Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drug-associated interstitial lung disease (ILD) is not uncommon, with diverse patterns ranging from benign infiltrates to the potentially fatal acute respiratory distress syndrome. As acute respiratory failure due to drug-associated ILD has an unpredictable onset and rapid time course, establishing a diagnosis is often difficult. An accurate diagnosis is based on clinical, radiological (including high-resolution computed tomography) and histological manifestations, although is often only possible by exclusion. Cancer chemotherapy is commonly associated with acute disease that, on pathology, is often diffuse alveolar damage. Furthermore, a combination of drugs with or without radiotherapy can increase the risk of ILD. This article reviews treatments for non-small-cell lung cancer (NSCLC) that are associated with the development of ILD and how systematic evaluation of the possible role of these drugs in ILD is warranted. A difference between Japan and the rest of the world in reporting rates of ILD when gefitinib ('Iressa') has been used in advanced NSCLC is also discussed. However, the difference remains unexplained, leaving important epidemiological and mechanistic questions.
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PMID:Interstitial lung disease associated with drug therapy. 1534 Mar 74

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

Gefitinib (Iressa), the first commercially available epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitor, is indicated in the management of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). However, approved uses differ between countries; in most markets, gefitinib is approved for third-line use only (e.g. the US, Canada and Switzerland), although in some it is approved for both second- and third-line use (e.g. Japan and Australia) and, additionally, in patients considered unsuitable for chemotherapy (e.g. Indonesia and the Philippines). Few third-line treatment options exist for patients with inoperable advanced NSCLC who have failed both platinum-based and docetaxel chemotherapies. Gefitinib represents a significant advance in the treatment of this population; a once-daily, oral dosage of 250 mg/day was well tolerated, produced objective tumour responses and disease stabilisation, and improved disease-related symptoms and quality of life. It also produced overall survival outcomes that compared favourably with historical outcomes in a similar group of patients treated with three or four different chemotherapy regimens. These findings have been supported by observations from a global compassionate-use programme. Ongoing or planned clinical trials are designed to confirm and/or further define the role of the drug in the above and other clinical settings.
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PMID:Gefitinib: a review of its use in the management of advanced non-small-cell lung cancer. 1548 4

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) have recently been described in patients with non-small-cell lung cancer (NSCLC) who achieve radiographic regressions to the EGFR inhibitor gefitinib. One of these mutations, L858R (Leu-->Arg), is also found in NSCLC cell line H3255, which is very sensitive to gefitinib treatment. We characterized nine NSCLC cell lines (three isolated from patients with bronchioloalveolar carcinoma and six isolated from patients with adenocarcinoma) for their in vitro sensitivity to gefitinib. Of these, only H3255 (EGFR(L858R)) and H1666 (EGFR(WT)) are sensitive to gefitinib with IC(50) values of 40 nmol/L and 2 micromol/L, respectively. We examined the effects of gefitinib on H3255 and cell lines containing wild-type EGFR that are either sensitive (H1666) or resistant (A549 and H441) to gefitinib exposure in vitro. Gefitinib treatment (1 micromol/L) leads to significant apoptosis accompanied by increased poly(ADP-ribose) polymerase cleavage only in the H3255 cell line, leads to G(1)-S arrest in H1666, and has no effects in the A549 and H441 cell lines. Although EGFR and AKT are constitutively phosphorylated in H3255, H1666, and H441 cell lines, AKT is completely inhibited by gefitinib treatment only in the H3255 cell line. These findings further characterize a mechanism by which gefitinib treatment of NSCLC harboring EGFR(L858R) leads to a dramatic response to gefitinib.
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PMID:Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. 1549 41

