MECHANISMS OF CELLULAR-RESISTANCE TO CYTOTOXIC DRUGS AND X-IRRADIATION - KEYNOTE ADDRESS

Lack of response to X-irradiation and cytotoxic chemotherapy is the major cause of treatment failure in patients with cancer. However, "resistance" to these modalities may be considered a normal cellular response. The ability to cure patients with particular tumor types may be related to hypersensitivity to these modalities caused by loss or abnormality of certain normal cellular constituents such as enzymes involved in DNA repair. It is likely that the initial chemo or radiosensitivity of a tumor will broadly reflect the intrinsic resistance of the tissue type from which the tumor arose. There are many cellular biochemical mechanisms responsible for this relative resistance to drugs and radiation. Many of these mechanisms, although present in normal tissues, may be inducible and can result in enhanced resistance to DNA damaging agents. Although certain resistance mechanisms would appear to be specific for drug resistance or for radiation resistance, there are other resistance mechanisms that potentially affect both modalities. In particular, the study of DNA repair genes in mammalian cells may give us greater insight into common mechanisms of resistance to these modalities.