Screening for and identification of novel agents directed at renal cell carcinoma.
We were interested in identifying novel agents for renal cell carcinoma (RCC) by screening for activities that model renal tumor biology. Searching for relative renal cell sensitivity and leukemia insensitivity among cytotoxicity profiles in the NCI Drug Screen database, we identified 16 potential agents with renal selectivity. We evaluated the agents in 10 RCC cell lines (of primary and metastatic origin) isolated from 5 patients. The 50% inhibitory concentrations (IC50) in these cell lines ranged from 0.019 +/- 0.013 to 11.4 +/- 0.55 microM and were comparable with values obtained with renal cell lines in the NCI Drug Screen panel. Because RCC are slowly growing tumors, we evaluated the compounds on rapidly (27% S phase) or slowly (6% S phase) growing cells. In contrast to doxorubicin, where cytotoxicity was restricted to rapidly proliferating cells, three compounds (NSC 280074, 281613, and 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 in vitro time exposure studies, four compounds, NSC 268965, 280074, 281613, and 281817, were maximally cytotoxic with as little as 3 h exposure time. From an analysis comparing the p53 genotype of the 60 cell lines of the National Cancer Institute (NCI) Drug Screen with the cytotoxicity profiles for the 16 putative renal compounds, 13 compounds were classified as likely to be indifferent to p53 status. We also developed a panel specificity detection method for the NCI Drug Screen database to evaluate the prevalence of renal sensitive compounds. Of the 16 studied compounds, 14 were among those identified as renal sensitive by the statistical analysis. Lastly, we found reduced tumor growth in mice with established renal human tumor xenografts after treatment with two of the renal active compounds. These studies describe compounds with potential renal activity that are candidates for preclinical development for renal cell carcinoma.
Mertins
S D
SD
Medicine Branch, National Cancer Institute, Bethesda, Maryland 20892, USA. smertins@box-s.nih.gov
Myers
T G
TG
Hollingshead
M
M
Dykes
D
D
Bodde
E
E
Tsai
P
P
Jefferis
C A
CA
Gupta
R
R
Linehan
W M
WM
Alley
M
M
Bates
S E
SE
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D016158:Genes, p53 / Q000235:genetics; D005838:Genotype; D006801:Humans; D020128:Inhibitory Concentration 50; D007680:Kidney Neoplasms / Q000188:drug therapy*; D007938:Leukemia / Q000188:drug therapy; D020714:Maximum Tolerated Dose; D051379:Mice; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D013997:Time Factors; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001973:Bromodeoxyuridine