tumor proliferation and the overexpression of P00533 REA in several GI cancers provides the rationale for targeting and interrupting this key signaling network . P00533 REA blockade through monoclonal antibodies ( C225 and DB01269 ) and tyrosine kinase inhibitors ( ZD1839 and DB00530 SUB ) has translated into promising evidence of clinical benefit . Ras-mediated signal transduction has been targeted using inhibitors of farnesyl transferase ( R115777 and SCH 66336 ) to block the post-translation modification of Ras . Inhibitors of vascular growth factor receptor ( bevacizumab and PTK 787 ) and matrix metalloproteinase target the effects of the host environment . P35354 REA inhibitors in colorectal cancer and STI 571 in GI stromal tumors represent novel therapies of interest for these specific GI cancers . Evidence suggests that novel agents can be administered alone or in combination with standard therapies with little additional toxicity . The results of ongoing and future research efforts will clarify the optimal use and survival benefit of targeted therapies for patients with GI malignancies .

P00533 REA tyrosine kinase inhibitors : application in non-small cell lung cancer . Despite treatment advances over the past decade , long-term survival for patients with non-small cell lung cancer ( NSCLC ) remains poor , and treatment options available after second-line therapy are limited . Increased understanding of cancer biology has led to the identification of several potential targets for treatment . The epidermal growth factor receptor ( P00533 REA ) belongs to a family of plasma membrane receptor tyrosine kinases that controls many important cellular functions , from growth and proliferation to cell death . This receptor is a particularly promising therapeutic target because it often is overexpressed in patients with NSCLC and has been implicated in the pathogenesis as well as the proliferation , invasion , and metastasis of lung cancer and other malignancies . New agents developed to inhibit P00533 REA function include small-molecule tyrosine kinase inhibitors , monoclonal antibodies to P00533 REA , and pan - P00533 REA inhibitors . Completed and ongoing clinical trials have shown that P00533 REA inhibitors have remarkable efficacy for patients with relapsed NSCLC . Among these , two phase 2 trials have shown that ZD1839 is effective when used as monotherapy . The response rates are comparable with those for docetaxel given in the second-line setting . Another phase 2 trial has shown that DB00530 SUB is effective in the same setting . Data from phase 3 trials indicate that adding an P00533 REA tyrosine kinase inhibitor to chemotherapy does not provide an additional survival benefit , as compared with standard chemotherapy alone for first-line treatment of NSCLC . It appears that P00533 REA tyrosine kinase inhibitors are safe and well tolerated by patients with cancer . Further studies will elucidate how these new agents can best be used for NSCLC and other tumor types .

Targeting epidermal growth factor receptor : novel therapeutics in the management of cancer . Overexpression of epidermal growth factor receptor ( P00533 REA ) in epithelial tumors , including head and neck , lung , breast , colon and other solid tumors , has frequently been correlated with poor prognosis , thus stimulating efforts to develop new cancer therapies that target P00533 REA . Monoclonal antibodies and tyrosine kinase inhibitors specifically targeting P00533 REA are the most well-studied and hold substantial promise of success . Several compounds of monoclonal antibodies and tyrosine kinase inhibitors targeting P00533 REA have been studied and clinical trials are now underway to test the safety and efficacy of these targeting strategies in several human tumors . This review will address each of these agents alone or in combination with radiation or chemotherapy and highlight some of these promising developments . Cetuximab ( Erbitux ) is being evaluated in combination with radiation or chemotherapy in Phase III trials . Other compounds such as h-R 3 , DB01269 , P50402 REA - 55900 and ICR - 62 have proved to be effective in targeting malignant cells alone or in combination with traditional therapies . Tyrosine kinase inhibitors targeting the intracellular domain of P00533 REA , including ZD - 1839 ( gefitinib , DB00317 ) , DB00530 SUB ( Erlotinib / Tarceva ) , PD - 153053 , PD - 168393 and DB05424 , have been studied in clinical setting alone or in combination with radiation or chemotherapy . ZD - 1839 is being studied in a Phase III trial in patients with advanced non-small cell lung cancer . P00533 REA targeted treatment by monoclonal antibodies and tyrosine kinase inhibitors have been proven to sensitize tumor cells to the effects of chemotherapy and radiation therapy . The synergistic activities and nonoverlapping toxicities of these compounds allow concomitant administration with cytotoxic therapy . Challenges of evaluating P00533 REA targeted agents exist in selecting the optimal dosages and determining long-term toxicity .

