Tuesday November 24 2009 | Biotechnology feed | All feeds
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Tuesday November 24 2009 | Biotechnology feed | All feeds
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ET(A) receptor antagonists as anti-cancer agents Endothelin-1 (ET-1) is a 21 amino acid peptide with vasoconstrictor, positive inotropic, mitogenic, and metabolic properties. In numerous disease states, including congestive heart failure, obesity, and diabetes, elevated levels of ET-1 have been reported and are thought to contribute to the pathology of the disease. At least 13 antagonists of the ET(A) ET-1 receptor have been developed. This represents a mature field with all products being in clinical development or on the market. Lead indications are in general hypertension and/or heart failure. ET-1 is also present at high concentrations in ovarian cancer ascites and is overexpressed in primary and metastatic ovarian carcinomas. In these tumors the presence of ET-1 is associated with enhanced neovascularization and with vascular endothelial growth factor (VEGF) expression. Furthermore, in these tumor cells, ET-1 as an autocrine growth factor and both effects are mediated via ET(A) receptors. Italian researchers have recently investigated the effects of the ET(A)-selective antagonist ABT-627 on the ET-1-induced mitogenic effect in both primary cultures and cell lines of ovarian carcinoma. All tumor cells were found to express the components of the ET-1 system and secrete ET-1. ET(A) blockade by ABT-627 was found to inhibit ET-1-induced mitogenic effects. The ET(B) antagonist BQ-788 was ineffective although all cell lines express both ET(A) and ET(B) mRNAs. Recent data from a multinational Phase II trials in 419 advanced prostate cancer patients, demonstrated that ABT-627 stabilized prostate cancer metastasis to the bone. In a subset of 244 patients, atrasentan delayed disease progression by 69 days. Likewise Yamanouchi's YM-598 is also in development for prostate cancer. The present data confirm that ET(A) receptor antagonists may be of use in the treatment of ovarian cancer and supports ABT-627 as a therapeutic candidate for this disease. Entry date October, 2002 Adapted from Salani et al, Clin Sci (Lond) 2002 Sep 1;103 Suppl 1:318S-21S
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