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)

Patients with non-small cell lung cancer (NSCLC) frequently present, or relapse, with unresectable disease that is resistant to standard chemotherapy. There is, therefore, an urgent need for new treatments for NSCLC and other solid tumors. ZD1839 (Iressa; AstraZeneca Pharmaceuticals LP, Wilmington, DE), an orally active, selective epidermal growth factor receptor-tyrosine kinase inhibitor, has shown promising antitumor responses in phase I clinical trials in heavily pretreated patients with advanced NSCLC and other solid tumors. Randomized, multicenter global and US-based clinical trials were conducted to investigate two doses of ZD1839 as second- or third-line monotherapy in patients with advanced NSCLC. The global trial, Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL)-1, was a double-blind, randomized, dose-comparative study that enrolled 210 patients with NSCLC at centers in Europe, Japan, South Africa, and Australia. This trial included patients with advanced unresectable stage III or IV NSCLC who had recurrent or progressive disease following one or two chemotherapy regimens, at least one of which was platinum based. IDEAL-1 showed that once-daily oral treatment with ZD1839 at 250 or 500 mg/day resulted in tumor response rates of 18% and 19%, respectively. Disease control rates, which included both tumor responses and stable disease, were 54% and 51%, respectively. Median progression-free survival was 83 days in the 250 mg/day group and 85 days in the 500 mg/day group. Rapid improvements in NSCLC-related symptoms were seen in the subpopulation of patients who were symptomatic and had completed a Lung Cancer Subscale questionnaire at baseline. Both the 250 mg/day and 500 mg/day doses of ZD1839 were well tolerated by patients in this trial. The majority of adverse events were grades 1 or 2 skin rash and diarrhea, which were readily manageable and reversible, and withdrawals were rare. The US monotherapy study in NSCLC, IDEAL-2, comprised 30 trial centers and enrolled 221 patients with NSCLC for third-line or greater therapy; 216 patients received treatment and were evaluable. This trial included patients with advanced stage III or IV NSCLC who had received two or more chemotherapy regimens that contained platinum and docetaxel, either concurrently or in separate regimens, with most patients having received more than two prior regimens. Although the IDEAL-1 and IDEAL-2 trials were similar in study design, patients in IDEAL-2 were sicker, as evidenced by a higher percentage of patients with a performance status of 2, metastatic disease, and disease-related symptoms. Because measuring the symptom improvement rate was a primary objective in IDEAL-2, all patients were symptomatic and were required to have a Lung Cancer Subscale score of 24 or less at trial entry. Objective tumor response rates (all partial responses) were 12% for the 250 mg/day group and 9% for the 500 mg/day group. Symptom improvement rates (increase of at least two points on the Lung Cancer Subscale) were 43% and 35%, respectively. Both doses of ZD1839 were well tolerated in this trial. The results of IDEAL-1 and IDEAL-2 indicate that ZD1839 monotherapy may offer a single-agent alternative for patients with advanced solid tumors who have received and progressed on prior chemotherapy, many of whom have exhausted their therapy options.
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PMID:Dose-comparative monotherapy trials of ZD1839 in previously treated non-small cell lung cancer patients. 1264 82

The majority of patients with non-small cell lung cancer (NSCLC) present with advanced disease, which is associated with a poor prognosis and symptoms such as pain, coughing, and shortness of breath. In patients who present at an earlier stage, the progressive nature of NSCLC and its resistance to treatment often result in recurrence, with the associated symptoms of advanced disease. These symptoms negatively affect patient quality of life and performance status rating, both of which are predictive of treatment response and survival. There is increasing interest in using assessments of improvements in symptoms and quality of life as outcomes in clinical trials for patients with advanced NSCLC. Patients with NSCLC have limited therapeutic options. Even those patients who are able to tolerate chemotherapy can expect median survival increases of only 2 to 4 months. The new targeted therapies for lung cancer, in contrast, are relatively nontoxic and may provide benefits for symptoms and quality of life in addition to tumor responses. The Functional Assessment of Cancer Therapy-Lung (FACT-L) scale is a validated, sensitive, and reliable patient questionnaire that evaluates and quantifies quality of life across several dimensions, including lung cancer-related symptoms (Lung Cancer Subscale). The Lung Cancer Subscale ranges from 0 (severe debilitation) to 28 (asymptomatic). A change of two points reflects a clinically significant change in NSCLC-related symptoms and quality of life. In phase I studies and also in the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 and IDEAL-2 phase II monotherapy trials, treatment of patients with advanced NSCLC with the epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 (Iressa; AstraZeneca Pharmaceuticals LP, Wilmington, DE) has shown tumor responses as well as rapid improvements in NSCLC-related symptoms and quality of life. In IDEAL-1 and IDEAL-2, improvements in NSCLC-related symptoms and quality of life, as measured by FACT-L, correlated with tumor response, and improvements in symptoms also correlated with progression-free and overall survival. Although symptom response is correlated with tumor response, it is also uniquely predictive of progression-free and overall survival. The FACT-L questionnaire has also been included in phase III trials of ZD1839 treatment in combination with chemotherapy regimens.
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PMID:Impact of ZD1839 on non-small cell lung cancer-related symptoms as measured by the functional assessment of cancer therapy-lung scale. 1264 83

