title: X-ray irradiation induces thymidine phosphorylase and enhances the efficacy of capecitabine (Xeloda) in human cancer xenografts.
abstract: Thymidine phosphorylase (dThdPase) is an essential enzyme for the activation of the cytostatics capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) and its intermediate metabolite 5'-deoxy-5-fluorouridine (5'-dFUrd) to 5-fluorouracil (5-FUra) in tumors. We observed previously that several cytokines and cytostatics up-regulated dThdPase expression and consequently enhanced the efficacy of capecitabine and 5'-dFUrd. In the present study, we found that X-ray irradiation also up-regulated dThdPase expression in several human cancer xenografts. A single-dose local irradiation at 5 Gy increased dThdPase levels by up to 13-fold at 9 days after the irradiation. Whole-body irradiation also up-regulated dThdPase in a tumor, but it did not increase the enzyme level in the liver. We also observed that the irradiation increased the levels of human tumor necrosis factor alpha (TNF-alpha), which is an up-regulator of dThdPase, prior to the dThdPase up-regulation. These results indicate that X-ray irradiation might increase dThdPase levels indirectly through the human TNF-alpha in the tumor tissue. In the WiDr colon and MX-1 mammary human cancer xenograft models, the combination of a single local X-ray irradiation with either capecitabine or 5'-dFUrd was much more effective than either radiation or chemotherapy alone. In contrast, treatment with X-ray irradiation and 5-FUra in combination showed no clear additive effects. Combined modality treatment of cancer patients with cape-citabine and X-ray irradiation would have greater potential usefulness than conventional radiochemotherapy with 5-FUra.
authors.affiliation: Cytostatics Group, Nippon Roche Research Center, Kanagawa, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Sawada
authors.forename: T
authors.initials: T
authors.lastname: Ishikawa
authors.forename: F
authors.initials: F
authors.lastname: Sekiguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Tanaka
authors.forename: H
authors.initials: H
authors.lastname: Ishitsuka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000069287:Capecitabine; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004790:Enzyme Induction / Q000528:radiation effects; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000628:therapy*; D013939:Thymidine Phosphorylase / Q000096:biosynthesis*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014964:X-Ray Therapy
chemical_list: D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; D003841:Deoxycytidine; D000069287:Capecitabine; D013939:Thymidine Phosphorylase; D005472:Fluorouracil