title: In vitro cytotoxic effects of fludarabine (2-F-ara-A) in combination with commonly used antileukemic agents by isobologram analysis.
abstract: Fludarabine phosphate (2-F-ara-AMP) is an adenine nucleoside analogue that shows significant activity against chronic lymphocytic leukemia and indolent lymphoma. We assessed the cytotoxic interaction produced by the combination of the active metabolite of fludarabine phosphate, fludarabine (9-beta-D-arabinofuranosyl-2-fluoroadenine, 2-F-ara-A), and some commonly used antileukemic agents against human hairy cell leukemia cell line JOK-1, human chronic lymphocytic leukemia cell line SKW-3, and adult T cell leukemia cell lines ED-40810 (-) and SALT-3. The leukemia cells were exposed simultaneously to 2-F-ara-A and to the other agents for 4 days. Cell growth inhibition was determined using MTT reduction assay. The isobologram method of Steel and Peckham was used to evaluate the cytotoxic interaction. 2-F-ara-A and cytarabine showed synergistic effects in SKW-3 cells, additive and synergistic effects in JOK-1 and SALT-3 cells, and additive effects in ED-40810(-) cells. 2-F-ara-A and doxorubicin showed additive effects in SKW-3, ED-40810(-) and SALT-3 cell lines, and additive and synergistic effects in JOK-1 cells. 2-F-ara-A showed additive effects with etoposide, 4-hydroperoxy-cyclophosphamide, and hydroxyurea in all four cell lines. 2-F-ara-A showed antagonistic effects with methotrexate and vincristine in all four cell lines. Our findings suggest that the simultaneous administration of fludarabine phosphate with cytarabine, doxorubicin, etoposide, cyclophosphamide, or hydroxyurea would be advantageous for cytotoxic effects. Among these agents, cytarabine may be the best agent for the combination with fludarabine phosphate. The simultaneous administration of fludarabine phosphate with methotrexate or vincristine would have little cytotoxic effect, and this combination may be inappropriate. These findings may be useful in clinical trials of combination chemotherapy with fludarabine phosphate and these agents.
authors.affiliation: Division of Medical Oncology, Tochigi Cancer Center, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kano
authors.forename: M
authors.initials: M
authors.lastname: Akutsu
authors.forename: S
authors.initials: S
authors.lastname: Tsunoda
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: A
authors.initials: A
authors.lastname: Ichikawa
authors.forename: Y
authors.initials: Y
authors.lastname: Furukawa
authors.forename: L
authors.initials: L
authors.lastname: Bai
authors.forename: K
authors.initials: K
authors.lastname: Kon
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity; D003561:Cytarabine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology / Q000633:toxicity; D007943:Leukemia, Hairy Cell / Q000473:pathology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology*; D008727:Methotrexate / Q000494:pharmacology / Q000633:toxicity; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D001084:Vidarabine Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology / Q000633:toxicity
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D003561:Cytarabine; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine; C011272:perfosfamide; D006918:Hydroxyurea; D008727:Methotrexate