title: The evaluation of gastric cancer sensitivity to 5-FU/CDDP in terms of induction of apoptosis: time- and p53 expression-dependency of anti-cancer drugs.
abstract: Clinical in vivo and in vitro studies have revealed pronounced gastric cancer activity using the combination of 5-fluorouracil (5-FU) and cisplatin (CDDP). In addition, the combination of 5-fluorouracil plus cisplatin (FP treatment) possesses synergistic cytotoxicity against gastric cancer. Sensitivity of two gastric cancer cell lines to anti-cancer drugs, 5-fluorouracil (5-FU) and/or cisplatinum (CDDP), was evaluated by use of either flow cytometric analysis (FACS) or morphological observation in terms of induction of apoptosis. In morphological observation, a new experimental technique was used in which cancer cells were distributed in thin collagen gel as one or two cell layers, and cultured with anti-cancer drugs. Thereafter, cells were stained with fluorescent Hoechst 33258 (Ho) and photographed, then stained with hematoxylin and eosin (H&E) and photographed again. Cell death patterns were determined by combining observations of Ho- and H&E-stained cells. While combined administration of 5-FU and CDDP did not induce apoptosis of MKN-28 (mutant-type p53), apoptotic cells were markedly observed in the case of MKN45 (wild-type p53). In addition, consecutive administration of CDDP for 3 h and 5-FU for 21 h effectively induced apoptosis of MKN45. These results indicated that the type of p53 expression in cancer cells could be a promising factor in predicting response to FP therapy and the administration of CDDP prior to 5-FU may be more effective in inducing apoptosis of gastric cancer cells with wild-type p53 expression. These data may provide evidence to support the idea that p53 expression is related to multidrug resistance (MDR) in FP therapy of gastric cancer cell lines.
authors.affiliation: Department of Surgical Oncology, Gifu University School of Medicine, 1-1 Yangido, Gifu City 501-1194, Japan. nobuhisa517@hotmail.com
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Matsuhashi
authors.forename: Masanao
authors.initials: M
authors.lastname: Saio
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsuo
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Shigetoyo
authors.initials: S
authors.lastname: Saji
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006690:Bisbenzimidazole / Q000737:chemistry; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D005434:Flow Cytometry / Q000379:methods; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D008856:Microscopy, Fluorescence / Q000379:methods; D009154:Mutation; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D006690:Bisbenzimidazole; D002945:Cisplatin; D005472:Fluorouracil