Dihydropyrimidine dehydrogenase (DPD) is responsible for degradation of the
pyrimidines uracil and
thymine and the inactivation of the chemotherapeutic agent
5-fluorouracil. DPD activity is highly variable in
cancer populations, and this variation may influence the antitumor efficacy of
5-fluorouracil. However, little is known about the regulation of DPD
mRNA expression in any tissues. Using a reverse transcription competitive PCR assay, we quantified DPD
mRNA levels in 10 matched
colorectal tumors and adjacent normal mucosae and 7 colorectal liver
metastases and adjacent normal livers. Lower levels of DPD
mRNA expression were observed in
colorectal tumor compared with adjacent normal colon mucosa (median, 0.01 versus 0.37
amole/microg total
RNA, P = 0.02). DPD
mRNA expression was also lower in
metastases than adjacent normal liver tissue (median, 0.11 versus 1.17
amole/microg total
RNA, P = 0.001). DPD
mRNA expression was higher in normal liver than normal colonic mucosa (median, 1.17 versus 0.37
amole/microg total
RNA, P = 0.02). A significant relationship was observed between DPD
mRNA and catalytic activity (r(s) = 0.66, P<0.001). The
tumor:normal ratio for DPD
mRNA,
protein, and activity was relatively stable in liver (0.25, 0.55, and 0.51, respectively) but varied considerably in colon (0.085, 0.9, and 1.25, respectively), consistent with enhanced translation of DPD transcript in primary
colorectal tumor. This suggests that DPD can be regulated at the levels of both transcription and translation.