Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Receptor tyrosine kinase genes were sequenced in non-small cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinib-insensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib.
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PMID:EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. 1573 72

Tyrosine kinase inhibitors (TKIs) are promising new agents for specific inhibition of malignant cell growth and metastasis formation. Because most of the TKIs have to reach an intracellular target, specific membrane transporters may significantly modulate their effectiveness. In addition, the hydrophobic TKIs may interact with so-called multidrug transporters and thus alter the cellular distribution of unrelated pharmacological agents. In the present work, we show that certain TKIs, already in the clinical phase of drug development, directly interact with the ABCG2 multidrug transporter protein with a high affinity. We found that in several in vitro assay systems, STI-571 (Gleevec; imatinib mesylate), ZD1839 (Iressa; gefitinib), and N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (EKI-785) interacted with ABCG2 at submicromolar concentrations, whereas other multidrug transporters, human multidrug resistance protein (P-glycoprotein, ABCB1) and human multidrug resistance protein 1 (ABCC1), showed much lower reactivity toward these agents. Low concentrations of the TKIs examined selectively modulated ABCG2-ATPase activity, inhibited ABCG2-dependent active drug extrusion, and significantly affected drug resistance patterns in cells expressing ABCG2. Our results indicate that multidrug resistance protein modulation by TKIs may be an important factor in the clinical treatment of cancer patients. These data also raise the possibility that an extrusion of TKIs by multidrug transporters, e.g., ABCG2, may be involved in tumor cell TKI resistance.
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PMID:High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter. 1515 41

Cytotoxic chemotherapy has only yielded modest gains in survival in lung cancer in the past decade. However, the development of agents targeting specific signaling pathways that drive carcinogenesis has heralded a major paradigm shift in the approach to treatment of cancer. In non-small cell lung cancer (NSCLC), many researchers have focused on the epidermal growth factor receptor (EGFR) because this protein is present on a relatively high proportion of non-small cell lung cancers and its intracellular tyrosine kinase activates a signaling cascade that drives tumor growth. Blockade of the EGFR by small molecule inhibitors of the tyrosine kinase, such as gefitinib and erlotinib, causes tumor regressions in NSCLC. Phase II monotherapy trials of EGFR tyrosine kinase inhibitors in patients with previously treated advanced NSCLC demonstrated anti-tumor activity with objective response rates of 10-19% with acceptable toxicities and an associated improvement in lung cancer symptomatology. Gefitinib is now an FDA approved treatment for advanced NSCLC previously treated with platinum and docetaxel-based therapies. However, phase III trials of gefitinib and erlotinib in combination with chemotherapy doublets have failed to demonstrate a survival advantage when compared with chemotherapy alone. It remains unclear why these drugs work so effectively in certain patients and so poorly in combination with chemotherapy. The goal of ongoing and future investigation is to identify which patients may benefit from this new therapeutic approach.
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PMID:Targeting non-small cell lung cancer with epidermal growth factor tyrosine kinase inhibitors: where do we stand, where do we go. 1518 24

In 2003, gefitinib (Iressa, AstraZeneca, London, UK) in 250 mg tablet form received accelerated approval by the US Food and Drug Administration. Gefitinib targets the cancer cell at the molecular level and has the ability to palliate lung cancer symptoms. Gefitinib's ability to control symptoms with minimal toxicity provides physicians with a new option to complement current symptom control methods. It is nonmarrow suppressive and seems to have an ability to control symptoms quickly, even in the absence of obvious tumor reduction. However, further studies are needed to compare gefitinib's ability to control symptoms with intensive palliative modalities for lung cancer, such as opioids, oxygen, and radiation therapy.
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PMID:Gefitinib: a new agent in palliative care. 1518 23

