Enhanced sensitivity of p53 mutated human colon cancers grafted into nude mice to 5-FU therapy

R Bras-Goncalves, PhD M. Abal, A. Caron, M. Pocard, M.F. Poupon

Institut Curie, Paris, Ile de France France

Abnormalities in the tumor suppressor gene p53 have been identified in over 60% of colorectal cancers. The status of p53 has been proposed as an important determinant that influence the tumor response to current standard therapy. The majority of these studies support the idea that inactivation of p53 can lead to decreased sensitivity to conventional chemotherapy. The unresponsiveness of p53-deficient tumors has been ascribed to their inability to enter apoptosis after drug treatment, allowing the cells to accumulate DNA lesions. However a significant percentage of reports present evidence of increased sensitivity to chemotherapeutic agents. Chemotherapy for human colorectal cancer (hCRC) is not very effective, with 5-Fluorouracil (5-FU) remaining the reference compound. We and others demonstrated that the response of hCRC to chemotherapeutic agents is related to the genetic status of the treated tumors, namely, to the inactivating p53 mutations or MSI status. In testing the antitumor efficacy of 5-FU alone or combined with the sodium-butyrate’s analogue, monoacetone glucose 3n-butyrate in a series of 12 hCRC implanted into nude mice, we found all tumors responsive to the combination, independently of the tumor characteristics studied, respectively, stage, p53 and MSI status and cytogenetic alterations, whereas only the p53-deficient tumors responded to 5-FU alone. Ongoing in vitro studies demonstrate enhanced apoptosis in HT-29, a p53 mutated colon cancer cell line, in comparison with HT-29 A4 expressing a functional p53, restored by transfection of a wild-type p53. Further investigations are needed to identify the role of p53 status in mediating the cytotoxic effects of 5-FU.

KEY WORDS: p53, colorectal cancer, butyrate.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Apoptosis - Molecular Mechanisms.