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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The epidermal growth factor receptor (EGFR) is a transmembrane receptor involved in the regulation of a complex array of essential biological processes such as cell proliferation and survival. Dysregulation of EGFR 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 EGFR was associated with antitumor effects in preclinical models. On the bases of these data, therapeutics targeting the EGFR were explore in clinical trials. Tarceva (OSI-774, OSI Pharmaceuticals, Uniondale, NY) is a small molecule selective inhibitor of the EGFR tyrosine kinase (TK). In preclinical studies, Tarceva inhibited the phosphorylation of the EGFR 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 EGFR TK which has shown promising activity in initial studies and is currently undergoing full development as an anticancer drug.
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PMID:Development of the epidermal growth factor receptor inhibitor Tarceva (OSI-774). 1290 62

Erlotinib (Tarceva) is an orally available selective small-molecule inhibitor of HER1/EGFR tyrosine kinase with a 50% inhibitory concentration of 2 nM for purified tyrosine kinase. This agent has been shown to produce stasis or regression of tumor growth in human cancer xenograft models, including non-small-cell lung cancer models. Ongoing preclinical investigations indicate that inhibition of the MAPK and Atk signaling pathways downstream of HER1/EGFR may be required for optimal antitumor effects. Erlotinib exhibits inhibition of MAPK and Atk kinases at concentrations higher than those required for HER1/EGFR tyrosine kinase inhibition; such findings suggest that maximal inhibition of HER1/EGFR, requiring high erlotinib doses, is necessary for optimum antitumor activity. These considerations are supported by tumor models, including non-small-cell lung cancer models, showing dose-related antitumor effects up to high doses of erlotinib. Erlotinib exhibits additive antitumor effects when combined with chemotherapeutic agents (cisplatin, doxorubicin, paclitaxel, gemcitabine [Gemzar], and capecitabine [Xeloda]), radiation therapy, and other targeted agents (e.g., bevacizumab [Avastin]). Recent studies indicate that erlotinib inhibits the EGFRvIII mutant at concentrations higher than those required for inhibition of wild-type receptor. Ongoing investigation will help to determine optimal dosing and dose frequency of erlotinib in various cancers in the clinical setting.
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PMID:Erlotinib: preclinical investigations. 1468 18

Lung cancer is very frequent and associated with a high mortality. In the last 25 years therapeutic progress have been limited and do not allow a 5 year global survival rate exceeding to 13-14%. Tumor biology permits a better comprehension of cancerization mechanisms and offers hope of new treatments with targeted therapies which would be specific of cancer cells and so more efficient and less toxic. Epidermal growth factor (EGF) pathway and its receptor (EGFR) expressed by most lung cancer cells is the most successfully completed example. The bond of EGF with its receptor stimulates tyrosine kinase domain of EGFR and allows transduction of an activating signal. Inhibition of this signaling pathway stops tumor growth. Several agents are in development, from preclinical studies to phase III trials. It is a matter of humanized monoclonal antibodies, such as C225 (cetuximab), targeted against EGFR, or small molecules inhibiting tyrosine kinase activity of EGFR including ZD1839 (Iressa), OS1774 (Tarceva) or CI1033, and last antisense oligonucleotides. Antibodies and small molecules are well tolerated and are responsible for limited amount of side effects, mostly cutaneous toxicity and diarrhoea. Antitumor activity has been observed in monotherapy reaching up to 25% of clinical responses in the best series. EGFR inhibition seems to be also promising in combination with chemotherapy according to the synergy observed in preclinical studies and response rate up to 50% have been reported. But phase III studies have been disappointing and additional studies are warranted before consideration for a current daily practice, mostly that severe secondary effects were reported with pulmonary toxicities. In particular it remains to explain why clinical responses do not appear correlated with EGFR expression.
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PMID:[Therapeutic implications of epidermal growth factor receptor in lung cancer]. 1476 45

