Activated Checkpoint Method Selectively Kills Cancer Cells

The study appeared February 21, 2003, in the online edition of the Proceedings of the National Academy of Sciences.

Beta-lapachone is an experimental drug developed by Cyclis Pharmaceuticals (Norwood, MA, USA). It is one of several being evaluated as part of a new approach to cancer therapy called activated checkpoint therapy (ACT). The goal is to trigger apoptosis in cancer cells without first causing DNA damage to the tumor cells and surrounding normal tissue.

After treating tumor cells and normal cells growing in culture with beta-lapachone, the researchers found that the compound selectively induced apoptosis in the tumor cells but not in normal cells. They further showed that ß-lapachone-treated cancer cells, but not normal cells, exhibited elevated E2F1 protein levels, indicating activation of a specific checkpoint apoptosis pathway. A new small molecule drug based on these findings, CO-501, is expected to enter clinical trials in 2003.

"When DNA damage occurs in normal cells, a checkpoint pathway is activated that triggers apoptosis when that damage cannot be repaired,” explained Dr. Chiang J. Li, senior author of the paper and vice president of research at Cyclis. "In cancer cells these pathways are defective, leading to uncontrolled growth. These studies strongly suggest that one such pathway, involving the E2F1 protein, can be turned on with small molecule drugs, leading to selective killing of cancer cells.”





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