Expression levels of thymidine phosphorylase and dihydropyrimidine dehydrogenase in various human tumor tissues.
Thymidine phosphorylase (dThdPase) is the rate-limiting enzyme that metabolizes 5'-deoxy-5-fluorouridine (5'-dFUrd, doxifluridine), an intermediate metabolite of capecitabine, to the active drug 5-fluorouracil (5-FUra), while dihydropyrimidine dehydrogenase (DPD) catabolizes 5-FUra to an inactive molecule. The susceptibility of tumors to fluoropyrimidines is reported to correlate with tumor levels of these enzymes. To obtain some insight into the tumor types susceptible to fluoropyrimidine therapy, we measured expression levels of these two enzymes in various types of human cancer tissues (241 tissue samples) by the ELISA methods. DPD exists in all the cancer types studied, such as bladder, breast, cervical, colorectal, esophageal, gastric, hepatic, pancreatic, prostate, and renal cancers. Among them, the cervical, hepatic, pancreatic, esophageal, and breast cancer tissues expressed high levels of DPD (median >70 U/mg protein), while high concentrations of the dThdPase were expressed in esophageal, cervical, breast, and pancreatic cancers and hepatoma (median >150 U/mg protein). The dThdPase/DPD ratio, which was reported to correlate with the susceptibility of human cancer xenografts to capecitabine, was high in esophageal, renal, breast, colorectal, and gastric cancers (median ratio of >1.5). In any of these three parameters, the inter-patient DPD variability for each cancer type was much larger than the DPD variability among cancer types; highest/lowest ratios for dThdPase, DPD, and dThdPase/DPD were 10-321, 7-513, and 2-293, respectively. These results indicate that measurements of the three parameters, DPD, dThdPase and dThdPase/DPD, would be useful criteria for selecting cancer patients suitable for fluoropyrimidine therapy rather than for selecting cancer types.
Mori
K
K
Cytostatics Group, Nippon Roche Research Center, Kamakura, Kanagawa, Japan.
Hasegawa
M
M
Nishida
M
M
Toma
H
H
Fukuda
M
M
Kubota
T
T
Nagasue
N
N
Yamana
H
H
Hirakawa-YS Chung
K
K
Ikeda
T
T
Takasaki
K
K
Oka
M
M
Kameyama
M
M
Toi
M
M
Fujii
H
H
Kitamura
M
M
Murai
M
M
Sasaki
H
H
Ozono
S
S
Makuuchi
H
H
Shimada
Y
Y
Onishi
Y
Y
Aoyagi
S
S
Mizutani
K
K
Ogawa
M
M
Nakao
A
A
Kinoshita
H
H
Tono
T
T
Imamoto
H
H
Nakashima
Y
Y
Manabe
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000069287:Capecitabine; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D042943:Dihydrouracil Dehydrogenase (NADP); D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D007564:Japan; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D010088:Oxidoreductases / Q000032:analysis / Q000378:metabolism*; D013939:Thymidine Phosphorylase / Q000032:analysis / Q000378:metabolism*; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D003841:Deoxycytidine; D000069287:Capecitabine; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D013939:Thymidine Phosphorylase; D005472:Fluorouracil