UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidermal growth factor (EGF) receptor (EGFR) is commonly amplified and/or mutated in high-grade gliomas. Abnormal signaling from this receptor tyrosine kinase is believed to contribute to the malignant phenotypes seen in these tumors. Highly specific small molecule inhibitors of this receptor tyrosine kinase have been developed and may potentially improve the treatment of these highly aggressive brain tumors. A glioma cell line overexpressing EGFR was developed to mimic the situation of a malignant glioma with amplified EGFR, and this line was used to characterize the response to specific EGFR inhibitors. Treatment of our in vitro glioma model with the EGFR kinase inhibitors ZD1839 (Iressa) or PD153035, synthetic anilinoquinazolines with high specificity for EGFR, resulted in significant suppression of EGFR autophosphorylation even with very low levels of drug. However, significantly higher levels of drug were required to fully inhibit signaling through the phosphatidylinositol 3'-kinase/AKT and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) pathways. Interestingly, not all downstream signaling pathways displayed this resistance to inhibition. EGF-dependent activation of signal transducers and activators of transcription-3 occurred at low doses of EGFR inhibitors. The uncoupling of EGFR autophosphorylation and signaling through AKT and ERK was not dependent on EGFR overexpression. In addition, although this response was seen in other glioma and the SK-BR3 breast cancer cell lines, it was not universally present. The SQ20B head and neck squamous carcinoma cell line demonstrated loss of EGF-dependent AKT and ERK activation even at low doses of inhibitor. Despite significant loss of EGF-dependent autophosphorylation, the inability of low levels of EGFR inhibitor to suppress some downstream signaling pathways in our model glioma cell line permitted continued EGF-responsive decreases in the expression of the cyclin-dependent kinase inhibitor p27KIP and EGF-dependent proliferation/cell cycle progression. Although the mechanism responsible for the differential sensitivity of the various signal transduction pathways to EGFR inhibitors remains unclear, signaling through erbB2 does not appear to be involved. The ability of certain tumor cells to maintain signaling through AKT and ERK under EGFR inhibition may represent a potential mechanism of resistance by which a tumor cell may escape the antiproliferative activity of this new class of drugs.
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PMID:Resistance to small molecule inhibitors of epidermal growth factor receptor in malignant gliomas. 1461 44

Gefitinib (brand name: Iressa) is a drug approved for molecule-targeting therapy in lung carcinoma patients. There are still many unresolved problems concerning the safety and mechanism of action of this drug. Based on the expectation that this drug combined with immunotherapy would be highly effective, we recently conducted an experiment in tumor-bearing mice. In this experiment, however, the tumor was not significantly reduced in size by this combined therapy. However, since the tumor in this animal model was EGFR positive and because tumor growth tended to be suppressed in mice with higher immune activity, it seems likely that additional studies of this therapy will contribute to identifying the optimum drugs to be combined with gefitinib and the optimum method of dosing that will lead to satisfactory efficacy and safety of gefitinib combined with immunotherapy.
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PMID:[Significance of gefitinib combined with immunotherapy in tumor-bearing mice]. 1461 16

Many malignant tumors including non-small cell lung cancer (NSCLC) express or over-express EGFR that have shown correlations with rapid growth, metastases, resistance to conventional chemotherapy or radiotherapy, and poor prognosis. Gefitinib is a potent and selective inhibitor of EGFR tyrosine kinase (EGFRTK). Gefitinib specifically inhibited EGF-stimulated cell proliferation in vitro and it also exhibited a broad anti-tumor spectrum against NSCLC, prostate, colorectal, and ovarian cancers in vivo. Gefitinib showed dose-dependent and reversible reduction of c-fos mRNA level and decreased Ki67 significantly in tumors in vivo. In in vitro studies, gefitinib arrested the cell cycle at G1 phase by inducing intrinsic cyclin-dependent kinase (cdk) inhibitors and following inhibition of cdk2. Apoptosis was also seen in gefitinib-treated tumor cells and skin biopsy samples from clinical study. Gefitinib inhibited VEGF production in tumor cells through inhibition of EGFR signaling, leading to suppression of angiogenesis. In clinical studies, gefitinib demonstrated therapeutic benefit in patients who failed conventional chemotherapy. No correlation has been established between the anti-tumor activity of gefitinib and EGFR expression level, whilst sensitivity factors to gefitinib are yet to be elucidated. Identification of sensitivity factors will be a key for effective use of EGFRTK inhibitors including gefitinib for cancer treatment.
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PMID:EGFR tyrosine kinase inhibitor "gefitinib (Iressa)" for cancer therapy. 1463 3

