title: 5-FU-induced apoptosis correlates with efficacy against human gastric and colon cancer xenografts in nude mice.
abstract: Apoptosis may be an important mechanism by which cancer cells are killed by certain agents. It is reported here that apoptosis is a key event in the killing of human tumor cells by 5-fluorouracil (5-FU) in vivo. Apoptosis induced by 5-FU was determined using two human gastrointestinal tumor xenografts serially transplanted into nude mice: a gastric carcinoma (SC-1-NU) highly sensitive to 5-FU and a colon carcinoma (Co-4) less sensitive to 5-FU. Apoptosis was assayed using the terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick end labeling method in paraffin-embedded tissue sections, and by flow-cytometric analysis. Apoptosis-positive cells increased gradually during treatment. 24 hours after the initiation of 5-FU treatment a maximum, of 15.4% of the Co-4 cells were apoptotic. 48 hours after the initiation of 5-FU treatment, apoptosis was found in 34% of the tumor cells in the SC-1-NU strain. Flow-cytometry demonstrated the increase of S-phase fractions in both strains after the administration of 5-FU, and this coincided with the appearance of apoptotic-positive cells. Although the intrinsic. TS activities of two strains differed, TS activities were markedly suppressed in both strains immediately after the administration of 5-FU. Concentration of 5-FU in RNA (F-RNA) increased gradually in both strains, reaching a maximum 24 hours after the administration of 5-FU. These results suggest that apoptosis and inhibition of DNA synthesis induced by 5-FU are closely associated with its antitumor effect.
authors.affiliation: Department of Surgery, Tochigi Cancer Center, Uitsunomiya, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Inada
authors.forename: A
authors.initials: A
authors.lastname: Ichikawa
authors.forename: T
authors.initials: T
authors.lastname: Kubota
authors.forename: Y
authors.initials: Y
authors.lastname: Ogata
authors.forename: A R
authors.initials: AR
authors.lastname: Moossa
authors.forename: R M
authors.initials: RM
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005434:Flow Cytometry; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D012334:RNA, Neoplasm / Q000096:biosynthesis; D016196:S Phase; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D013997:Time Factors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D012334:RNA, Neoplasm; D013940:Thymidylate Synthase; D005472:Fluorouracil