Related Experiment Videos
Screening for and identification of novel agents directed at renal cell carcinoma
S D Mertins1, T G Myers, M Hollingshead
1Medicine Branch, National Cancer Institute, Bethesda, Maryland 20892, USA. smertins@box-s.nih.gov
Abstract:
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.
Insights
Researchers identified novel agents for renal cell carcinoma (RCC) by screening for renal selectivity. Some compounds showed greater cytotoxicity in slowly proliferating RCC cells and reduced tumor growth in mice, indicating potential for preclinical development.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Renal cell carcinoma (RCC) is a complex malignancy with a need for novel therapeutic agents.
- Existing drug screening methods may not fully capture the unique biology of renal tumors.
Purpose of the Study:
- To identify novel compounds with selective activity against renal cell carcinoma (RCC).
- To evaluate the efficacy of identified compounds based on tumor growth rate and p53 status.
- To assess the in vivo efficacy of promising compounds in a xenograft model.
Main Methods:
- Screening the NCI Drug Screen database for compounds with relative renal cell sensitivity and leukemia insensitivity.
- Evaluating 16 potential agents in 10 RCC cell lines from primary and metastatic origins.
- Assessing compound cytotoxicity on rapidly and slowly proliferating cells, and conducting in vitro time exposure studies.
- Analyzing compound efficacy in relation to p53 genotype and in vivo tumor xenografts in mice.
Main Results:
- 16 potential renal-selective agents were identified, with IC50 values comparable to existing renal cell lines.
- Three compounds (NSC 280074, 281613, 281817) demonstrated higher cytotoxicity in slowly proliferating RCC cells.
- Four compounds showed maximal cytotoxicity with short exposure times (3 hours).
- 14 of the 16 compounds were identified as renal-sensitive by statistical analysis.
- Reduced tumor growth was observed in mice with human RCC xenografts treated with two of the identified compounds.
Conclusions:
- Novel compounds with potential activity against renal cell carcinoma have been identified.
- Specific agents show promise due to selective cytotoxicity and efficacy in preclinical models.
- These compounds represent promising candidates for further preclinical development in RCC therapy.