Our objective was the preclinical assessment of the pharmacokinetics, monotherapy and combined antitumor activity of the epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor erlotinib in athymic nude mice bearing non-small cell lung cancer (NSCLC) xenograft models. Immunohistochemistry determined the HER1/EGFR status of the NSCLC tumor models. Pharmacokinetic studies assessed plasma drug concentrations of erlotinib in tumor- and non-tumor-bearing athymic nude mice. These were followed by maximum tolerated dose (MTD) studies for erlotinib and each chemotherapy. Erlotinib was then assessed alone and in combination with these chemotherapies in the NSCLC xenograft models. Complete necropsies were performed on most of the animals in each study to further assess antitumor or toxic effects. Erlotinib monotherapy dose-dependently inhibited tumor growth in the H460a tumor model, correlating with circulating levels of drug. There was antitumor activity at the MTD with each agent tested in both the H460a and A549 tumor models (erlotinib 100 mg/kg: 71 and 93% tumor growth inhibition; gemcitabine 120 mg/kg: 93 and 75% tumor growth inhibition; cisplatin 6 mg/kg: 81 and 88% tumor growth inhibition). When each compound was given at a fraction of the MTD, tumor growth inhibition was suboptimal. Combinations of gemcitabine or cisplatin with erlotinib were assessed at 25% of the MTD to determine efficacy. In both NSCLC models, doses of gemcitabine (30 mg/kg) or cisplatin (1.5 mg/kg) with erlotinib (25 mg/kg) at 25% of the MTD were well tolerated. For the slow growing A549 tumor, there was significant tumor growth inhibition in the gemcitabine/erlotinib and cisplatin/erlotinib combinations (above 100 and 98%, respectively), with partial regressions. For the faster growing H460a tumor, there was significant but less remarkable tumor growth inhibition in these same combinations (86 and 53% respectively). These results show that in NSCLC xenograft tumors with similar levels of EGFR expression, the antitumor activity of erlotinib is robust both as monotherapy and in combination with chemotherapies.
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PMID:Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models. 1516 26

Molecular targeting strategies for cancer therapy are distinct from conventional chemotherapy and radiotherapy in their potential to provide increased tumor specificity. One particular molecular target of high promise in oncology is the epidermal growth factor receptor (EGFR). The EGFR is overexpressed, dysregulated or mutated in many epithelial malignancies, and EGFR activation appears important in tumor growth and progression. Advances in signal transduction biology continue to sharpen our understanding regarding specific contributions of EGFR signaling networks to cancer behavior. Two predominant classes of EGFR inhibitors have been developed including monoclonal antibodies (mAbs) that target the extracellular domain of EGFR, such as cetuximab (Erbitux), and small molecule tyrosine kinase inhibitors (TKIs) that target the receptor catalytic domain of EGFR, such as gefitinib (Iressa) and erlotinib (Tarceva). Mechanisms of action for EGFR inhibitors have been investigated in preclinical model systems. Safety, activity, pharmacokinetics and pharmacodynamics have been assessed in clinical trials. The anti-EGFR mAbs and TKIs have partially overlapping toxicity profiles, but distinct routes of administration, serum half-lives and therefore dosing schedules. Both classes of agents show clear antitumor activity, and cetuximab and gefitinib have been recently FDA approved for colorectal and lung cancer indications respectively. However, the absence of survival benefit for EGFR TKIs in combination with chemotherapy in large-scale phase III lung cancer trials in 2003 underscores a major challenge in anti-EGFR oncology therapeutics; namely to identify those tumors and patients that will respond predictably to EGFR inhibitor approaches. Newly identified mutations in the EGFR catalytic domain that appear to confer sensitivity to EGFR TKIs promise to open new doors of investigation regarding response prediction. Advances will also require enhanced molecular understanding of the overall EGFR signaling network, and improved methods to gauge the dependence of individual tumors on EGFR signaling pathways for growth advantage. Results from newly reported phase III trials in 2004 now confirm a survival advantage for the use of EGFR inhibitors in combination with high-dose radiation in head and neck cancer, and in refractory lung cancer respectively. It appears likely that EGFR inhibitors (and other rationally designed molecular growth inhibitors) will play a meaningful role in cancer therapy in the years to come.
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PMID:Epidermal growth factor receptor inhibition strategies in oncology. 1561 46

