title: Experimental combination chemotherapy with thymidylate synthetase and ribonucleotide reductase inhibitors.
abstract: The synergistic cytotoxic effects on exponentially growing 9L rat brain tumor cells of several inhibitors of thymidylate synthetase (TS) and ribonucleotide reductase (RNR) used in combination were investigated using a colony forming efficiency assay as the experimental endpoint. A 24 h treatment with nontoxic (0.1 µg/ml) or low (1.0 µg/ml) doses of 5-fluorouracil (FUra), 5-fluorodeoxyuridine, 5,8-dideazaisofolic acid, or 2'-deoxy-2'-fluoro-ara-uracil markedly enhanced cell kill caused by subsequent administration of 100 µg/ml hydroxyurea (HU) for 6 h. When a similar dose of HU or 1-formylisoquinoline thiosemicarbazone was administered for 6 h immediately after a 24 h treatment with either a 0.1 µg/ml or 1.0 µg/ml of FUra, a cell kill of approximately 1 log in addition to that caused by each drug alone was obtained. Thus a synergistic cell kill was consistently obtained when a low dose of TS inhibitors was administered 24 h before a 6 h treatment with another low dose of agents that act as RNR inhibitors. This synergism was not observed when FUra-treated cells were treated with methotrexate, 6-mercaptopurine, vincristine, or l,3-bis(2-chloroethyl)-1-nitrosourea. Similarly, a 6 h treatment with 1 µg/ml of FUra of cells that had been treated for various periods with 100 µg/ml of HU did not increase cell kill more than that obtained with HU alone (30% cell kill).
authors.affiliation: Brain Tumor Research Center of the Department of Neurological Surgery, University of California, San Francisco, California, 94143, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kobayashi
authors.forename: T
authors.initials: T
authors.lastname: Hoshino
authors.forename: D V
authors.initials: DV
authors.lastname: Santi