Preoperative radiotherapy and concomitant capecitabine treatment induce thymidylate synthase and thymidine phosphorylase mRNAs in rectal carcinoma.

This work is intended to study the effect of preoperative capecitabine and radiotherapy treatment on the levels of thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) mRNAs in rectal carcinoma. 55 patients with locally advanced rectal carcinoma (cT3-4, N0, M0 or cT2-4,N+, M0) were treated with capecitabine 825 mg/m2 twice a day and pelvic radiotherapy 1,8 Gy daily up to cumulative dose of 45 Gy, boosting up to 50,4 Gy. Patients underwent surgery 6th week after the completion of chemoradiotherapy. Biopsies of rectal carcinoma were taken before starting therapy and 14 days after its cesation. Biopsies were examined for TS, DPD and TP mRNA levels. CEA in serum was examined to monitor relapses. Both TP and TS mRNA increase two weeks after starting therapy (p<0,001). TP mRNA median levels were elevated 2,3x after starting therapy. Moreover responders exhibit 1,5x higher induction than non-responders both before and after starting therapy, but difference is significant before therapy only (p=0,017). Non-responders have most frequent TS induction. Complete remission was observed in 17% and substantial responses with microscopic residuum only in additional 19% of cases were achieved. The pathologic downstaging rate was 76%. Our data show that TS and TP mRNA are induced by preoperative chemoradiotherapy in both responders and nonresponders. TP induction is in accordance with the expected role of TP in the activation of capecitabine and the known promoting role of TP in tissue fibrosis frequently associated with tumor regression.