NCI's anticancer drug screening program may not be selecting for clinically active compounds

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.