BACKGROUND: Our aim was to clarify the significance of widely accepted irinotecan (CPT-11)/5-fluorouracil (5-FU) combinations in colon cancer by investigating their sequential effect. METHODS: The sequential effect of CPT-11/5-FU in two colon cancer cell lines, LoVo and SW480, was evaluated by WST-8 colorimetric assay. The cell cycle distributions of each drug were analyzed by flow cytometry, and then the chemoresistant mechanisms and expression of a drug transporter (MDR1), the bcl-2 apoptotic pathway, metabolizing enzymes [carboxylesterase (CE), dihydropyrimidine dehydrogenase], and target enzymes (topoisomerase I, thymidine synthase) associated with sequence-dependent cytotoxicity were examined. RESULTS: The cytotoxicity of 5-FU (10, 100, 1000 microM) followed by CPT-11 (1 microM) was significantly greater than that of CPT-11 (1 microM) followed by 5-FU (10, 100, 1000 microM) (P < 0.05). Reverse transcription-polymerase chain reaction analysis revealed that exposure to 5-FU downregulated both MDR1 and bcl-2 mRNA and simultaneously upregulated CE2 mRNA expression, suggesting enhancement of subsequent CPT-11 cytotoxicity. CONCLUSIONS: The cytotoxic effects of the CPT-11/5-FU combinations were shown to be schedule-dependent in human colon cancer cells. The findings suggest that 5-FU followed by CPT-11 administration might be the optimal sequence for CPT-11/5-FU treatment of advanced colon cancer.
BACKGROUND: Our aim was to clarify the significance of widely accepted irinotecan (CPT-11)/5-fluorouracil (5-FU) combinations in colon cancer by investigating their sequential effect. METHODS: The sequential effect of CPT-11/5-FU in two colon cancer cell lines, LoVo and SW480, was evaluated by WST-8 colorimetric assay. The cell cycle distributions of each drug were analyzed by flow cytometry, and then the chemoresistant mechanisms and expression of a drug transporter (MDR1), the bcl-2 apoptotic pathway, metabolizing enzymes [carboxylesterase (CE), dihydropyrimidine dehydrogenase], and target enzymes (topoisomerase I, thymidine synthase) associated with sequence-dependent cytotoxicity were examined. RESULTS: The cytotoxicity of 5-FU (10, 100, 1000 microM) followed by CPT-11 (1 microM) was significantly greater than that of CPT-11 (1 microM) followed by 5-FU (10, 100, 1000 microM) (P < 0.05). Reverse transcription-polymerase chain reaction analysis revealed that exposure to 5-FU downregulated both MDR1 and bcl-2 mRNA and simultaneously upregulated CE2 mRNA expression, suggesting enhancement of subsequent CPT-11cytotoxicity. CONCLUSIONS: The cytotoxic effects of the CPT-11/5-FU combinations were shown to be schedule-dependent in humancolon cancer cells. The findings suggest that 5-FU followed by CPT-11 administration might be the optimal sequence for CPT-11/5-FU treatment of advanced colon cancer.
Authors: H C Pitot; D B Wender; M J O'Connell; G Schroeder; R M Goldberg; J Rubin; J A Mailliard; J A Knost; C Ghosh; R J Kirschling; R Levitt; H E Windschitl Journal: J Clin Oncol Date: 1997-08 Impact factor: 44.544
Authors: V Pavillard; P Formento; P Rostagno; J L Formento; J L Fischel; M Francoual; M C Etienne; G Milano Journal: Biochem Pharmacol Date: 1998-11-15 Impact factor: 5.858
Authors: T Ohmori; E R Podack; K Nishio; M Takahashi; Y Miyahara; Y Takeda; N Kubota; Y Funayama; H Ogasawara; T Ohira Journal: Biochem Biophys Res Commun Date: 1993-04-15 Impact factor: 3.575
Authors: Federica Di Nicolantonio; Stuart J Mercer; Louise A Knight; Francis G Gabriel; Pauline A Whitehouse; Sanjay Sharma; Augusta Fernando; Sharon Glaysher; Silvana Di Palma; Penny Johnson; Shaw S Somers; Simon Toh; Bernie Higgins; Alan Lamont; Tim Gulliford; Jeremy Hurren; Constantinos Yiangou; Ian A Cree Journal: BMC Cancer Date: 2005-07-18 Impact factor: 4.430