Analisi dell'espressione di geni coinvolti nella resistenza al 5-fluorouracile nel carcinoma colorettale

5-FU-based chemotherapy (CT)is widely used in CC treatment. However, many patients (pts) still fail on these regimens due to natural or acquired tumor resistance mainly caused by increased expression of the target enzyme, thymidylate synthase (TS). In addition, a decreased activity of the folypolyglutamate synthetase (FPGS) enzyme has been associated with 5-FU resistance presumable due to the resulting depletion of folate polyglutamates, destabilizing the inhibitory TS-fluorodeoxyurilydate-folate coenzyme ternary complex. In tumor samples from 31CC pts, we measured TS and FPGS expression to establish their predictive role in prognosis for 5-FU based CT, by analizing TS and FGPS mRNA levels by RT-PCR and TS protein by immunohistochemistry. The median TS/beta-actin ratio was 41.36x10-3 (range 2,49x10-3-294,54x10-3). The TS immunostaining intensity was absent or weak in 54,8% and medium or strong in 45,2% samples. A statistically significant correlation was observed between TS mRNA and protein levels (p=0,0018). Overall median survival (OS) was significantly longer for pts with TS mRNA levels lower than the median value compared with those with higher levels (p=0.0103). Also the OS of pts with completely resected tumors (n=26) was longer for those with low TS expression compared with those with high TS expression (p=0.0092), as was disease-free survuval (DFS) (P=0.0923). Analysis of TS protein expression gave a similar correlation, although significnat only for OS of pts with completely resected tumors (p==.0041). DFS and OS data in the same pts demonstrated a significant difference between CT treated pts and surgical controls in pts with high Ts mRNA expression (p=0.0012 and 0.0006, respectively) but not in those with low TS expression. In pts undergoing surgery alone, high TS levels were unfavourable prognostic factor. Our data confirm the prognostic role of TS expression, as determined by both methods, for 5-FU based adjuvant CT. No correlation has been found between FPGS gene expression and usrvival of CC pts. The large scale evaluation of these and other molecular determinants of sensitivity may help tailor CT for CC pts and thus obtain improved efficacy.