Tyrosine kinase blockers : new hope for successful cancer therapy . Tyrosine kinases ( TKs ) are attractive targets for cancer therapy , as quite often their abnormal signaling has been linked with tumor development and growth . Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair , apoptosis , and cell proliferation . During the last few years , thorough analysis of the mechanism underlying tyrosine kinase ' s activity led to novel cancer therapy using TKs blockers . These drugs are remarkably effective in the treatment of various human tumors including head and neck , gastric , prostate and breast cancer and leukemias . The most successful example of kinase blockers is Imatinib ( Imatinib mesylate , Gleevec , STI 571 ) , the inhibitor of Bcr / Abl oncoprotein , which has become a first-line therapy for chronic myelogenous leukemia . The introduction of STI 571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed . Others kinase inhibitors used recently in cancer therapy include Dasatinib ( BMS - 354825 ) specific for P00519 REA non-receptor cytoplasmic kinase , Gefitinib ( DB00317 ) , Erlotinib ( DB00530 SUB , Tarceva ) and DB01268 ( SU 11248 , Sutent ) specific for P15692 REA receptor kinase , AMN 107 ( DB04868 MEN ) and INNO - 406 ( NS - 187 ) specific for c - P10721 REA kinase . The following TK blockers for treatment of various human tumors are in clinical development : DB01259 ( DB01259 ditosylate , DB01259 , GW - 572016 ) , Canertinib ( DB05424 ) , DB05294 ( DB05294 ) , DB04879 ( PTK 787 / ZK 222584 ) , DB00398 ( Bay 43-9006 , Nexavar ) , and Leflunomide ( SU101 , DB01097 ) . Herein , we discuss the chemistry , biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment .

Phase II clinical trial data with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib ( DB00530 SUB ) in non-small-cell lung cancer . Erlotinib ( DB00530 SUB ; Tarceva ) is an orally available , highly specific epidermal growth factor receptor ( P00533 REA ) tyrosine kinase inhibitor . The results of 3 phase II studies with erlotinib in non-small-cell lung cancer ( NSCLC ) are reviewed herein : ( 1 ) in patients with chemotherapy-resistant , P00533 REA / P00533 REA - expressing NSCLC of all histologies , ( 2 ) in patients with bronchoalveolar carcinoma previously untreated or treated with chemotherapy , and ( 3 ) as first-line therapy in elderly patients with NSCLC of all histologies . These studies have evaluated tumor response , survival , and symptom improvement . Erlotinib was given as an oral , continuous daily dose of 150 mg . The drug was well tolerated ; drug-related cutaneous rash and diarrhea were observed in approximately two thirds of patients . Withdrawals caused by toxicity were rare . The response rates were 12.3 % , 25 % , and 13.3 % , respectively . Mature survival data are available for the first trial . The median survival was 8.4 months , and the 1 - year survival rate was 40 % . All responding patients in the first and second trials presented skin rash . In addition , survival correlated with the occurrence and severity of rash in the first trial . No data on the correlation between rash and survival are available for the second and third trials . Erlotinib is active and well tolerated in patients with NSCLC as first - and second-line therapy . Cutaneous rash appears to be a surrogate marker of clinical benefit , but this finding needs to be confirmed in ongoing and future studies .

Targeted therapy in non-small-cell lung cancer . Although treatment of advanced non-small-cell lung cancer has been improved with the availability of such new agents as the taxanes , topoisomerase inhibitors , vinorelbine ( Navelbine ) , and gemcitabine ( Gemzar ) , platinum-based combination therapy has appeared to reach a threshold of therapeutic effectiveness . A paradigm shift in approach to non-small-cell lung cancer and other tumors may be heralded by the development of agents targeting specific biologic pathways in tumor development . Such new agents include antibody epithelial growth factor receptor ( P00533 REA ) inhibitors ( eg , the monoclonal antibodies trastuzumab [ Herceptin ] and cetuximab [ IMC-C 225 , Erbitux ] ) and P00533 REA tyrosine kinase inhibitors ( eg , ZD1839 [ DB00317 ] and DB00530 SUB ) , angiogenesis inhibitors ( eg , matrix metalloproteinase inhibitors ) , vascular endothelial growth factor ( P15692 REA ) inhibitors ( eg , monoclonal antibody to P15692 REA ligand and small-molecule tyrosine kinase ) , and signal transduction inhibitors ( eg , ISIS - 3521 , an antisense oligonucleotide to protein kinase C-alpha ) . A number of these agents have entered advanced-phase clinical investigation . It is likely that targeted therapy will have applications in combination with cytotoxic chemotherapy or radiation therapy at all stages of treatment , including maintenance therapy . It is even possible that these new biologic therapies will be used together as rational combinations ( based on pathologic diagnosis ) for advanced non-small-cell lung cancer .