Erlotinib (Tarceva) is an orally available HER1 (epidermal growth factor receptor, EGFR) tyrosine kinase inhibitor advancing through clinical trials for the treatment of a range of human malignancies. In this study, we examine the capacity of erlotinib to modulate radiation response and investigate specific mechanisms underlying these interactions in human tumor cell lines and xenografts. The impact of erlotinib on cell cycle kinetics was analyzed using flow cytometry, and the impact on apoptosis was evaluated via fluorescein-labeled pan-caspase inhibition and poly(ADP-ribose) polymerase cleavage. Radiation-induced EGFR autophosphorylation and Rad51 expression were examined by Western blot analysis. Radiation survival was analyzed using a clonogenic assay and assessment of in vivo tumor growth was done using a mouse xenograft model system. Microarray studies were carried out using 20 K human cDNA microarray and select genes were validated using quantitative reverse transcription-PCR (RT-PCR). Independently, erlotinib and radiation induce accumulation of tumor cells in G(1) and G(2)-M phase, respectively, with a reduction of cells in S phase. When combined with radiation, erlotinib promotes a further reduction in S-phase fraction. Erlotinib enhances the induction of apoptosis, inhibits EGFR autophosphorylation and Rad51 expression following radiation exposure, and promotes an increase in radiosensitivity. Tumor xenograft studies confirm that systemic administration of erlotinib results in profound tumor growth inhibition when combined with radiation. cDNA microarray analysis assessing genes differentially regulated by erlotinib following radiation exposure identifies a diverse set of genes deriving from several functional classes. Validation is confirmed for several specific genes that may influence radiosensitization by erlotinib including Egr-1, CXCL1, and IL-1beta. These results identify the capacity of erlotinib to enhance radiation response at several levels, including cell cycle arrest, apoptosis induction, accelerated cellular repopulation, and DNA damage repair. Preliminary microarray data suggests additional mechanisms underlying the complex interaction between EGFR signaling and radiation response. These data suggest that the erlotinib/radiation combination represents a strategy worthy of further examination in clinical trials.
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PMID:Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). 1583 66

Angiogenesis is a strongly regulated process, which is dependent upon a complex interplay between inhibitory and stimulatory angiogenic factors. It is essential for tumor growth and metastasis: increased angiogenesis is correlated with poor prognosis in cancer patients. Many novel compounds that potently inhibit formation of neoplastic blood vessels have been recently developed. Major categories of angiogenesis antagonists include protease inhibitors, direct inhibitors of endothelial cell proliferation and migration, angiogenic growth factor suppressors, inhibitors of endothelial-specific integrin/survival signalling, copper chelators, and inhibitors with other specific mechanisms. There is increasing interest in developing angio-suppressive agents for colorectal cancer treatment. Some 20 direct and indirect antiangiogenesis drugs are currently being evaluated in clinical trials in colorectal cancer (CRC). Promising results have been reported. These include an increase in overall survival and reduction in the risk of death (Bevacizumab), reversal of cellular resistance (Cetuximab) and activity as second-line therapy in patients who have exhausted other available treatment options (Cetuximab, ABX-EGF, PTK-787, Gefitinib, Erlotinib). This review will outline the mechanisms of action of the principal antiangiogenic drugs, summarize the available data on the use of these new drugs in colorectal cancer, discuss their impact in clinical practice and offer a glimpse into how antiangiogenetic therapy will be integrated into the future care of patients with gastrointestinal cancers.
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PMID:Colorectal cancer and antiangiogenic therapy: what can be expected in clinical practice? 1589 May 25

In many solid tumors, overexpression of human epidermal growth factor receptors (e.g., HER1/EGFR and HER2) correlates with poor prognosis. Erlotinib (Tarceva) is a potent HER1/EGFR tyrosine kinase inhibitor. Pertuzumab (Omnitarg), a novel HER2-specific, recombinant, humanized monoclonal antibody, prevents heterodimerization of HER2 with other HERs. Both mechanisms disrupt signaling pathways, resulting in tumor growth inhibition. We evaluated whether inhibition of both mechanisms is superior to monotherapy in tumor cell lines expressing different HER levels. Human non-small cell lung cancer (NSCLC) cells (Calu-3: HER1/EGFR 0+, HER2 3+; QG56: HER1/EGFR 2-3+, HER2 0+) and breast cancer cells (KPL-4: HER1/EGFR 2-3+, HER2 3+) were implanted into BALB/c nu/nu mice and severe combined immunodeficient beige mice, respectively. Tumor-bearing mice (n = 12 or 15 per group) were treated with vehicle (Captisol or buffer), erlotinib (orally, 50 mg/kg/d), pertuzumab (i.p. 6 mg/kg/wk with a 2-fold loading dose), or erlotinib and pertuzumab for 20 (QG56), 27 (KPL-4), or 49 (Calu-3) days. Drug monotherapy had antitumor activity in all models. Tumor volume treatment-to-control ratios (TCR) with erlotinib were 0.36 (Calu-3), 0.79 (QG56), and 0.51 (KPL-4). Pertuzumab TCR values were 0.42, 0.51, and 0.64 in Calu-3, QG56, and KPL-4 models, respectively. Combination treatment resulted in additive (QG56: TCR 0.39; KPL-4: TCR 0.38) or greater than additive (Calu-3: TCR 0.12) antitumor activity. Serum tumor markers for NSCLC (Cyfra 21.1) and breast cancer (soluble HER2) were markedly inhibited by combination treatment (80-97% in Calu-3 and QG56; 92% in KPL-4), correlating with decreased tumor volume. Overall, erlotinib and pertuzumab are active against various human xenograft models, independently of HER1/EGFR or HER2 expression. A combination of these HER-targeted agents resulted in additive or greater than additive antitumor activity.
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PMID:Combination treatment with erlotinib and pertuzumab against human tumor xenografts is superior to monotherapy. 1603 49