Gefitinib is a small-molecule agent specifically targeted to inhibit the epidermal growth factor receptor-tyrosine kinase (EGFR-TK). Tumor responses have been achieved with gefitinib treatment in large, randomized monotherapy trials. In preclinical studies, gefitinib has shown additive and even supra-additive antitumor effects when combined with different cytotoxic agents. In phase I clinical trials, gefitinib was found to be well tolerated, with clinical efficacy observed well below the maximum tolerated dose. The pharmacokinetics of gefitinib allow it to be administered as a once-daily oral tablet. Several phase I studies have investigated the safety of gefitinib at daily doses of 250 mg or 500 mg in combination with chemotherapy agents for first-line treatment of a variety of common solid tumors. The potential for drug interactions between gefitinib and cytotoxic agents was evaluated through pharmacokinetic assessments. A randomized, crossover study investigated the interaction of gefitinib and carboplatin/paclitaxel in the treatment of advanced non-small-cell lung cancer (NSCLC). A second trial with an open-label design studied the combination of gefitinib with cisplatin/gemcitabine in patients with a variety of solid tumors, including NSCLC. In both pilot studies, the addition of gefitinib to chemotherapy did not increase the exposure of any of the chemotherapy agents tested. However, increased exposure to gefitinib was seen with the carboplatin/paclitaxel regimen. The addition of gefitinib to these chemotherapy regimens was generally well tolerated, and there was no apparent increase in higher-grade toxicity. Additional trials are evaluating gefitinib treatment in combination with chemotherapy.
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PMID:Pharmacokinetic evaluation of gefitinib when administered with chemotherapy. 1464 90

The aims of chemoprevention in lung cancer are to prevent the appearance of disease (primary prevention) and to stop or reverse the progression of premalignant lesions (secondary prevention). Until recently, there was little hope that these goals could be attained. However, the results achieved with tamoxifen in the prevention of breast cancer, and the emergence of new therapies specifically targeted to molecules involved in the pathogenesis of lung cancer have set the stage for investigation of these agents for chemoprevention of lung cancer. Two of these new molecular targeted agents are gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase activity, and tipifarnib (R115777, Zarnestra ), an inhibitor of the farnesyltransferase enzyme, which is required for the proper localization and function of the ras oncogene. Tumor responses and disease stabilization have been achieved with both agents in clinical trials. In the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 and IDEAL-2 phase II trials, gefitinib was demonstrated to be effective for disease control in patients with advanced non-small-cell lung cancer. The SPORE (Specialized Program of Research Excellence) Trials of Lung Cancer Prevention (STOP) are 2 parallel studies that will investigate the potential effectiveness of gefitinib and tipifarnib in preventing the appearance and progression of premalignant lesions in former or current smokers with a history of smoking-related cancer. These trials should provide information not only about the potential role of gefitinib and tipifarnib in lung cancer chemoprevention, but also about the molecular changes that underlie tumorigenesis and that may serve as markers of disease progression. The STOP trial objectives are to evaluate the effect of gefitinib and tipifarnib on histologic and biologic parameters in patients with evidence of sputum atypia, to evaluate various parameters as potential predictors of the effectiveness of these agents, and to evaluate the tolerability of these agents over a 6-month course of treatment. Histologic response, defined as prevention of appearance or progression of premalignant lesions, is the primary endpoint of these trials. New targeted molecular therapies such as gefitinib and tipifarnib may offer the opportunity to make chemoprevention a viable treatment modality in lung cancer as well as in other human solid tumors.
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PMID:Primary and secondary prevention of non-small-cell lung cancer: the SPORE Trials of Lung Cancer Prevention. 1464 93

Epidermal growth factor receptor [EGFR (HER1, erbB1)] is a receptor with associated tyrosine kinase activity, and is expressed in colorectal cancers and many other solid tumors. We examined the effect of the selective EGFR tyrosine kinase inhibitor (EGFR-TKI) gefitinib ("Iressa") in combination with the DNA topoisomerase I inhibitor CPT-11 (irinotecan) on human colorectal cancer cells. EGFR mRNA and protein expression were detected by RT-PCR and immunoblotting in all 7 colorectal cancer cell lines studied. Gefitinib inhibited the cell growth of the cancer cell lines in vitro with an IC(50) range of 1.2-160 microM by 3,(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Lovo cells exhibited the highest level of protein and autophosphorylation of EGFR and were the most sensitive to gefitinib. The combination of gefitinib and CPT-11 induced supra-additive inhibitory effects in COLO320DM, WiDR and Lovo cells, assessed by an in vitro MTT assay. Administration of gefitinib and CPT-11 had a supra-additive inhibitory effect on WiDR cells and tumor shrinkage was observed in Lovo cell xenografts established in nude mice, whereas no additive effect of combination therapy was observed in COLO320DM cells. To elucidate the mechanisms of synergistic effects, the effect of CPT-11-exposure on phosphorylation of EGFR was examined by immunoprecipitation. CPT-11 increased phosphorylation of EGFR in Lovo and WiDR cells in time- and dose-dependent manners. This EGFR activation was completely inhibited by 5 microM gefitinib and gefitinib-induced apoptosis was enhanced by combination with CPT-11, measured by PARP activation although no PARP activation was induced by 5 microM CPT-11 alone. These results suggested that these modification of EGFR by CPT-11, in Lovo cells, is a possible mechanism for the synergistic effect of CPT-11 and gefitinib. These findings imply that the EGFR-TKI gefitinib and CPT-11 will be effective against colorectal tumor cells that express high levels of EGFR, and support clinical evaluation of gefitinib in combination with CPT-11, in the treatment of colorectal cancers.
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PMID:Synergistic interaction between the EGFR tyrosine kinase inhibitor gefitinib ("Iressa") and the DNA topoisomerase I inhibitor CPT-11 (irinotecan) in human colorectal cancer cells. 1464 15

