P53 MUTATIONS AS A POSSIBLE PREDICTOR OF RESPONSE TO CHEMOTHERAPY IN METASTATIC COLORECTAL CARCINOMAS

Although intrahepatic infusion therapy with 5-fluorouracil for unresec table colorectal liver metastases may lead to improved overall surviva l for some patients, it is not clear why a response is not observed in others. Gene alterations in oncogenes or tumor-suppressor genes are c ritical events in tumor formation, and some of them could play a role in the process of drug resistance. The tumor-suppressor gene p53, whic h is known to trigger cell arrest or apoptosis in response to DNA dama ge, is found to be mutated in a wide range of human tumors, The aim of this work is to establish whether a relationship is found between p53 mutations and survival in patients undergoing adjuvant chemotherapy f or advanced Dukes' D colorectal cancers. Seventeen tumors from patient s treated with 5-fluorouracil regimen via intrahepatic infusion for un resectable colorectal hepatic metastasis were considered, p53 mutation s from tumor DNA were detected, after amplification by PCR of exons 5 to 8, by non-radioactive single-strand conformation polymorphism and d irect DNA sequencing. Patients with mutated p53 colorectal tumors had short survival, whereas prolonged survival was associated with the pre sence of wild-type p53 (p = 0.019), Our data suggest that mutated p53 colorectal tumors had a weak response, or even no response, to chemoth erapeutic treatment, Routine assessment of p53 status would be helpful in selecting patients with only wild-type p53 gene who have a predict ably better response to chemotherapy. (C) 1996 Wiley-Liss, Inc.