Overexpression of receptor-type tyrosine kinases in various cancers is associated with an aggressive tumor phenotype and poor outcome, but their expression had never been evaluated in large cell neuroendocrine carcinoma (LCNEC) of the lung. In the present study, we investigated the expression of three receptor tyrosine kinases, epidermal growth factor receptor (EGFR), c-erbB-2, and c-kit protein, by comparing surgically resected 40 LCNECs with other neuroendocrine (NE) lung tumors: 9 typical carcinoids (TCs), 5 atypical carcinoids (ACs), and 13 small cell lung carcinomas (SCLCs). None of the NE lung tumors showed expression of EFGR or c-erbB-2, but c-kit was overexpressed in 55% of the LCNEC tumor cells and 46% of the SCLC tumor cells. None of the clinicopathologic factors in either the LCNEC or SCLC patients correlated with c-kit overexpression. The finding that c-kit expression in LCNEC is similar to its expression in SCLC suggests that inhibition of c-kit may be effective as a therapy targeting LCNEC as well as SCLC.
Lung Cancer 2003 May
PMID:Frequent overexpression of the c-kit protein in large cell neuroendocrine carcinoma of the lung. 1271 Nov 18

Cells dividing at the time of carcinogen exposure are at particular risk for neoplasia. Tobacco smoke contains numerous carcinogens, and we find that smoke, in the absence of exogenous growth factors, is capable of stimulating cell proliferation. The smoke-triggered mechanism includes the generation of oxygen radicals, which in turn stimulate tumor necrosis factor alpha-converting enzyme (a disintegrin and metalloproteinase (ADAM) 17) to cleave transmembrane amphiregulin, a ligand for the epidermal growth factor receptor (EGFR). The binding of amphiregulin to EGFR then stimulates proliferation of lung epithelial cells. These results shed light on the pathogenesis of lung cancer, suggest novel drug targets for the reduction of cancer risk in smokers, and provide insight into how EGFR integrates responses to diverse noxious stimuli.
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PMID:Tobacco smoke-induced lung cell proliferation mediated by tumor necrosis factor alpha-converting enzyme and amphiregulin. 1271 7

The 1999 World Health Organization/International Association for the Study of Lung Cancer histological classification of preneoplastic bronchial lesions has been shown to be reproducible but little is known about its biological significance. The current study evaluated the correspondence between the morphological changes of the bronchial epithelium and epidermal growth factor receptor (EGF-R) expression. Thirteen normal bronchial epithelia, 19 hyperplasia, 16 metaplasia, 10 mild dysplasia, one moderate dysplasia, 10 severe dysplasia (SD), 14 carcinoma in situ (CIS) and 11 microinvasive tumours were assessed. A global EGF-R score obtained by the sum of the positivity score plus the EGF-R staining intensity score was calculated for each lesion. A global EGF-R score of >5 was reached only in one metaplasia, in six SD, in six CIS and in six microinvasive tumours. There was no difference in EGF-R expression between normal, hyperplastic and metaplastic epithelia versus mild dysplasia or between severe dysplasia versus CIS and microinvasive tumours but there was a statistically significant difference between mild versus severe dysplasia. This study demonstrates that epidermal growth factor receptor expression rate changes with the stage of the bronchial lesion, increasing from normal epithelium to carcinoma in situ and microinvasive tumours with a statistically significant difference between mild versus severe dysplasia.
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PMID:Epidermal growth factor receptor expression in pre-invasive and early invasive bronchial lesions. 1276 44

ZD1839 is an orally active inhibitor selective for the epidermal growth factor receptor tyrosine kinase and has shown promise in the treatment of non-small cell lung cancer (NSCLC). We now present a case of diffuse alveolar damage (DAD) that developed in a 67-year-old man treated with ZD1839. On day 8 of ZD1839 administration, the patient complained of dyspnea and a new-ground glass opacity was apparent on a chest X-ray and computed tomography scan. Despite high-dose steroid therapy, the patient died 13 days after the first administration of ZD1839. Postmortem analysis of lung tissue revealed a pattern of DAD. No evidence of infection or of other specific etiologies was apparent. This case is the first reported of respiratory failure after ZD1839 treatment in a patient with NSCLC. Physicians should therefore be aware of the potential pulmonary toxicity of ZD1839.
Lung Cancer 2003 Jun
PMID:Diffuse alveolar damage after ZD1839 therapy in a patient with non-small cell lung cancer. 1278 34

