MULTIPLE MECHANISMS OF ACTION OF THE BENZAMIDES AND NICOTINAMIDES AS SENSITIZERS OF RADIOTHERAPY - OPPORTUNITIES FOR DRUG DESIGN

The benzamides and nicotinamides are a well-known class of drugs that contain many analogs having radio-and chemosensitizing properties. Thi s study reports on a structural analysis in order to explain the chemi cal features important to their mechanisms of action. In general, N-su bstituted analogs are distinguished from the non-N-substituted analogs because they (i) are susceptible to radiolysis, (ii) induce cytotoxic ity by apoptosis but not necrosis, (iii) inhibit cell proliferation, ( iv) activate poly adenosine diphosphate ribosyl transferase (poly ADPR T), and (v) have a much-reduced effect on microregional tumor blood pe rfusion. It was concluded that the mechanism of action of N-substitute d analogs is shifted from primary effects on tumor vascularization as is seen with the non-N-substituted analogs to one where radiosensitiza tion can be explained by selective induction of apoptosis via radiolys is and accumulation of DNA damage. This knowledge may be useful in the design of drugs possessing multiple mechanisms of radiosensitizing ac tion.