Erlotinib (Tarceva, OSI-774) is a potent, orally available, small-molecule inhibitor of HER1/EGFR tyrosine-kinase activity. In this study, the antitumor activity of erlotinib was evaluated in two human colorectal tumor xenograft models (LoVo and HCT116) in athymic mice. When erlotinib was administered as monotherapy, significant tumor growth inhibition (TGI) was seen in the LoVo model at both 100 mg/kg [TGI > 100%, P < 0.001; 6/10 partial regressions (PRs)] and 25 mg/kg (TGI = 79%, P < 0.001) doses. However, the HCT116 xenograft model was not responsive to any dose of erlotinib tested. The differential response to erlotinib of these two tumor models was not a result of differences in HER1/EGFR expression levels since these were similar in both cell lines. However, it was demonstrated that resistance to erlotinib in the HCT116 model may be a result of persistent activation of ERK in these tumors. Based on the single agent activity of erlotinib in LoVo tumors, a combination study with CPT-11 (Camptosar, irinotecan) was performed. CPT-11 at the optimal dose of 60 mg/kg or a lower dose of 15 mg/kg resulted in significant TGI (TGI > 100%, P < 0.001, and TGI = 93%, P < 0.001, respectively) in LoVo-bearing mice. Combination treatment with erlotinib (25 mg/kg) and CPT-11 (15 mg/kg) produced significantly greater antitumor activity (TGI > 100%, P < 0.001; 10/10 PRs) than either agent alone (P < 0.05), with no increase in toxicity. These data indicate that erlotinib can enhance the antitumor activity of CPT-11, without enhanced toxicity, in the LoVo human colorectal tumor xenograft model.
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PMID:Antitumor activity of HER1/EGFR tyrosine kinase inhibitor erlotinib, alone and in combination with CPT-11 (irinotecan) in human colorectal cancer xenograft models. 1693 4

Clinical trials using rapamycin analogues or HER1/epidermal growth factor receptor (EGFR) inhibitors show that each class of agent has activity against a range of human solid tumors. Because blockade of mitogen-activated protein kinase signaling occurs following HER1/EGFR inhibition in some cell types, we tested the combination of rapamycin and erlotinib in SiHa, Me180, and CaSki human cervical carcinomas xenografts in severe combined immunodeficient mice. In tissue culture, all three cell lines showed decreased phosphorylated S6 ribosomal protein and decreased phosphorylated extracellular signal-regulated kinase (ERK) following treatment with rapamycin and erlotinib, respectively. In SiHa tumors, suppression of phosphorylated S6 was induced by either drug alone, whereas phosphorylated ERK decreased with erlotinib, and enhancement of these effects was obtained with the combination. Continuous treatment of xenografts for 3 weeks led to significant tumor growth delay compared with vehicle control for rapamycin as single agent (P = 0.003) and greater for the combination (P = 0.04 versus rapamycin). Significant antiangiogenic effect was obtained in SiHa xenografts using the drugs together (measured by microvascular density and vascular endothelial growth factor plasma levels) but not for the single agents. Me180 and CaSki xenografts showed significant growth delay with rapamycin but not with erlotinib. Erlotinib treatment resulted in decreased phosphorylated ERK, associated with enhanced suppression of phosphorylated S6 and improved growth delay in Me180 but not in CaSki tumors. These results support the further clinical investigation of rapamycin and EGFR inhibitor combinations in anticancer therapy but highlight the problem of intertumoral heterogeneity in the prediction of in vivo response.
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PMID:Signaling interactions of rapamycin combined with erlotinib in cervical carcinoma xenografts. 1704 Oct 93


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