APOPTOSIS AND CANCER-CHEMOTHERAPY

The major disseminated cancers remain stubbornly resistant to systemic therapy. Drug-resistant tumours include both slow and fast growing ty pes, with the carcinomas constituting the major problem. Strategies fo r drug discovery have, in the past, been focused on attempts to design antiproliferative agents, largely targeted to interfere with DNA inte grity and replication. The malignant phenotype might be characterized by the emergence of cell populations with a greater survival potential : a lower proclivity to undergo apoptosis. This idea provides a possib le explanation of the genesis and progression of cancer and of the inh erent resistance of tumour cells to engage apoptosis. Work is describe d which identifies the molecular basis for differences in the survival potential of stem cells in the crypts of the colon and small intestin e. The advantageous survival of colonic stem cells, provided by expres sion of bcl-2 and a muted p53 response to DNA damage, allows damaged c ells to survive. Continued expression of bcl-2 renders tumour cells re sistant to drug-induced DNA damage by a mechanism different from class ical mechanisms of drug resistance. The attenuation of cell survival i s described as a key component in strategies for the drug treatment of disseminated cancers.