Gefitinib (Iressa, ZD1839), an inhibitor of epidermal growth factor receptor-tyrosine kinase, has shown potent anti-tumor effects and improved symptoms and quality-of-life of a subset of patients with advanced non-small cell lung cancer (NSCLC). However, a large portion of the patients showed no effect to this agent. To establish a method to predict the response of NSCLC patients to gefitinib, we used a genome-wide cDNA microarray to analyze 33 biopsy samples of advanced NSCLC from patients who had been treated with an identical protocol of second to seventh line gefitinib monotherapy. We identified 51 genes whose expression differed significantly between seven responders and 10 non-responders to the drug. We selected the 12 genes that showed the most significant differences to establish a numerical scoring system (GRS, gefitinib response score), for predicting response to gefitinib treatment. The GRS system clearly separated the two groups without any overlap, and accurately predicted responses to the drug in 16 additional NSCLC cases. The system was further validated by the semi-quantitative RT-PCR, immunohistochemistry and ELISA for serological test. Moreover, we proved that the anti-apoptotic activity of amphiregulin, a protein that was significantly over-expressed in non-responders but undetectable in responders, leads to resistance of NSCLC cells to gefitinib in vitro. Our results suggested that sensitivity of a given NSCLC to gefitinib can be predicted according to expression levels of a defined set of genes that may biologically affect drug sensitivity and survival of lung cancer cells. Our scoring system might eventually lead to achievement of personalized therapy for NSCLC patients.
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PMID:Prediction of sensitivity of advanced non-small cell lung cancers to gefitinib (Iressa, ZD1839). 1549 27

(1) Platinum-based chemotherapy is generally used to treat advanced-stage non small-cell lung cancer (stages III and IV), but has only a modest impact on survival. There is no reference treatment. (2) Gefitinib inhibits the tyrosine kinase activity of the receptor for EGF (epidermal growth factor), which is thought to be involved in tumour growth. It has a temporary licence in France and is used on a named-patient basis, but full marketing authorisation has already been granted in Japan, the United States, and elsewhere. (3) Two double-blind dose-finding studies compared two doses of oral gefitinib monotherapy (250 mg/day and 500 mg/day) in patients in whom at least two lines of chemotherapy had failed. The results were favourable, with a median survival of 6 months and a symptomatic improvement in some patients, but they are undermined by the absence of a placebo group and by major protocol violations. (4) Two double-blind trials, each in more than 1000 patients, showed that gefitinib does not increase the efficacy of first-line platinum combinations. (5) About 15% of patients receiving gefitinib monotherapy in clinical trials stopped taking the treatment because of adverse events. The most frequent were gastrointestinal (diarrhea, nausea, vomiting) and cutaneous (rash, acne, dry skin, pruritus). (6) Interstitial pneumonitis occurred in about 1% of patients, and was fatal in about one-third of cases. (7) Gefitinib is metabolised by the cytochrome P450 isoenzyme CYP3A4, so carries a potentially high risk of interactions. (8) In practice, more thorough assessment of gefitinib is needed to determine whether this new drug is beneficial for patients with non small-cell lung cancer. Marketing authorisation is not currently justified.
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PMID:Gefitinib: new preparation. Non small-cell lung cancer: stricter assessment needed. 1549 96

Combination chemotherapy has been established as the cornerstone of systemic treatment for advanced lung cancer in the last ten to fifteen years. However, improvements with new drug combinations in recent years have been rather small and a general outcome plateau has been reached with one-year survival rates of about 40% and two-year survival rates of less than 15%. Survival over three to four years is still a rare event in this disease, and more and more efforts are being made to develop innovative systemic treatment strategies with mechanisms of action different from conventional cytotoxic drugs. These molecular targeted agents have made a strong move forward in the management of this disease since Gefitinib--a small molecule EGF-receptor tyrosine kinase inhibitor--was registered in 2003 by the FDA and a number of further countries for the third-line treatment of non-small-cell lung cancer. Since then, every month findings have been reported about new cellular targets on lung-cancer cells and, consequently, new agents aiming at these molecular targets are being developed, preclinically. Some of these agents have already been tested in the clinics within phase-I, phase-II and some even within randomised phase-III trials. In this review we will try to summarise the current knowledge and data on the clinical activity of these new drugs in lung cancer and to give a perspective on the future for these new treatment principles. The most promising strategies have been aiming at the EGF-receptor family, serum-VEGF and the VEGF-receptor family (VEGF-1 and -2, respectively). Results from pivotal registration trials are expected within the next one or two years for a number of these new drugs, and the standards of care for advanced lung cancer may change dramatically, comparable to what we have seen in other solid tumours such as metastasised breast and colon cancer.
Lung Cancer 2004 Aug
PMID:New targeted treatments in lung cancer--overview of clinical trials. 1555