Patients with advanced non-small cell lung cancer (NSCLC) who fail to respond to cytotoxic chemotherapy or who cannot tolerate chemotherapy have limited treatment options. In addition, patients with advanced NSCLC often experience disease-related symptoms that impact their quality of life. Treatment goals in this setting include palliation of symptoms and improvement in quality of life, in addition to tumor response or disease stabilization and increased survival. ZD1839 (Iressa, gefitinib) is an orally active, small-molecule, epidermal growth factor receptor-tyrosine kinase inhibitor that has shown single-agent efficacy for previously treated advanced NSCLC. In phase I clinical trials, ZD1839 provided relief from symptoms often associated with lung cancer, including fatigue, shortness of breath, and chest pain. The IRESSA Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 and IDEAL-2 clinical trials evaluated ZD1839 treatment at 250 mg/day and 500 mg/day in patients with advanced NSCLC for objective tumor response and safety, as well as for improvements in NSCLC-related symptoms and health-related quality of life. The majority of patients enrolled in these studies had received multiple prior treatments. Rapid, sustained symptom improvement was documented for many patients receiving ZD1839 at 250 mg/day or 500 mg/day in both IDEAL trials and was positively associated with clinical benefits, such as tumor response and increased survival.
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PMID:Effects of ZD1839 (Iressa, gefitinib) treatment on symptoms and quality of life in patients with advanced non-small cell lung cancer. 1520 79

Gefitinib (Iressa) is a novel targeted therapy that inhibits the tyrosine kinase activity of the epidermal growth factor receptor by competitively blocking the ATP binding site. In preclinical studies gefitinib has shown potent activity in a number of tumor models, including several lung cancer cell lines and xenografts. Two large randomized Phase II studies (IDEAL 1 and IDEAL 2) in pretreated non-small cell lung cancer reported a response rate approaching 20% in second-line patients and approximately 10% in those pretreated with two or more chemotherapy regimens. The median survival in these two studies approached 6-8 months. As a first-line therapy, gefitinib has been assessed in combination with two different chemotherapy regimens in two large randomized studies (INTACT 1 and INTACT 2). Both studies failed to show an improvement in survival on a total patient accrual of >1000 patients in each study. Other end points (e.g., time to progression and response rate) were also not improved by the addition of gefitinib. Additional studies are indicated to assess the possible role of gefitinib in the maintenance of patients who received chemotherapy or chemoradiotherapy. Studies investigating gefitinib as first-line monotherapy are also required.
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PMID:The role of gefitinib in lung cancer treatment. 1521 64

Molecular inhibition of epidermal growth factor receptor (EGFR/HER1) signaling is under active investigation as a promising cancer treatment strategy. We examined the potency of EGFR inhibition achieved by combining anti-EGFR monoclonal antibody and tyrosine kinase inhibitor, which target extracellular and intracellular domains of the receptor, respectively. We specifically studied the combination of cetuximab (Erbitux, C225; ImClone Systems, New York, NY) with either gefitinib (Iressa, ZD1839; AstraZeneca, Macclesfield, UK) or erlotinib (Tarceva, OSI-774; Genentech, South San Francisco, CA) across a variety of human cancer cells. The combination of cetuximab plus gefitinib or erlotinib enhanced growth inhibition over that observed with either agent alone. As measured by immunostaining, inhibition of EGFR phosphorylation with the combination of cetuximab plus gefitinib or erlotinib was augmented over that obtained with single-agent therapy in head and neck (H&N) cancer cell lines. Phosphorylation inhibition of downstream effector molecules [mitogen-activated protein kinase (MAPK) and AKT] also was enhanced in tumor cells treated with the combination of cetuximab plus gefitinib or erlotinib. Flow cytometry and immunoblot analysis demonstrated that treatment of H&N tumor cells with cetuximab in combination with either gefitinib or erlotinib amplified the induction of apoptosis. Following establishment of cetuximab-resistant cell lines, we observed that gefitinib or erlotinib retained the capacity to inhibit growth of lung and H&N tumor cells that were highly resistant to cetuximab. Treatment with gefitinib or erlotinib, but not cetuximab, also could further inhibit the activation of downstream effectors of EGFR signaling in cetuximab-resistant cells, including MAPK and AKT. These data suggest that tyrosine kinase inhibitors may further modulate intracellular signaling that is not fully blocked by extracellular anti-EGFR antibody treatment. Finally, animal studies confirmed that single EGFR inhibitor treatment resulted in partial and transient tumor regression in human lung cancer xenografts. In contrast, more profound tumor regression and regrowth delay were observed in mice treated with the combination of cetuximab and gefitinib or erlotinib. Immunohistochemical staining, which demonstrated significant reduction of the proliferative marker proliferating cell nuclear antigen in mice treated with dual EGFR inhibitors, further supported this in vivo observation. Together, these data suggest that combined treatment with distinct EGFR inhibitory agents can augment the potency of EGFR signaling inhibition. This approach suggests potential new strategies to maximize effective target inhibition, which may improve the therapeutic ratio for anti-EGFR-targeted therapies in developing clinical trials.
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PMID:Dual-agent molecular targeting of the epidermal growth factor receptor (EGFR): combining anti-EGFR antibody with tyrosine kinase inhibitor. 1528 42

