Suppression of p53: a new approach to overcome side effects of antitumor therapy

The p53 protein is traditionally believed to be a tumor suppressor. Activat ion of p53-dependent apoptosis in response to damage to cell DNA provides f or the elimination of possible tumor cell precursors. However, in some case s the activity of p53 can be dangerous for the organism. Thus, p53-dependen t apoptosis induced in normal tissues during chemo- and radiotherapy call c ause severe side effects of antitumor therapy and, therefore, limits its ef ficiency. This review analyzes experimental data on the role of p53 in the primary and late tissue response to DNA-damaging exposures. Comparison of n ormal and p53-deficient mice indicated that the apoptosis in radiosensitive tissues during the first hours after irradiation is really caused by the a ctivity of p53 which, in turn, is determined by a high level of expression of mRNA of p53. We supposed that a temporary suppression of p53 can decreas e the damage to sensitive tissues and accelerate their recovery after the a ntitumor radio- and chemotherapy. To test this hypothesis, we have isolated a chemical inhibitor of p53 and determined its activity in vitro and in vi vo. This compound, called pifithrin-alpha, protects wild-type mice against lethal doses of radiation, has nd effect on p53-deficient animals, and does not induce visible tumors. These results show that the suppression of p53 is a promising approach in the prevention of side effects of antitumor ther apy.