P53 POINT MUTATIONS AND THYMIDYLATE SYNTHASE MESSENGER-RNA LEVELS IN DISSEMINATED COLORECTAL-CANCER - AN ANALYSIS OF RESPONSE AND SURVIVAL

Recent studies suggest that there may be a strong correlation between the p53 status of a tumor and a patient's response to chemotherapy, Th erefore, we determined p53 status in 36 patients with disseminated col orectal cancer by cDNA sequencing and immunohistochemical staining, as well as by the gene expression level of thymidylate synthase (TS), th e target enzyme of 5-fluorouracil (5-FU), by reverse transcription-PCR , Ten patients (28%) experienced a clinical response to 5-FU chemother apy, Overall, TS expression and response to chemotherapy were associat ed: 9 of 18 (50%) patients with TS less than or equal to 3.0 x 10(-3) responded, compared to 1 of 18 (6%) patients with TS less than or equa l to 3.0 x 10(-3) (P = 0.003), p53 mutations were found in 21 of 36 pa tients (58%) using cDNA cycle sequencing, and p53 protein overexpressi on was found in 20 of 32 patients (62%) using immunohistochemistry sta ining. Overall p53 status and response to chemotherapy were associated : 5 of 10 (50%) patients with wildtype p53 or negative p53 staining ex perienced a response, but only 5 of 26 (19%) patients with mutant p53 or p53 overexpression responded. TS expression, but not expression of p53, was significantly associated with overall survival (P = 0.002), P atients with wild-type p53 had significantly lower TS levels compared to patients with mutated p53 (P = 0.044), In this study, we also prese nt data linking specific p53 point mutations to TS expression levels a nd resistance to 5-FU, Although the number of patients is relatively s mall, these results identify p53 status and TS gene expression as asso ciated with response in disseminated colorectal cancer; independent st udies are needed to confirm these findings and to provide information leading to a better understanding of the role of 5-FU-based chemothera py in the treatment of colorectal cancer.