Since epidermal growth factor receptor (EGFR) is involved in tumor proliferation and angiogenesis, and in the mechanisms of resistance to chemo- and hormono-therapy, it represents a unique promising target for anticancer treatment. Gefinitib (Iressa, ZD1839), an inhibitor of the EGFR tyrosine kinase activity able to bind the intracellular domain of the receptor, is at present in clinical development. In preclinical models Gefitinib induced a dose-dependent response rate in tumor xenografts obtained from different human cancer cells lines. The expression of EGFR in the prior tumor did not appear to be a predictive marker for Gefitinib sensitivity. Furthermore, long-term drug use was well tolerated in mice without inducing resistance. However, tumors started to grow again after treatment interruption. Laboratory findings and in vivo data have prompted the evaluation of Gefitinib administered as a single oral daily dose alone or in combination with conventional anticancer treatment.
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PMID:[Preclinical and clinical results with the epidermal growth factor receptor inhibitor Gefitinib (ZD1839, Iressa)]. 1528 51

Treatment of solid tumors with chemotherapy regimens commonly is associated with debilitating or life-threatening side effects. Careful patient management, appropriate and prompt management of side effects, and interruption of therapy frequently are required for patients receiving chemotherapy. Furthermore, the systemic toxicity associated with chemotherapy may result in irreversible and incapacitating side effects, such as peripheral neuropathy, that lead to poor quality of life in patients. Gefitinib (Iressa, ZD1839, AstraZeneca Pharmaceuticals LP, Wilmington, DE) is a biologically based, molecular targeted therapy with a novel mechanism of action: selective inhibition of the epidermal growth factor receptortyrosine kinase (EGFR-TK) activity. Once-daily oral treatment with gefitinib is well tolerated. In clinical trials, treatment with gefitinib resulted in durable tumor responses and improvement in lung cancer-related symptoms in patients with advanced non-small cell lung cancer who had received prior chemotherapy. Trials are under way to explore the full potential of gefitinib and additional EGFR-TK inhibitors for other solid tumors and in other treatment settings, including prevention. Biologically based, molecular-targeted therapies such as gefitinib are providing new treatment options for patients and adding a new dimension to clinical practice for oncology nurses.
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PMID:New directions in oncology nursing care: focus on gefitinib in patients with lung cancer. 1535 25

GW572016 (Lapatinib) is a tyrosine kinase inhibitor in clinical development for cancer that is a potent dual inhibitor of epidermal growth factor receptor (EGFR, ErbB-1) and ErbB-2. We determined the crystal structure of EGFR bound to GW572016. The compound is bound to an inactive-like conformation of EGFR that is very different from the active-like structure bound by the selective EGFR inhibitor OSI-774 (Tarceva) described previously. Surprisingly, we found that GW572016 has a very slow off-rate from the purified intracellular domains of EGFR and ErbB-2 compared with OSI-774 and another EGFR selective inhibitor, ZD-1839 (Iressa). 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.
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PMID:A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. 1537 80


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