title: Schedule-dependent interactions between pemetrexed and cisplatin in human carcinoma cell lines in vitro.
abstract: The combination of pemetrexed and cisplatin shows good clinical activity against mesothelioma and lung cancer. In order to study the potential cellular basis for this, and provide leads as to how to optimize the combination, we studied the schedule-dependent cytotoxic effects of pemetrexed and cisplatin against four human cancer cell lines in vitro. Tumor cells were incubated with pemetrexed and cisplatin for 24 h at various schedules. The combination effects after 5 days were analyzed by the isobologram method. Both simultaneous exposure to pemetrexed and cisplatin for 24 h and sequential exposure to cisplatin for 24 h followed by pemetrexed for 24 h produced antagonistic effects in human lung cancer A549, breast cancer MCF7, and ovarian cancer PA1 cells and additive effects in colon cancer WiDr cells. Pemetrexed for 24 h followed by cisplatin for 24 h produced synergistic effects in MCF7 cells, additive/synergistic effects in A549 and PA1 cells, and additive effects in WiDr cells. Cell cycle analysis of MCF7 and PA1 cells supported these findings. Our results suggest that the simultaneous clinical administration of pemetrexed and cisplatin may be suboptimal. The optimal schedule of pemetrexed in combination with cisplatin at the cellular level is the sequential administration of pemetrexed followed by cisplatin and this schedule is worthy of clinical investigations.
authors.affiliation: Division of Hematology, Tochigi Cancer Center, 4-9-13, 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: Hiroyuki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Koichi
authors.initials: K
authors.lastname: Inoue
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mori
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Fujii
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mano
authors.forename: Tsogbadrakh
authors.initials: T
authors.lastname: Odgerel
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Furukawa
mesh_terms: D002277:Carcinoma / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004347:Drug Interactions; D005434:Flow Cytometry; D005971:Glutamates / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D000068437:Pemetrexed; D013997:Time Factors
chemical_list: D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D002945:Cisplatin