Gene expression profile of 5-fluorouracil metabolic enzymes in primary colorectal cancer: potential as predictive parameters for response to fluorouracil-based chemotherapy

Abstract

Background: Thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and orotate phosphoribosyltransferase (OPRT) have been reported to be predictive parameters for the efficacy of fluoropyrimidine-based chemotherapy. Therapy guided by chemotherapy sensitivity and resistance assays may lead to rational treatment decisions.

Materials and methods: mRNA expression of TS, DPD, TP, and OPRT were quantified by reverse-transcriptase polymerase chain reaction (RT-PCR) after harvesting from paraffin embedded specimens through microdissection. In vitro chemosensitivity testing by histoculture drug response assay (HDRA) was performed with fresh specimens of the primary tumor from 49 patients with colorectal cancer. Correlations between the results of a chemosensitivity test (the T/C ratio; the percentage of optical density of a tumor treated with anticancer drugs in relation to the optical density of the tumor cultured in RPMI 1640 medium only) and the gene expression were assessed.

Results: The gene expression of TS, TP, and OPRT had no correlation with clinicopathological factors, survival, and T/C ratio. The DPD mRNA levels (0.295 vs. 0.381, p = 0.2460) and OPRT/DPD ratio (5.535 vs. 4.394. p = 0.226) had a weak correlation with the T/C ratio. Of the eleven patients who were actually treated with chemotherapy, the responders had higher OPRT/DPD ratios (8.065 vs. 4.081, p = 0.090).

Conclusion: The DPD mRNA level and OPRT/DPD ratio evaluated from paraffin embedded specimens are candidates for further evaluation as predictors of response against 5-fluorouracil-based chemotherapy in colorectal cancer.