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NCI's anticancer drug screening program may not be selecting for clinically active compounds
1Department of Radiation Oncology, Stanford University School of Medicine, CA 94305-5468, USA.
Abstract:
To discover new anticancer drugs the U.S. National Cancer Institute (NCI) currently screens roughly 10,000 compounds annually against a panel of 60 human tumor cell lines. Drug activity is determined using a 2-day growth inhibition assay with the cells maintained in contact with the drugs for the 2-day period. Analyses of the more than 60,000 compounds screened to date against this panel of cell lines have revealed surprisingly detailed correlations between drug activities and the molecular genotypes and phenotypes of the cells. For example, most of the drugs, particularly those active in the clinic, are most active against p53 wild-type cells. This commentary points out, however, that these patterns of activity, and by implication the compounds identified as active, may not be relevant to tumor response in vivo. This is because tumor response is determined by tumor cell kill, and there is no reason to suppose that drug-induced short-term growth inhibition should correlate with drug-induced cell kill, usually measured by the ability of the cell to divide indefinitely to form a colony. We have tested a subset of the panel of NCI cell lines for cell kill by clonogenic assay using cisplatin and mitomycin C and have found only a weak and nonsignificant correlation between cell kill and activity determined by the NCI using the growth inhibition assay. It is concluded that a more extensive comparison of the 2-day growth inhibition and clonogenic assays should be made, as well as a test of which is more relevant to the response of human tumor xenografts.
Insights
The U.S. National Cancer Institute (NCI) screens anticancer drugs using growth inhibition assays. However, these results may not predict actual tumor cell kill, questioning their relevance for discovering effective cancer drugs.
Area of Science:
- Pharmacology
- Oncology
- Drug Discovery
Background:
- The U.S. National Cancer Institute (NCI) screens approximately 10,000 compounds annually for anticancer drug discovery.
- Drug activity is assessed using a 2-day cell growth inhibition assay against a panel of 60 human tumor cell lines.
- Previous analyses show correlations between drug activity and tumor cell molecular profiles, with many drugs being more active against p53 wild-type cells.
Purpose of the Study:
- To evaluate the relevance of the NCI's standard 2-day growth inhibition assay for predicting anticancer drug efficacy.
- To determine if short-term growth inhibition correlates with long-term tumor cell kill, a critical factor in actual tumor response.
- To assess the clinical relevance of compounds identified through current NCI screening methods.
Main Methods:
- A subset of NCI's tumor cell lines was tested for cell kill using a clonogenic assay.
- Cisplatin and mitomycin C were used as model anticancer drugs in the clonogenic assay.
- The results from the clonogenic assay were compared with activity data from the NCI's standard 2-day growth inhibition assay.
Main Results:
- A weak and statistically nonsignificant correlation was found between cell kill (measured by clonogenic assay) and growth inhibition (measured by the NCI assay).
- This suggests that the standard NCI assay may not accurately reflect a drug's ability to kill tumor cells.
- The findings raise concerns about the relevance of identified active compounds for predicting in vivo tumor response.
Conclusions:
- The standard 2-day growth inhibition assay used by the NCI may not be a reliable indicator of anticancer drug efficacy in terms of cell kill.
- Further comparative studies are needed between growth inhibition and clonogenic assays.
- Testing the relevance of these assays against human tumor xenografts is recommended to better predict in vivo drug response.