THE P53 GENE IS A POTENT DETERMINANT OF CHEMOSENSITIVITY AND RADIOSENSITIVITY IN GASTRIC AND COLORECTAL CANCERS

We previously reported that introduction of the wild-type p53 gene int o human cancer cells with deleted p53 enhanced apoptosis induced by ch emotherapy [Fujiwara et al. (1994) Cancer Res 54:2287]. This suggests that p53 status could be a potent determinant of the therapeutic effic acy of DNA-damaging cancer therapy. We analyzed 24 patients with gastr ic or colorectal cancer for p53 mutations and apoptotic changes in sur gical specimens. Out of 11 patients with gastric cancer, 3 were treate d with chemotherapeutic drugs before resection; 5 of 13 patients with colorectal cancer had 30 Gy radiation prior to surgery. p53 mutations were detected in 4 cases of gastric cancer (36.4%) and in 6 cases of c olorectal cancer (46.2%) by immunohistochemical staining. The preopera tive DNA-damaging therapies increased the number of apoptotic cells in wild-type-p53-expressing tumors; tumors with mutant p53, however, sig nificantly showed fewer apoptotic cells compared with those expressing wild-type p53. The p53-inducible WAF1/CIP1 protein was immunohistoche mically observed in wild-type-p53-containing tumors, whereas mutant-p5 3-expressing tumors expressed no detectable WAF1/CIP1. Taken together, we conclude that p53 mutations are associated with the poor response of chemotherapy and radiotherapy.