Regulation of Dihydropyrimidine Dehydrogenase in Colorectal Cancer

Stephen J. Johnston; Susan A. Ridge; James Cassidy; Howard L. McLeod

DOI: Published September 1999

Abstract

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/μg 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/μg total RNA, P = 0.001). DPD mRNA expression was higher in normal liver than normal colonic mucosa (median, 1.17 versus 0.37 amole/μg 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.

Footnotes

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵1 Supported in part by an Aberdeen Royal Infirmary Endowment grant, a University of Aberdeen Faculty Research Award, and a University of Aberdeen Faculty studentship.
↵2 To whom requests for reprints should be addressed, at Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom. Phone: (44) 1224-681818 ext. 52730; Fax: (44) 1224-273066.
↵3 The abbreviations used are: 5FU, 5-fluorouracil; DPD, dihydropyrimidine dehydrogenase; cPCR, competitive PCR.
↵4 S. J. Johnston and H. L. McLeod, unpublished data.
- Accepted June 29, 1999.
- Received April 20, 1999.
- Revision received June 24, 1999.