Thymidine phosphorylase and dihydropyrimidine dehydrogenase protein expression in colorectal cancer

It is essential for actively proliferating cells to increase their rate of DNA synthesis to progress through the cell cycle. This is reflected in the increased uracil usage that is a common feature in solid tumours. Thymidine phosphorylase (TP) anabolises formation of pyrimidine nucleosides availabl e for DNA synthesis, whereas dihydropyrimidine dehydrogenase (DPD) cataboli ses the degradation of pyrimidine bases, thereby reducing levels of uracil and thymine available for DNA synthesis. In addition, tissue levels of TP o r DPD have been associated with the clinical efficacy of pyrimidine antimet abolites commonly used in the treatment of colorectal cancer. There is litt le information, however, on the relative expression or degree of co-ordinat ed regulation of either protein in primary or metastatic colorectal cancer. DPD and TP protein levels were measured in 15 primary colorectal carcinoma s, 10 colorectal liver metastases and 25 adjacent uninvolved tissues. DPD w as reduced in 67% (10/15) of colorectal tumours (mean tumour/normal=0.52) a nd in all liver metastases (mean tumour/normal=0.41) compared with the corr esponding normal tissue. In contrast, TP was increased in 80% (12/15) of co lorectal tumours (mean tumour/normal=18.91) and in all metastases (mean tum our/normal=3.70). TP and DPD protein expression were highly variable in uni nvolved and tumour tissues. The ratio of TP: DPD was higher in 87% of color ectal tumours and in all liver metastases compared with the adjacent uninvo lved tissues. This suggests the presence of co-ordinated regulation of thes e pyrimidine metabolic enzymes and offers a strategy for optimising the use of pyrimidine-based chemotherapy. (C) 2001 Wiley-Liss, Inc.