title: Schedule-dependent in vitro combination effects of methotrexate and 5-fluorouracil in human tumor cell lines.
abstract: Because of conflicting reports of clinical synergy, we used the tetrazolium-based colorimetric (MTT) assay to test in vitro combination effects of methotrexate (MTX) plus 5-fluorouracil (FUra) in 4 schedules on 2 human non-small-cell lung cancer cell lines (adenocarcinoma, NC1-H23; bronchio-alveolar-cell carcinoma, NC1-H358), and 1 human colorectal adenocarcinoma cell line (SNU-C1). The complete 3 dimensional set of isoboles in the dose range under study was generated by a microcomputer-based method. We found that the combination effects of 8-hr sequential FUra-MTX, simultaneous administration of MTX-FUra, and 8-hr sequential MTX-FUra were clearly antagonistic for all 3 cell lines. In contrast, the combination cytotoxic effects of 24-hr sequential MTX-FUra were much more active. Our in vitro model thus clearly shows that MTX-FUra interactions are highly schedule-dependent. This provides a rational basis for testing sequential MTX-FUra with a longer administration interval than usually employed clinically.
authors.affiliation: Chest Department, Veterans General Hospital-Taipei, Taiwan, Republic of China.
authors.forename: C M
authors.initials: CM
authors.lastname: Tsai
authors.forename: A F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: R P
authors.initials: RP
authors.lastname: Perng
authors.forename: B S
authors.initials: BS
authors.lastname: Kramer
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000188:drug therapy / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D004334:Drug Administration Schedule; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008727:Methotrexate / Q000008:administration & dosage; D008838:Microcomputers; D008968:Molecular Conformation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012984:Software; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D005472:Fluorouracil; D008727:Methotrexate