Clinical role of orotate phosphoribosyl transferase and dihydropyrimidine dehydrogenase in colorectal cancer treated with postoperative fluoropyrimidine.
BACKGROUND
Orotate phosphoribosyl transferase (OPRT) is an essential enzyme for activation of 5-fluorouracil (5-FU) and its derivatives. Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme for degradation of 5-FU. In colorectal cancer (CRC), few studies have evaluated the relationship between OPRT, DPD, and clinicopathologic features.


METHODS
The study included 150 patients whose CRCs were classified into stage II to IV, and resected operatively. OPRT and DPD expression were evaluated using immunohistochemistry with new antibodies. Relationships between their expressions and clinicopathologic features. Survival curves were calculated using Kaplan-Meier method, and differences were evaluated with log-rank test. Cox proportional hazards model was also used.


RESULTS
OPRT expression showed a negative correlation with advances in venous invasion (P=.041), though DPD expression showed positive correlations with advances in venous invasion (P=.0053), and cancer stage (P=.0064). The patients survival rates were higher in those OPRT(+) than in those OPRT(-) (P=.004), and higher in those DPD(-) than in those DPD(+) (P=.008). The estimated hazard ratio for patients death with OPRT and DPD expression were 2.43 and 6.55 (P=.0047 and .0096) respectively.


CONCLUSIONS
OPRT expression was associated negatively with CRC progression and related with better prognosis, although DPD expression was positively correlated with CRC progression and related with poor prognosis. The overall patients survival rates were best in the patients OPRT(+)DPD(-), and worst in those OPRT(-)DPD(+) in treatment with fluoropyrimidine after operation.
Tokunaga
Yukihiko
Y
Department of Surgery, Osaka North Japan Post Hospital, Osaka, Japan. tokunagay@usay6.com
Sasaki
Hirokazu
H
Saito
Tohru
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000401:mortality / Q000601:surgery; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000276:immunology / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009962:Orotate Phosphoribosyltransferase / Q000276:immunology / Q000378:metabolism*; D011379:Prognosis; D016016:Proportional Hazards Models; D015996:Survival Rate; D005641:Tegafur / Q000627:therapeutic use; D014498:Uracil / Q000627:therapeutic use
D000906:Antibodies; D014408:Biomarkers, Tumor; D005641:Tegafur; D014498:Uracil; D042943:Dihydrouracil Dehydrogenase (NADP); D009962:Orotate Phosphoribosyltransferase