Clinical role of thymidine phosphorylase and dihydropyrimidine dehydrogenase in colorectal cancer treated with postoperative fluoropyrimidine.
OBJECTIVE
Thymidine phosphorylase (TP) 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), several studies have evaluated the relationship between TP, DPD, and clinicopathological features. However, the results may not be definitive since monoclonal antibody sensitive for human TP and DPD has not been established. Now, new monoclonal antibodies for human TP (1C6-203) and human DPD (2H9-1b) are available.


METHODS
The study included 150 patients whose CRCs were classified into stage II to IV, and resected surgically. TP and DPD expression were evaluated using immunohistochemistry with new antibodies and relationships between their expressions and clinicopathological 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
TP and DPD expression showed positive correlations with advances in lymphatic invasion (p=0.049 and 0.032 respectively), venous invasion (p=0.027 and 0.005), and cancer stage (p=0.0003 and 0.006). The patients survival rates were higher in those TP(-) than in those TP(+) (p=0.007), and higher in those DPD(-) than in those DPD(+) (p=0.008). The survival rate was best in the patients negative for TP and DPD, and worst in those positive for both TP and DPD. In regard to the combination of TP and DPD expression, the best survival curve was obtained for the TP(-) DPD(-) group followed by those for the TP(+) DPD(-), TP(-) DPD(+), and TP(+) DPD(+) groups in descending order. The estimated hazard ratio for patients' death with TP and DPD expression were 3.10 and 6.55 (p=0.01 and 0.01) respectively.


CONCLUSIONS
Using new sensitive monoclonal antibodies, the present results indicated that TP and DPD expression were associated with CRC progression, and closely related with poor prognosis in postoperative CRC patients. CRC patients positive for both TP and DPD expression had a poorer prognosis than those negative for one of these expressions in treatment with fluoropyrimidine after surgery. The use of two determinants of response may identify a high percentage of responding patients.
Tokunaga
Yukihiko
Y
Department of Surgery, Osaka North Japan Post Hospital, Japan.
Takahashi
Keichi
K
Saito
Tohru
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D003082:Colectomy / Q000379:methods; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality* / Q000601:surgery; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000032:analysis* / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011336:Probability; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D013939:Thymidine Phosphorylase / Q000032:analysis* / Q000187:drug effects; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D042943:Dihydrouracil Dehydrogenase (NADP); D013939:Thymidine Phosphorylase; D005472:Fluorouracil