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 available for DNA synthesis, whereas dihydropyrimidine dehydrogenase (DPD) catabolises the degradation of pyrimidine bases, thereby reducing levels of uracil and thymine available for DNA synthesis. In addition, tissue levels of TP or DPD have been associated with the clinical efficacy of pyrimidine anti-metabolites commonly used in the treatment of colorectal cancer. There is little information, however, on the relative expression or degree of co-ordinated regulation of either protein in primary or metastatic colorectal cancer. DPD and TP protein levels were measured in 15 primary colorectal carcinomas, 10 colorectal liver metastases and 25 adjacent uninvolved tissues. DPD was reduced in 67% (10/15) of colorectal tumours (mean tumour/normal = 0.52) and in all liver metastases (mean tumour/normal = 0.41) compared with the corresponding normal tissue. In contrast, TP was increased in 80% (12/15) of colorectal tumours (mean tumour/normal = 18.91) and in all metastases (mean tumour/normal = 3.70). TP and DPD protein expression were highly variable in uninvolved and tumour tissues. The ratio of TP:DPD was higher in 87% of colorectal tumours and in all liver metastases compared with the adjacent uninvolved tissues. This suggests the presence of co-ordinated regulation of these pyrimidine metabolic enzymes and offers a strategy for optimising the use of pyrimidine-based chemotherapy.
Collie-Duguid
E S
ES
Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, Scotland. e.collie-duguid@abdn.ac.uk
Johnston
S J
SJ
Boyce
L
L
Smith
N
N
Cowieson
A
A
Cassidy
J
J
Murray
G I
GI
McLeod
H L
HL
D015179:Colorectal Neoplasms / Q000201:enzymology*; D042943:Dihydrouracil Dehydrogenase (NADP); D006801:Humans; D010088:Oxidoreductases / Q000032:analysis*; D013939:Thymidine Phosphorylase / Q000032:analysis*
D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D013939:Thymidine Phosphorylase