The epidermal growth factor receptor (EGFR) signaling pathway plays an important role in a number of processes that are key to tumor progression, including cell proliferation, angiogenesis, metastatic spread, and inhibition of apoptosis. EGFR is expressed or overexpressed in non-small-cell lung cancer (NSCLC), and EGFR-mediated growth has been associated with advanced disease and poor prognosis in NSCLC patients. ZD1839 (Iressa) is an orally active, selective EGFR-tyrosine kinase inhibitor that blocks EGFR signal transduction. In preclinical studies using NSCLC cell lines, ZD1839 has been shown to inhibit tumor cell growth. In addition, ZD1839, as monotherapy and in combination with commonly used cytotoxic agents, has produced growth delay in NSCLC human xenografts. Preliminary results from phase I trials in patients with advanced disease have shown that ZD1839 has excellent bioavailability, an acceptable tolerability profile, and promising clinical activity in patients with a variety of tumor types, particularly in NSCLC. ZD1839 is currently in phase III clinical development for the treatment of advanced NSCLC.
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PMID:ZD1839 (Iressa) in non-small-cell lung cancer. 1465 86

We present a series of cases that illustrate potential benefits of the targeted agent gefitinib for patients with advanced and heavily pretreated non-small-cell lung cancer (NSCLC). In 2 phase II clinical trials, 250 mg/day of gefitinib produced objective tumor response rates of 18% and 11%, with excellent tolerance in patients with advanced NSCLC who had previously received standard chemotherapy. Treatment with gefitinib also led to improvements in disease-related symptoms in approximately 40% of cases. Gefitinib is one of a class of agents that selectively inhibit the epidermal growth factor receptor-tyrosine kinase, which is aberrantly activated in many human solid tumors. Gefitinib treatment resulted in objective radiographic regressions of tumor and symptom improvement in patients with advanced, heavily pretreated NSCLC in clinical trials and in the Expanded Access Program. This series illustrates that the benefits of gefitinib are not limited to patients selected for clinical trial participation but can be generalized to the broader population of patients with NSCLC.
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PMID:Antitumor activity and tolerability of gefitinib in patients with non-small-cell lung cancer treated in an expanded access program. 1466 75

Rash is a class effect of HER1/epidermal growth factor receptor (EGFR)-targeted agents, and has occurred with high frequency and in a dose-dependent manner in clinical trials of these agents in cancer patients. Analysis of phase II trials of erlotinib (Tarceva) in non-small-cell lung cancer, head and neck cancer, and ovarian cancer shows a significant association between rash severity and objective tumor response. Rash severity was highly significantly associated with survival in patients with non-small-cell lung cancer receiving erlotinib; median survival in patients with no rash was 46.5 days, compared with 257 days in those with grade 1 rash (P < .0001) and 597 days in those with grade 2/3 rash (P < .0001). Similarly, for the combined non-small-cell lung cancer, head and neck cancer, and ovarian cancer studies, median survival in patients with no rash was 103 days, compared with 191 days in those with grade 1 rash (P = .0001) and 266 days in those with grade 2/3/4 rash (P = .0001). Similar findings have been made with cetuximab (Erbitux) and in some settings with gefitinib (Iressa). The strong association of rash severity with response/survival suggests that rash may serve as a marker of response to erlotinib treatment and may be used to guide treatment to obtain optimal response. Dosing erlotinib at the maximum tolerated dose, which is associated with more frequent and more severe rash, may improve response rates and survival durations. Further study of the potentially important association between rash and outcome of treatment with EGFR-targeted agents is needed.
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PMID:Can rash associated with HER1/EGFR inhibition be used as a marker of treatment outcome? 1468 20

Symptom monitoring and quality-of-life (QOL) evaluation in lung cancer patients might improve care. Brief, valid, and responsive tools are available to measure symptoms and their effect on QOL. Instruments available for use in lung cancer patients can be classified into 3 categories: generic, cancer-specific, and lung cancer symptom-specific. These instruments might assist clinicians in assessing and interpreting treatment outcomes from the patient perspective. They also can assist in treatment decision making, symptom palliation, and they might even be prognostic of survival. Over the past 20 years, these brief evaluations have been used in clinical trials to evaluate patient-reported outcomes. Now, with the advent of less toxic, targeted molecular therapies such as gefitinib (Iressa) in non-small-cell lung cancer, these instruments' value in showing symptomatic improvement from tumor control or regression might be further enhanced. To date, however, such assessments are not widely implemented in routine clinical practice. To better understand benefits of such assessments, we review existing evidence surrounding the instruments' use, evaluate their success, and highlight recent developments. We hope to encourage clinicians to incorporate these evaluations in clinical practice.
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PMID:The validity and clinical utility of symptom monitoring in advanced lung cancer: a literature review. 1470 64

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