title: Immunohistochemical demonstration of fluoropyrimidine-metabolizing enzymes in various types of cancer.
abstract: Fluoropyrimidines [5-Fluorouracil (5-FU) and its prodrugs] have been widely used in the treatment of solid cancers. The anticancer effects primarily depend on intratumoral levels of enzymes metabolizing the drugs, such as dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP), and thymidylate synthase (TS). In order to know the tumor types susceptible to respective fluoropyrimidines, we investigated the expression of DPD, OPRT, TP and TS in various types of cancer with the immunoperoxidase method. These four enzymes existed in all of the cancer types studied, such as pulmonary, gastric, colorectal, hepatic, cholecystic, pancreatic, renal, urocystic, and mammary cancers. Respective types of cancers presented characteristic immunohistochemical features as follows: pulmonary adenocarcinoma, DPD- and TP-high; pulmonary squamous cell carcinoma, TS- and TP-high; intestinal-type gastric adenocarcinoma, TP-high; diffuse-type gastric adenocarcinoma, DPD-low and TS-high; colorectal adenocarcinoma, DPD- and TP-low, hepatocellular carcinoma, DPD-high, and TS- and OPRT-low; cholecystic adenocarcinoma, DPD- and TS-high; renal cell carcinoma, DPD-low, and OPRT- and TP-high; urocystic transitional cell carcinoma, DPD-high and OPRT-low; and mammary ductal carcinoma, OPRT-low, and TS- and TP-high. The enzyme expression pattern in cancer tissue was generally similar to that of their normal counterparts. However, TP immunoreactivity in adenocarcinomas of the lung, stomach and gallbladder, and urothelial carcinoma of the urinary bladder was stronger, and DPD immunoreactivity in adenocarcinoma of the breast was weaker, when compared with normal epithelial cells. Non-epithelial cells were also positive for these enzymes. These results indicated that the key enzymes influencing the effects of fluoropyrimidines differ from cancer to cancer. Fluoropyrimidine treatment may be selected, based on the simultaneous immunohistochemical evaluation of the fluoropyrimidine metabolic enzymes.
authors.affiliation: Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan. skamo@fujita-hu.ac.jp
authors.forename: Shingo
authors.initials: S
authors.lastname: Kamoshida
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shiogama
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Shimomura
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Inada
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Sakurai
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ochiai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matuoka
authors.forename: Kotaro
authors.initials: K
authors.lastname: Maeda
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tsutsumi
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000378:metabolism* / Q000494:pharmacology*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism; D004351:Drug Resistance; D005472:Fluorouracil / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D009962:Orotate Phosphoribosyltransferase / Q000378:metabolism; D013939:Thymidine Phosphorylase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D009962:Orotate Phosphoribosyltransferase; D013939:Thymidine Phosphorylase; D005472:Fluorouracil