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.
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.
Matsuhashi
Nobuhisa
N
Department of Surgical Oncology, Gifu University School of Medicine, 1-1 Yangido, Gifu City 501-1194, Japan. nobuhisa517@hotmail.com
Saio
Masanao
M
Matsuo
Atsushi
A
Sugiyama
Yasuyuki
Y
Saji
Shigetoyo
S
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*
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D006690:Bisbenzimidazole; D002945:Cisplatin; D005472:Fluorouracil