Cytotoxic chemotherapy treatment options for patients with non-small-cell lung cancer (NSCLC) have limited efficacy and are often associated with significant toxicity. Therefore, there is an unmet need for novel drugs that are not only effective in treating this disease but are also well tolerated. Gefitinib is an orally active epidermal growth factor receptor tyrosine kinase inhibitor that blocks the signal transduction pathways implicated in cancer cell growth and survival. It has recently been approved for the treatment of advanced/refractory NSCLC. This review presents the tolerability data from phase I and II gefitinib monotherapy trials, along with data from the worldwide 'Expanded Access Programme' and post-marketing use of gefitinib. Gefitinib was found to be generally well tolerated at the approved dosage of 250 mg/day; the most commonly reported adverse drug reactions (ADRs) were mild to moderate skin rash and diarrhoea, which were manageable and non-cumulative. Other ADRs observed with the use of gefitinib included: dry skin, pruritus, acne, nausea, vomiting, anorexia, asthenia and asymptomatic elevations in liver transaminase levels. Well recognised adverse effects seen with cytotoxic chemotherapy (such as bone marrow depression, neurotoxicity and nephrotoxicity) were not observed. Although the frequency and severity of ADRs increased with the dosage across the range studied (50-1000 mg/day), few patients required dosage reductions or the withdrawal of treatment, and those who did usually received gefitinib >or=600 mg/day.Thus, the available data indicate that gefitinib is well tolerated in patients with a range of solid tumours, including locally advanced or metastatic NSCLC.
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PMID:Overview of the tolerability of gefitinib (IRESSA) monotherapy : clinical experience in non-small-cell lung cancer. 1555 44

Twenty years after the epidermal growth factor receptor (EGFR) was identified as a potential anticancer target, the EGFR inhibitor gefitinib (Iressa; AstraZeneca) has been approved for the treatment of patients with advanced non-small-cell lung cancer in many countries. Studies have indicated its potential for treating patients with other types of solid tumours. Investigation of gefitinib has not only increased our knowledge about the biology of EGFR signalling, but is contributing to our evolving understanding of which tumours are EGFR dependent.
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PMID:Gefitinib--a novel targeted approach to treating cancer. 1557 17

Recent advances in cancer therapy have resulted in the development of drugs that target mechanisms involved in neoplastic change and angiogenesis. One example is gefitinib ('Iressa', ZD1839), an orally-active epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that blocks EGFR signaling in vitro, thereby inhibiting the growth, proliferation and survival of many solid tumors. Clinical trial data show that gefitinib monotherapy is generally well tolerated in patients with a wide range of tumor types (including lung, head and neck, colon, breast, and prostate cancers). The most common adverse events (AEs) were mild and reversible skin and gastrointestinal disorders (National Cancer Institute common toxicity criteria grade 1/2). Few drug-related grade 3/4 skin and gastrointestinal disorders were observed, and drug-related hematologic AEs were uncommon. The clinical benefit of gefitinib in non-small-cell lung cancer (NSCLC), head and neck, colon, breast, and prostate cancer is being investigated, as antitumor activity has been observed in a range of solid tumors, including NSCLC. In two large phase II NSCLC trials (IDEAL ['Iressa' Dose Evaluation in Advanced Lung Cancer] 1 and 2) objective tumor responses of 18.4% and 11.8%, and disease control rates (complete and partial responses plus stable disease) of 54.4% and 42.2%, respectively, were seen in patients given 250 mg/day gefitinib. Additionally, disease-related symptoms improved in 40.3% and 43.1% of patients, and improved quality of life was experienced by 23.9% and 34.3% patients in IDEAL 1 and 2, respectively. Furthermore, the majority of patients who had an objective response also experienced symptom improvement. Gefitinib has been approved for the treatment of advanced NSCLC in Japan, the USA, and other countries. This review discusses the potential of gefitinib in a wide range of solid tumors. 'Iressa' is a trademark of the AstraZeneca group of companies.
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PMID:Gefitinib (Iressa, ZD1839): a novel targeted approach for the treatment of solid tumors. 1558 98


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