c-myc/p53 interaction determines sensitivity of human colon carcinoma cells to 5-fluorouracil in vitro and in vivo

Colon carcinoma cells overexpress c-myc due to defective Wnt signaling, but only patients whose tumors have an amplified c-myc gene show improved dise ase-free and overall survival in response to 5-fluoruracil (5FU), Here we s how that in two colon carcinoma cell lines that do not have an amplified c- myc gene but differ in their p53 status, high c-myc levels can be further e levated by introducing a c-myc expression vector. Whereas sensitivity to lo w serum-induced apoptosis was imposed on the parental lines independent of p53 status and was unaffected by further elevation of c-myc, sensitivity to 5FU-induced apoptosis was dependent on both the higher c-myc levels due to the expression vector and wild-type p53 function, The elevated c-myc level s led to higher c-myc transactivation activity in the p53 wild-type cell li ne, but not in the mutant p53 cell line, The requirement for both elevated c-myc and p53 for 5FU sensitivity was confirmed using antisense c-myc and p ifithrin-alpha, a specific inhibitor of p53, Finally, the in vitro data pre dicted that only patients with both amplified c-myc and wild-type p53 in th eir primary tumors would be responsive to 5FU-based therapy, which was born e out by analysis of tumors from 135 patients entered into a Phase III clin ical trial of 5FU-based adjuvant therapy, The data provide significant insi ght into mechanisms that establish colon tumor cell sensitivity to 5FU, cle arly demonstrate the necessity of exercising caution in considering combini ng novel strategies that target elevated c-myc with standard 5FU-based ther apy, and suggest alternative therapeutic strategies that target c-myc and/o r p53 mutations in the treatment of colon cancer.