Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although cytotoxic chemotherapy has had a significant impact on the treatment of some malignancies, its impact against most solid tumors is limited. This is especially true in the case of non-small cell lung cancer (NSCLC) in which about 90% of patients ultimately die from metastatic disease. Although chemotherapy has produced modest improvements in response rates and survival in a subset of patients with advanced NSCLC, its primary objective remains to provide palliation of disabling disease-related symptoms. It is hoped that the introduction of new, rationally designed anticancer agents, with greater specificity and less toxicity, will improve the outcome for patients with a range of tumor types, including NSCLC. ZD1839 (Iressa) is the first of a new class of epidermal growth factor receptor tyrosine kinase inhibitors. The results of two large phase II trials have shown that ZD1839 provides clinically significant symptom relief for many patients with extensively pretreated advanced NSCLC. Moreover, this improvement in disease-related symptoms correlated with improved survival and tumor response. ZD1839 also had an acceptable tolerability profile: most drug-related adverse events were mild and reversible and quite different from those typically associated with cytotoxic agents. Some patients also experienced improved quality of life, particularly those with a partial response or stable disease. Thus, ZD1839 offers a new treatment option providing meaningful symptom relief for many patients with advanced NSCLC.
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PMID:ZD1839 (Iressa): what's in it for the patient? 1220 85

Iressa (ZD1839) is a p.o.-active, selective, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that blocks signal transduction pathways implicated in cancer cell proliferation, survival, and host-dependent processes promoting cancer growth. EGFR is up-regulated in primary malignant tumors of the central nervous system (CNS) and in many systemic tumors that metastasize to the CNS. The purpose of our study was to evaluate the efficacy and toxicity of p.o.-administered ZD1839 for the treatment of established intracerebral (i.c.) tumors expressing EGFR or the tumorigenic mutated variant EGFRvIII, which is constitutively phosphorylated. Oral administration of ZD1839 at 50 or 100 mg/kg/day for 3 weeks in athymic mice with established i.c. A431 human epidermoid carcinoma expressing EGFR increased median survival by 88% (P = 0.009) and 105% (P < 0.001), respectively. Additionally, there was no evidence of systemic or CNS toxicity. However, ZD1839 failed to inhibit either s.c. or i.c. in vivo tumor growth when tumorigenicity was conferred by EGFRvIII. Western blotting revealed that treatment with ZD1839 virtually ablated phosphorylation of EGFR Tyr-1173 in A431 tumors. However, treatment of NR6M tumors with ZD1839 only partially decreased phosphorylation of EGFRvIII Tyr-1173 while up-regulating overall expression, suggesting that EGFRvIII may not be susceptible to the same molecular mechanisms of tyrosine kinase inhibition as EGFR. In conclusion, ZD1839 is active in a brain tumor model expressing EGFR, but not EGFRvIII, as EGFR mutations may lead to relative therapeutic resistance. On the basis of these observations, we believe that clinical trials of ZD1839 against brain tumors expressing EGFR are warranted, but that special consideration should be given to tumors that coexpress EGFRvIII.
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PMID:Brain tumors in mice are susceptible to blockade of epidermal growth factor receptor (EGFR) with the oral, specific, EGFR-tyrosine kinase inhibitor ZD1839 (iressa). 1242 40

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

BACKGROUND: Bronchorrhea is one of late complaints in patients with bronchioloalveolar carcinoma (BAC) and hampers their quality of life. Although an effective treatment for bronchorrhea in these patients has not been established, recently we have treated effectively one case of persistent bronchorrhea associated with clinical recurrent BAC with gefitinib (ZD1839, 'Iressa trade mark '; AstraZeneca Japan; Osaka, Japan). CASE PRESENTATION: A 63-year-old Japanese female had undergone left pneumonectomy with radical lymph node dissection (ND2a) for diffuse type bronchioloalveolar carcinoma originated in left lower lobe. Multiple pulmonary metastases in right lung were found one year after operation. Pulmonary metastatic lesion has grown and she complained of progressive symptoms of massive watery sputum and dyspnea, four years after operation. Although her symptom was getting worse in spite of routine treatment, it completely disappeared within 2 weeks of starting oral gefitinib. Thereafter, she has been symptom-free and shows good partial response on repeat scan after 9 months of oral gefitinib. CONCLUSIONS: The dramatic remission of persistent bronchorrhea by gefitinib in the presented case suggests that gefitinib might be a promising option for bronchioloalveolar carcinoma, particularly in cases with severe bronchorrhea. Although it is not possible to comment on whether the improvement came from tumor cell death itself or suppressive effect of mucin synthesis by the epidermal growth factor receptor-tyrosine kinase inhibitory action.
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PMID:Successful treatment of persistent bronchorrhea by gefitinib in a case with Recurrent Bronchioloalveolar Carcinoma: a case report. 1291 17

High expression of epidermal growth factor receptor (EGFR) is frequently observed in many solid tumor types including oral squamous cell carcinomas (OSCC). This study investigated whether treatment with gefitinib ('Iressa'), an EGFR-tyrosine kinase inhibitor, would inhibit the metastatic spread in OSCC cells. This was evaluated using orthotopic xenografts of highly metastatic OSCC. Metastasis was observed in six of 13 gefitinib treated animals (46.2%), compared with all of 12 control animals (100%). After exposure to gefitinib, OSCC cells showed a marked reduction in cell adhesion ability to fibronectin and in the expression of integrin alpha3, alphav, beta1, beta4, beta5 and beta6.
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PMID:Gefitinib ('Iressa'), an epidermal growth factor receptor tyrosine kinase inhibitor, mediates the inhibition of lymph node metastasis in oral cancer cells. 1460 28

