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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Improved understanding of tumor biology has led to the identification of numerous growth factors that are involved in malignant transformation and tumor progression. Many of these factors induce cellular responses through receptors with intrinsic tyrosine kinase (TK) activity. Therefore, inhibiting the activity of TK receptors is one of the ways to effectively block the disordered proliferation of cancer that arises from these pathways. The human epidermal growth factor receptor (HER) family is overexpressed or dysfunctional in many human malignancies. Therefore, these receptors have been identified as targets for cancer therapy. Several agents have been developed that reversibly or irreversibly inhibit one, two, or all of the HER receptors. Iressa and Tarceva are HER1-specific TK inhibitors that are in advanced development. The large phase II study of Iressa (IDEAL1) in patients with non-small-cell lung cancer (NSCLC) in whom previous platinum-based therapy has failed, found that the median survival time (MST) was 7.6 months, which was no less than that with Docetaxel treatment. Other dual or pan-HER, reversible or irreversible, TK inhibitors are being investigated in phase I trials. Early data show that they are generally well tolerated and have provided evidence of against activity tumors. HER-TK inhibitors are likely to have a substantial impact on the treatment of cancer patients.
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PMID:Molecular target-based cancer therapy: tyrosine kinase inhibitors. 1295 75

ZD1839 ('Iressa') is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that inhibits EGFR signaling. Emerging evidence indicates that ZD1839 has clinical potential in lung cancer, but very little is known about the molecular characteristics of lung cancers that may determine sensitivity to ZD1839. We examined a panel of 19 lung cancer cell lines to investigate possible association between ZD1839 sensitivity and histological type, expression level and constitutive phosphorylation of EGFR and K-ras gene status. Our results indicate that neither expression level nor constitutive activation status of EGFR seems to predict sensitivity to ZD1839. In addition, ZD1839 sensitivity was not associated with expression of human epidermal growth factor receptor-2 (HER-2), another member of this tyrosine kinase receptor family nor with co-expression of EGFR and HER-2. Finally, no correlation was found between the presence of activating mutations of the K-ras gene, an important downstream mediator of the EGFR-transduced signals and the relative resistance to ZD1839. These findings warrant future study to clarify how ZD1839 inhibits lung cancer cell growth and to find a useful marker for prediction of sensitivity to this novel and promising agent for the treatment of lung cancers.
Lung Cancer 2003 Oct
PMID:The sensitivity of lung cancer cell lines to the EGFR-selective tyrosine kinase inhibitor ZD1839 ('Iressa') is not related to the expression of EGFR or HER-2 or to K-ras gene status. 1451 85

Gefitinib (ZD1839, Iressa ), a selective inhibitor of the epidermal growth factor receptor-tyrosine kinase, is currently in clinical trials to treat a variety of solid tumors. Similar side effects were seen in numerous clinical trials of gefitinib, including recent phase II trials (Iressa Dose Evaluation in Advanced Lung Cancer [IDEAL]-1 and IDEAL-2) in patients with advanced, previously treated non-small-cell lung cancer (NSCLC). The most frequent drug-related adverse effects reported in these trials were diarrhea, dry skin, acneiform rash, and nausea and vomiting. Recently, IDEAL-2 investigators and oncology nurses participated in a panel discussion on the management of dermatologic adverse effects associated with gefitinib treatment. These dermatologic effects were related to the mechanism of action of gefitinib and were not caused by a drug-related allergic reaction. In IDEAL-2, investigators managed the symptoms of dry skin and rash with a variety of treatments, including topical clindamycin, antibiotics, and corticosteroids. Most patients had a high level of tolerance for the dermatologic effects associated with gefitinib, which were milder than toxicities associated with chemotherapy. The severity of skin effects cycled over time during treatment but typically subsided after several weeks of gefitinib treatment. In general, dermatologic effects of gefitinib were easily managed, reversible, and well tolerated by these patients with advanced NSCLC.
Clin Lung Cancer 2003 May
PMID:Dermatologic side effects associated with gefitinib therapy: clinical experience and management. 1459 2

The ErbB family of receptor tyrosine kinases, of which the epidermal growth factor receptor (EGFR) is the prototype, is associated with the formation and malignant progression of most of the common solid tumors. These molecules play a key role in a complex network of signal transduction pathways that function in normal development as well as in neoplastic transformation. The EGFR and other family members are therefore promising targets for new anticancer therapies. In normal tissues, EGFR-tyrosine kinase (TK) activity is strictly controlled. However, in tumor cells, there are multiple mechanisms that can lead to increased or inappropriate EGFR-TK activity, including altered expression of EGFR, its ligand, or interacting molecules; decreased deactivation through phosphatases or downregulation; or mutation of the EGFR protein. Novel therapeutic approaches aimed at inhibiting increased EGFR-TK activity include antibodies that block the extracellular ligand-binding site, antibody or ligand fusion proteins that specifically target toxins to the tumor cells, or small-molecule TK inhibitors (TKIs) that act intracellularly to block downstream signal transduction from EGFR. Studies have shown that such blockade can lead to reduced cellular proliferation, inhibition of survival signals, and inhibition of tumor metastasis and angiogenesis. Additionally, some agents, including EGFR antibodies and TKIs such as gefitinib have been demonstrated to be effective against various human solid tumors in preclinical models and have shown activity in advanced non-small-cell lung cancer and other solid tumors.
Clin Lung Cancer 2003 Sep
PMID:The impact of gefitinib on epidermal growth factor receptor signaling pathways in cancer. 1464 88