P42892 REA and β-arrestins exert spatiotemporal control of DB05875 - induced inflammatory signals . Although the intracellular trafficking of G protein-coupled receptors controls specific signaling events , it is unclear how the spatiotemporal control of signaling contributes to complex pathophysiological processes such as inflammation . By using bioluminescence resonance energy transfer and superresolution microscopy , we found that DB05875 ( SP ) induces the association of the neurokinin 1 receptor ( P25103 REA ) with two classes of proteins that regulate SP signaling from plasma and endosomal membranes : the scaffolding proteins β-arrestin ( βARRs ) 1 and 2 and the transmembrane metallopeptidases ECE - 1c and ECE - 1d . In HEK 293 cells and non-transformed human colonocytes , we observed that G protein-coupled receptor kinase 2 and β P49407 REA / 2 terminate plasma membrane Ca ( 2 + ) signaling and initiate receptor trafficking to endosomes that is necessary for sustained activation of ERKs in the nucleus . βARRs deliver the SP - P25103 REA endosomes , where P42892 REA associates with the complex , degrades SP , and allows the P25103 REA , freed from βARRs , to recycle . Thus , both P42892 REA and βARRs mediate the resensitization of P25103 REA Ca ( 2 + ) signaling at the plasma membrane . Sustained exposure of colonocytes to SP activates NF-κB and stimulates P10145 REA secretion . This proinflammatory signaling is unaffected by inhibition of the endosomal P29323 REA pathway but is suppressed by P42892 REA inhibition or β P32121 REA knockdown . Inhibition of protein phosphatase 2A , which also contributes to sustained P25103 REA signaling at the plasma membrane , similarly attenuates P10145 REA secretion . Thus , the primary function of βARRs and P42892 REA in SP-dependent inflammatory signaling is to promote resensitization , which allows the sustained P25103 REA signaling from the plasma membrane that drives inflammation .

The emerging role of epidermal growth factor receptor inhibitors in ovarian cancer . P00533 REA ( P00533 REA ) inhibitors are a new biologically targeted therapy , which may offer new hope in the treatment of patients with advanced or recurrent ovarian cancers . In this review , we summarize and discuss the results of research to date on P00533 REA inhibitors with particular emphasis on ovarian cancer . We reviewed data identified by searches of MEDLINE , PubMed , and abstracts from the proceedings of the American Society of Clinical Oncology meetings from 1998 to 2006 , with the search terms " Ovarian Cancer , " " P00533 REA , " " gefitinib , ZD1839 , DB00317 , " " erlotinib , DB00530 SUB , Tarceva , " " DB05424 , " " DB01259 , lapatinib , " " PKI - 166 , " " Q9Y259 REA 569 , " " anti - P00533 REA antibodies , " " trastuzumab , Herceptin , " " cetuximab , Erbitux , IMC-C 225 , " " matuzumab , P50402 REA 72000 , " " panitumamab , DB01269 , " " pertuzumab , " and " vandetanib , rINN , DB05294 , DB05294 . " Phase II trials of both small molecule inhibitors of P00533 REA - and antibody-based inhibitors are currently ongoing in ovarian cancer and emerging data suggest that their activity in unselected women with advanced or recurrent ovarian cancer is modest , when utilized as a single agent . It is possible that these agents will be highly effective in smaller subsets of patients whose tumors are dependent on P00533 REA signaling , perhaps through activating mutations in P00533 REA or its downstream pathway . Targeted therapy with P00533 REA inhibitors is an untapped potential resource in the treatment of advanced or recurrent ovarian cancer . Ongoing trials will elucidate the most effective strategies to use these agents individually or in combination with traditional chemotherapeutic agents .

DB01032 MEN reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 REA receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell-derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .

Enhanced sensitivity to the P00533 REA / epidermal growth factor receptor tyrosine kinase inhibitor erlotinib hydrochloride in chemotherapy-resistant tumor cell lines . PURPOSE : Erlotinib ( Tarceva , DB00530 SUB ) is a potent and specific inhibitor of the P00533 REA / epidermal growth factor receptor ( P00533 REA ) tyrosine kinase . In phase II clinical studies , oral erlotinib monotherapy has shown antitumor activity in patients with advanced non-small cell lung cancer , head and neck cancer , and ovarian cancer after the failure of standard chemotherapy . We hypothesized that some tumors treated with multiple cytotoxic therapies may become more dependent on the P00533 REA / P00533 REA signaling pathways for survival . EXPERIMENTAL DESIGN : The growth-inhibitory effect of erlotinib was tested on 10 pairs of chemosensitive , parental , and chemoresistant tumor cell lines . RESULTS : Enhanced sensitivity to erlotinib was observed in the doxorubicin-resistant human breast cancer cell line MCF - 7 , paclitaxel-resistant human ovarian carcinoma cell line A2780 , and cisplatin-resistant human cervical carcinoma cell line ME180 . The IC ( 50 ) values of erlotinib in the resistant cell lines were 2 - to 20 - fold lower than those in the corresponding parental cell lines . This enhanced sensitivity to erlotinib correlated with higher P00533 REA / P00533 REA and phospho - P00533 REA / P00533 REA expression when compared with the corresponding parental cell lines . Acquired resistance to cytotoxic agents was not associated with cross-resistance to erlotinib . AE-ME 180 / DB00515 - resistant xenografts showed greater sensitivity to erlotinib than parental ME180 xenografts did . CONCLUSIONS : Our findings suggest that acquired resistance to cytotoxic therapy in some tumors is associated with enhanced sensitivity to P00533 REA / P00533 REA inhibitors , which correlates with increased P00533 REA / P00533 REA expression . These data may explain some of the observed clinical activity of P00533 REA / P00533 REA inhibitors in patients previously treated with multiple therapies . P00533 REA / P00533 REA tyrosine kinase inhibitors may be more effective as second - or third-line treatment for certain patients with tumors that were previously treated with multiple chemotherapy regimens .

Response of chondrocytes to shear stress : antagonistic effects of the binding partners O00206 REA and caveolin - 1 . Osteoarthritis ( OA ) is often a consequence of excessive mechanical loading of cartilage , which produces hydrostatic stress , tensile strain , and fluid flow . Application of high fluid shear to chondrocytes recapitulates the earmarks of OA , as evidenced by the induction of cyclooxygenase - 2 , prostaglandins ( PGs ) , and interleukin - 6 ( P05231 REA ) . Here , we delineated the signaling pathway by which high fluid shear mediates the temporal regulation of P05231 REA synthesis in human chondrocytes . We determined that O00206 REA ( O00206 REA ) and caveolin - 1 are binding partners in chondrocytes . Their expression is temporally regulated by fluid shear via the sequential up-regulation of microsomal PGE synthase - 1 ( mPGES - 1 ) and L-PGDS . High shear stress rapidly induces an 8 - fold up-regulation of O00206 REA expression via an mPGES - 1 - dependent pathway , whereas prolonged shear exposure concurrently down-regulates O00206 REA by > 4 - fold and up-regulates caveolin - 1 expression by > 2.5- fold in an L-PGDS-dependent manner . O00206 REA and caveolin - 1 exert opposing effects on the activation of P27361 REA / 2 , P19957 REA - K and PKA signaling pathways , which , in turn , regulate the NF-κB-dependent P05231 REA synthesis in a time-dependent fashion . Reconstructing the signaling network regulating shear-induced P05231 REA expression in chondrocytes may provide insights for developing therapeutic strategies to combat osteoarthritis .

Rationale and clinical validation of epidermal growth factor receptor as a target in the treatment of head and neck cancer . Recurrent / metastatic head and neck cancer is an area of high , unmet treatment need . There is a strong rationale for targeting the epidermal growth factor receptor ( P00533 REA ) in head and neck cancer as most of these tumors express high levels of P00533 REA relative to normal tissue , with high expression correlating with poor patient outcome . This rationale has been validated in extensive preclinical studies . Two small molecules with P00533 REA inhibitory activity , gefitinib ( ' DB00317 ' , ZD1839 ) and erlotinib ( ' Tarceva ' , DB00530 SUB ) , and a humanized monoclonal antibody against the P00533 REA extracellular domain , cetuximab ( ' Erbitux ' , C225 ) , are in clinical trials for advanced head and neck cancer . The initial results of these trials are promising . Gefitinib and erlotinib show activity as monotherapy in patients with recurrent or metastatic head and neck cancer , and have an acceptable safety profile compared with conventional chemotherapy . Gefitinib , which can be given at doses below the maximum tolerated dose , is associated with slightly lower rates of adverse events than erlotinib , which is dosed at the maximum tolerated dose . Combinations of cetuximab with radiotherapy or platinum-based chemotherapy have also shown activity in phase I / II studies . Both gefitinib and cetuximab have entered phase III studies . The results of these trials , which will mature over the next few years , will help determine the optimal use of P00533 REA agents in head and neck cancers .