Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase

We had previously shown that high gene expressions (mRNA levels) of thymidy late synthase (TS; Leichman et al., J. Clin. Oncol., 15: 3223-3229, 1997) a nd thymidine phosphorylase (TP; Metzger et al., Clin. Cancer Res., 4: 2371- 2376, 1998) in pretreatment tumor biopsies could identify tumors that mould be nonresponsive to 5-fluorouracil (5-FU)-based therapy. In this study, we investigated the association between intratumoral gene expression of the p yrimidine catabolism enzyme dihydropyrimidine dehydrogenase (DPD) and the r esponse of colorectal tumors to the same 5-FU-based protocol. DPD expressio ns; mere measured by quantitative reverse transcription-PCR in 33 pretreatm ent biopsies of colorectal tumors from patients mho went on to receive trea tment with 5-FU and leucovorin (LV). The range of DPD gene expression in th ose tumors that were nonresponsive to 5-FU was much broader than that of th e responding tumors. None of the tumors with basal-level DPD expressions ab ove a DPD:beta-actin ratio of 2.5 x 10(-3) (14 of 33) were responders to 5- FU/LV therapy, whereas those tumors with DPD gene expressions below DPD:bet a-actin ratio of 2.5 x 10(-3) had a response rate of 50%. There was no corr elation among DPD, TS, and TP expression values in this set of colorectal t umors, which indicated that these gene expressions are independent variable s. All of the tumors that responded to 5-FU therapy (11 of 33) had expressi on values of all three of the genes, TS, TP, and DPD, below their respectiv e nonresponse cutoff values, whereas, in each of the nonresponding tumors, at least one of these gene expressions was high. The patients with low expr ession of all three of the genes had significantly longer survival than pat ients with a high value of any one of the gene expressions. The results of this study show that intratumoral gene expression level of DPD is associate d with tumor response to 5-FU and that the use of more than one independent determinant of response permits the identification of a high percentage of responding patients.