The epidermal growth factor receptor (EGFR) has emerged in recent years as a key target of molecular therapy for solid tumors. The postembryonic role of EGFR is normally limited. In cancer, however, abnormal EGFR-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 EGFR-mediated activity in tumor cells, including monoclonal antibodies directed at the ligand-binding portion of the EGFR and small-molecule agents that directly inhibit the intracellular TK domain of EGFR. Two of these TK inhibitors, gefitinib and erlotinib (OSI-774, 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
Clin Lung Cancer 2003 Sep
PMID:Biologically targeted treatment of non-small-cell lung cancer: focus on epidermal growth factor receptor. 1464 89

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.
Clin Lung Cancer 2003 Sep
PMID:Pharmacokinetic evaluation of gefitinib when administered with chemotherapy. 1464 90

Although advances in chemotherapy have provided some improvement in overall survival for patients with advanced non-small-cell lung cancer (NSCLC), outcomes remain poor. Several targeted therapies for lung cancer are in development, and it is hoped that these new approaches will continue to improve survival for patients with advanced NSCLC. These new therapies are targeted specifically to the molecular pathways and processes that characterize tumor growth and progression, including uncontrolled cell growth, invasion, metastasis, angiogenesis, and resistance to apoptosis. Some molecules, such as protein kinase C and the epidermal growth factor receptor-tyrosine kinase, play central roles in cellular activity and are involved in many of the different signaling pathways underlying malignant transformation. Other molecules are dedicated to a specific process, such as the role of vascular endothelial growth factor in angiogenesis. New approaches use a variety of technologies to target these molecules, including small-molecule inhibitors, antibodies, and antisense oligonucleotides, among others. Many of these therapies are currently being tested alone or in combination with each other and with standard treatments for a variety of tumors. This article summarizes data on treatment of NSCLC with some of the agents that are the furthest along in clinical development. It is possible to envision a future in which a combination of therapies treat lung cancer on multiple fronts, significantly enhancing tumor responses and improving survival beyond current expectations.
Clin Lung Cancer 2003 Sep
PMID:Molecular targeted agents in non-small-cell lung cancer. 1464 91

Even when diagnosed at the earliest stages, non-small-cell lung cancer (NSCLC) has often begun to metastasize, leading to frequent systemic relapses and a poor prognosis. There is an urgent need for effective adjuvant systemic therapy in conjunction with surgery to reverse or control further growth of micrometastases in early-stage NSCLC. Several approaches have been investigated in the search for such a therapy, including various chemotherapies, applied preoperatively or postoperatively, chemopreventive agents, and molecular-targeted agents. This article presents an overview of clinical trials for these adjunctive therapies, including completed trials and trials whose results are anticipated. Although standard postoperative chemotherapy has been found to offer little benefit, likely because of the acquisition of resistance in advanced tumors, some clinical trials with neoadjuvant or alternative chemotherapies have produced encouraging results. Targeted agents such as the epidermal growth factor receptor/tyrosine kinase inhibitor gefitinib have shown early promise for effective disease control. A combination of these new approaches and standard therapy for NSCLC may improve long-term survival in patients with lung cancer
Clin Lung Cancer 2003 Sep
PMID:Adjuvant systemic therapies in early-stage non-small-cell lung cancer. 1464 92

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.
Clin Lung Cancer 2003 Sep
PMID:Primary and secondary prevention of non-small-cell lung cancer: the SPORE Trials of Lung Cancer Prevention. 1464 93

Chemotherapy is the standard of care for patients with advanced non-small cell lung cancer (NSCLC). Over the past 20 years, advances in chemotherapy have shown minimal incremental improvement in the survival outcomes of patients with advanced NSCLC. With the identification of molecular and genetic alterations in lung cancer, several new potential rationally designed therapeutic targets have emerged. One of these is the epidermal growth factor receptor (EGFR) and member of the ErbB family of receptor tyrosine kinases. Several inhibitors, both antibodies directed at the extra-cellular portion of the receptor, and small molecule inhibitors directed at the tyrosine kinase domain of EGFR are in clinical development in lung cancer. This article will review the pre-clinical rationale and the clinical studies of EGFR inhibitors alone and/or in combination with chemotherapy that have been performed to date in advanced NSCLC.
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PMID:The role of epidermal growth factor receptor in advanced non-small cell lung carcinoma. 1464 27


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