Screening for and identification of novel agents directed at renal cell carcinoma

We were interested in identifying novel agents for renal cell carcinoma (RC C) by screening for activities that model renal tumor biology, Searching fo r relative renal cell sensitivity and leukemia insensitivity among cytotoxi city profiles in the NCI Drug Screen database, we identified 16 potential a gents with renal selectivity. We evaluated the agents in 10 RCC cell lines (of primary and metastatic origin) isolated from 5 patients. The 50% inhibi tory concentrations (IC,,) in these cell lines ranged from 0.019 +/- 0.013 to 11.4 +/- 0.55 muM and were comparable with values obtained with renal ce ll lines in the NCI Drug Screen panel. Because RCC are slowly growing tumor s, we evaluated the compounds on rapidly (27% S phase) or slowly (6% S phas e) growing cells. In contrast to doxorubicin, where cytotoxicity was restri cted to rapidly proliferating cells, three compounds (NSC 280074, 281613, a nd 281817) were more cytotoxic in slowly proliferating cells. NSC 72151 and 268965 were equitoxic for both populations. NSC 94889, 638850, and 630938 were more cytotoxic in rapidly growing cells. In irt vitro time exposure st udies, four compounds, NSC 268965, 280074, 281613, and 281817, were maximal ly cytotoxic with as little as 3 h exposure time. From an analysis comparin g the p53 genotype of the 60 cell lines of the National Cancer Institute (N CI) Drug Screen with the cytotoxicity profiles for the 16 putative renal co mpounds, 13 compounds were classified as likely to be indifferent to p53 st atus. We also developed a panel specificity detection method for the NCI Dr ug Screen database to evaluate the. prevalence of renal sensitive compounds . Of the 16 studied compounds, 14 were among those identified as renal sens itive by the statistical analysis, Lastly, we found reduced tumor growth in mice with established renal human tumor xenografts after treatment with tw o of the renal active compounds, These studies describe compounds with pote ntial renal activity that are candidates for preclinical development for re nal cell carcinoma.