Expression levels of thymidine phosphorylase and dihydropyrimidine dehydrogenase in various human tumor tissues

Thymidine phosphorylase (dThdPase) is the rate-limiting enzyme that metabol izes 5'-deoxy-5-fluorouridine (5'-dFUrd, doxifluridine), an intermediate me tabolite of capecitabine, to the active drug 5-fluorouracil (5-FUra), while dihydropyrimidine dehydrogenase (DPD) catabolizes 5-FUra to an inactive mo lecule. The susceptibility of tumors to fluoropyrimidines is reported to co rrelate with tumor levels of these enzymes. To obtain some insight into the tumor types susceptible to fluoropyrimidine therapy, we measured expressio n 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 s tudied, 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 can cers and hepatoma (median >150 U/mg protein). The dThdPase/DPD ratio, which was reported to correlate with the susceptibility of human cancer xenograf ts to capecitabine, was high in esophageal, renal, breast, colorectal, and gastric cancers (median ratio of >1.5). In any of these three parameters. t he 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 r esults indicate that measurements of the three parameters, DPD, dThdPase ac id dThdPase/DPD, would be useful criteria for selecting cancer patients sui table for fluoropyrimidine therapy rather than for selecting cancer types.