Positive correlation between the efficacy of capecitabine and doxifluridine and the ratio of thymidine phosphorylase to dihydropyrimidine dehydrogenase activities in tumors in human cancer xenografts.
Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a new fluoropyrimidine carbamate, which is converted to 5-fluorouracil (5-FUra) selectively in tumors through the intermediate metabolite 5'-deoxy-5-fluorouridine (5'-dFUrd, doxifluridine). 5'-dFUrd is metabolized to 5-FUra by thymidine phosphorylase (dThdPase) located in high levels in various types of solid tumors from patients, whereas 5-FUra generated is catabolized to dihydrofluorouracil by dihydropyrimidine dehydrogenase (DPD). The present study investigated whether the efficacy of capecitabine and its intermediate metabolite 5'-dFUrd correlates with levels of these enzymes in various human cancer xenograft models. Capecitabine and 5'-dFUrd were highly effective and inhibited tumor growth by more than 50% in 18 of 24 xenograft lines (75%) and 15 of 24 xenograft lines (63%), respectively, whereas 5-FUra and a mixture of tegafur and uracil were effective only in 1 of 24 (4.2%) and 5 of 24 (21%), respectively. The efficacy of capecitabine correlated with dThdPase activity. However, capecitabine was effective even in tumors with lower levels of dThdPase if DPD levels were also lower. In contrast, it was not as effective even in tumors with sufficient levels of dThdPase if DPD levels were very high. The efficacy of capecitabine consequently correlated very well with and depended on the ratio of these two enzymes in tumors. These results indicate that capecitabine might exert its efficacy through 5-FUra generated in tumor tissues but not through that generated in normal organs. On the other hand, there was no correlation between the efficacy of a mixture of tegafur and uracil and these enzyme activities in tumors. The efficacy of capecitabine would be optimized by selecting patients who have tumors with a high ratio of dThdPase to DPD activities.
Ishikawa
T
T
Cytostatics Group, Nippon Roche Research Center, Kamakura-City, Kanagawa, Japan.
Sekiguchi
F
F
Fukase
Y
Y
Sawada
N
N
Ishitsuka
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000069287:Capecitabine; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism; D042943:Dihydrouracil Dehydrogenase (NADP); D005467:Floxuridine / Q000627:therapeutic use*; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D010088:Oxidoreductases / Q000378:metabolism*; D013939:Thymidine Phosphorylase / Q000378:metabolism*
D000970:Antineoplastic Agents; D005467:Floxuridine; D003841:Deoxycytidine; D000069287:Capecitabine; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D013939:Thymidine Phosphorylase; D005472:Fluorouracil; C025034:doxifluridine