To date, no single or multiple molecular markers have been successful in predicting sensitivity of individual patients to anti-cancer drugs. As the nature of a specific cancer is considered to be defined by the proteins being expressed in the tumor cells, systematic analysis of gene-expression profiles may provide information reflecting sensitivity of a given tumor to certain drugs. Recent progress in genome technology has enabled us to examine expression profiles of thousands of genes in a single experiment. We used this approach to examine 13 xenografts of human tumors implanted into nude mice for sensitivity to an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), ZD1839 (Iressa). To identify genes that might be associated with sensitivity to this drug we used a cDNA microarray representing 23,040 genes to analyze expression profiles of the 13 xenografts and identified 114 genes whose expression levels correlated significantly with sensitivity of the tumors to ZD1839. We then investigated alteration of expression profiles in response to the ZD1839 treatment in four non-small cell lung cancer (NSCLC) xenografts, of which two (LC6 and LC11) were sensitive and the other two (Lu116 and L27) were resistant to this EGFR-TKI. Systematic analysis of expression at various time points during oral treatment for 14 days, compared with corresponding untreated samples, identified a set of genes whose expression levels changed in the two sensitive tumors but not in the two resistant tumors. The data obtained here should provide useful information on the molecular mechanism underlying clinical responses to EGFR-TKIs, aid the development of novel therapies for lung cancer, and potentially identify predictive molecular markers for sensitivity to ZD1839.
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PMID:Gene-expression profiles of human tumor xenografts in nude mice treated orally with the EGFR tyrosine kinase inhibitor ZD1839. 1279 73

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 the 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 basis of these data, therapeutics targeting the EGFR were explored in clinical trials. OSI-774 is a small-molecule selective inhibitor of the EGFR tyrosine kinase. In preclinical studies, OSI-774 inhibited the phosphorylation of the EGFR in a dose-dependent and concentration-dependent manner resulting in cell cycle arrest and induction of apoptosis. In in vivo studies, this agent caused tumor growth inhibition and showed synergistic effects when combined with conventional chemotherapy. Subsequent single-agent phase I studies and phase I studies in combination with chemotherapy showed 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 tumors. Preliminary reports from phase II studies confirmed the excellent tolerability of OSI-774 and 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, OSI-774 is a novel inhibitor of the EGFR tyrosine kinase that 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 OSI-774. 1280 92

Bronchioloalveolar carcinoma (BAC), a form of pulmonary adenocarcinoma, presents unique clinical features, such as endobronchial spread and bronchorrhea in advanced stages. The prognosis for BAC patients in advanced stages is poor, as is the case for patients with other non-small-cell lung cancer (NSCLC) types, because of low susceptibility to conventional chemotherapy. Recently, an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI), ZD1839 ("Iressa"), has been investigated in phase II clinical studies (IDEAL 1 and IDEAL 2) as monotherapy against chemotherapy-refractory NSCLC, and provided clinically significant antitumor activity. In this study, we examined the therapeutic efficiency of ZD1839 in chemotherapy-refractory BAC patients with bronchorrhea. Two female BAC patients with bronchorrhea were treated once daily with ZD1839 (250 mg/day). In both cases, serous sputum production was dramatically reduced within 3 days of starting the treatment, and hypoxia and radiographic signs of bilateral lung consolidation were visibly improved within 7 days. Following more than 8 months of treatment, no evidence of recurrence or severe adverse events has been observed. These results suggest that this selective EGFR-TKI, ZD1839, may be a powerful agent for treatment of chemotherapy-refractory BAC patients with bronchorrhea.
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PMID:A report of two bronchioloalveolar carcinoma cases which were rapidly improved by treatment with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 ("Iressa"). 1282 93

Overexpression of receptor tyrosine kinases including the epidermal growth factor receptor (EGF-R) as well as nonreceptor tyrosine kinases, such as Src, have been implicated in the formation of human lung cancers. In addition, cytokines like interleukin-6 (IL-6) have been demonstrated to modulate lung cancer cell growth and elevated levels of IL-6 have been shown to be an adverse prognostic factor for patients with lung cancer. Despite a large body of evidence pointing to their potential importance, few direct studies into the role of signal transducers and activators of transcription (STAT) pathways in human lung cancer have been undertaken. Here we demonstrate that multiple nonsmall cell lung cancer cell lines demonstrate constitutive Stat3 DNA-binding activity. Stat3 DNA-binding activity is specifically upregulated by the addition of epidermal growth factor (EGF), IL-6, and hepatocyte-derived growth factor (HGF). Furthermore, the stimulation of Stat3 DNA-binding activity by EGF requires the activity of EGF-R tyrosine kinase as well as Src-kinase, while the upregulation of Stat3 activity by IL-6 or HGF requires only Src-kinase activity. Treatment of A549 lung cancer cells with PD180970 or SU6656, both pharmacological inhibitors of Src-kinase, resulted in reduced Src and Stat3 activity, cell cycle arrest in G2, and reduced viability of cells accompanied by induction of apoptosis. Treatment of Stat3-positive A549 and H358 cells with antisense Stat3 oligonucleotides results in complete loss of Stat3 DNA-binding activity and apoptosis, while Stat3-positive H1299 cells remained healthy. Finally, an adenoviral vector expressing a dominant-negative Stat3 isoform results in loss of Stat3 DNA-binding activity, apoptosis, and reduced cellular viability. These results demonstrate a role of Stat3 in transducing survival signals downstream of tyrosine kinases such as Src, EGF-R, and c-Met, as well as cytokines such as IL-6, in human nonsmall cell lung cancers.
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PMID:Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. 1283 38


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