title: Schedule-dependent synergism and antagonism between pemetrexed and paclitaxel in human carcinoma cell lines in vitro.
abstract: Pemetrexed is a novel multitargeted antifolate with significant clinical activity against a variety of tumors. We studied the schedule-dependent cytotoxic effects of pemetrexed in combination with paclitaxel in vitro to improve our understanding of how this combination might be used clinically. Human lung cancer A549 cells, breast cancer MCF7, ovarian cancer PA1, and colon cancer WiDr cells were exposed to both pemetrexed and paclitaxel in vitro. Cell growth inhibition after 5 days was determined and the effects of drug combinations were analyzed by the isobologram method (Steel and Peckham). Simultaneous exposure to pemetrexed and paclitaxel for 24 h produced antagonistic effects in A549 and PA1 cells, additive/antagonistic effects in MCF7 cells, and additive effects in WiDr cells. Pemetrexed for 24 h followed by paclitaxel for 24 h produced synergistic effects in A549 and MCF7 cells and additive effects in PA1 and WiDr cells, while the reverse sequence produced additive effects in all four cell lines. Cell cycle analysis supported these observations. Our findings suggest that the simultaneous administration of pemetrexed and paclitaxel is suboptimal. The optimal schedule of pemetrexed in combination with paclitaxel is the sequential administration of pemetrexed followed by paclitaxel, and this schedule should be assessed in clinical trials for the treatment of solid tumors.
authors.affiliation: Division of Hematology, Tochigi Cancer Center, Yonan, Utsunomiya, Tochigi, 320-0834, Japan. ykano@tcc.pref.tochigi.jp
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kano
authors.forename: Miyuki
authors.initials: M
authors.lastname: Akutsu
authors.forename: Saburo
authors.initials: S
authors.lastname: Tsunoda
authors.forename: Tohru
authors.initials: T
authors.lastname: Izumi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mori
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Fujii
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yazawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mano
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Furukawa
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D005971:Glutamates / Q000008:administration & dosage / Q000494:pharmacology*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D000068437:Pemetrexed; D014407:Tumor Cells, Cultured
chemical_list: D005493:Folic Acid Antagonists; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D017239:Paclitaxel