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

Despite new therapies and several treatment options, metastatic breast cancer (MBC) remains incurable. One reason for the low median survival rate may be intense cross-talk between growth factor receptors such as the epidermal growth factor receptor (EGFR/HER1) and the HER2 growth factor receptor. This report describes the case history of a patient with MBC whose disease had progressed despite surgery, radiotherapy and four different chemotherapy regimens, including trastuzumab (a monoclonal antibody that specifically blocks HER2) combined with docetaxel. However, treatment with 500 mg/day gefitinib ('Iressa', ZD1839), an EGFR tyrosine kinase inhibitor, and trastuzumab (2 mg/kg/week) caused a rapid and sustained regression of breast cancer metastases in skin and lymph nodes. Thus, for patients with MBC whose tumors co-express EGFR and HER2, gefitinib in combination with trastuzumab may prevent receptor cross-talk, improving the outcome of MBC.
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PMID:Induction of remission in a patient with metastatic breast cancer refractory to trastuzumab and chemotherapy following treatment with gefitinib ('Iressa', ZD1839). 1501 56

Despite an initial response to antihormonal therapies, the development of resistance will occur in a significant number of breast cancer patients. The mechanisms that underlie acquired resistance are not yet clear. Using a previously established in vitro cell model of tamoxifen resistance in MCF7 cells, shown to display autocrine epidermal growth factor receptor (EGFR) signalling, we assessed how resistance might modulate their metastatic phenotype in vitro, as metastatic disease is the single most important factor affecting the mortality of cancer patients. Furthermore, we investigated the effect of the EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib ('Iressa', ZD1839; AstraZeneca), on this behaviour. The acquisition of tamoxifen resistance in MCF7 cells was accompanied by a dramatic and significant increase in their invasive and motile nature. The affinity of these cells for matrix components was also enhanced. Inhibition of EGFR signalling with gefitinib reduced both basal and TGF-alpha-stimulated invasion and motility and reduced cell-matrix adhesion. In conclusion, we demonstrate here that resistance to tamoxifen in breast cancer cells is accompanied by a significant increase in their basal motile and invasive activity, properties associated with increased metastatic potential. Inhibition of EGFR signalling by gefitinib significantly inhibited cell motility and invasion thus suggesting a role for the EGF receptor in the aggressive phenotype of tamoxifen-resistant breast cancer cells.
Clin Exp Metastasis 2004
PMID:Tamoxifen resistance in breast cancer cells is accompanied by an enhanced motile and invasive phenotype: inhibition by gefitinib ('Iressa', ZD1839). 1538 70

Prognosis and survival of patients with hepatocellular carcinoma (HCC) is still very poor, and no therapies are currently available to inhibit tumour growth and metastases. Recently, we reported that the expression of an extracellular matrix component (ECM), namely Laminin-5 (Ln-5), is directly related to poor prognosis in HCC patients. The aim of our study is to investigate the preclinical effect of gefitinib in an in vitro HCC model. We found that the IC(50) of gefitinib in HCC cells ranged from 0.7 to 10.0 muM, whereas Ln-5 inhibited the activity of gefitinib in a dose-dependent manner. Complete inhibition of phosphorylated (p)-EGFR (epidermal growth factor receptor) was obtained within 6 h exposure to gefitinib and complete restoration of the receptor status was obtained after 24 h. A downstream effect yields a decrease in p-Akt and p-Erk 1/2. The addition of exogenous Ln-5 has no effect on p-EGFR, whereas it restores p-Erk 1/2 and p-Akt. Consistently, Ln-5 induces recovery of HCC cells from Gefitinib-induced apoptosis. In conclusion, gefitinib inhibits HCC cell growth and we report for the first time that Ln-5, but not other ECM molecules, reduces the ability of gefitinib to inhibit cell growth via Akt. As patients with HCC have different Ln-5 expression levels, these results may help to better understand which patients might benefit from gefitinib treatment.
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PMID:Laminin-5 offsets the efficacy of gefitinib ('Iressa') in hepatocellular carcinoma cells. 1554 72

This report highlights the case of a symptomatic 77-year-old non-smoking female patient who was diagnosed with advanced non-small-cell lung cancer (NSCLC), metastatic to the liver and contralateral lung. After tumor progression in the liver and lung following polychemotherapy, multiple diffuse brain and cerebellar metastases were apparent. Oral treatment with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa') 250 mg/day resulted in progressive and durable symptom relief, and improvements in quality of life and performance status. Reductions in the size of the primary pulmonary tumor and brain, cerebellar, and liver metastases were observed. Furthermore, gefitinib was well tolerated with an absence of adverse events. These results provide evidence that oral gefitinib is active in patients with advanced NSCLC and central nervous system metastases.
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PMID:Gefitinib ('Iressa', ZD1839) is active against brain metastases in a 77 year old patient. 1573 17


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