INFLUENCE OF POLYAMINE DEPLETION CAUSED BY ALPHA-DIFLUOROMETHYLORNITHINE, AN ENZYME-ACTIVATED IRREVERSIBLE INHIBITOR OF ORNITHINE DECARBOXYLASE, ON ALKYLATION-INDUCED AND CARBAMOYLATION-INDUCED CYTO-TOXICITY IN 9L RAT-BRAIN TUMOR-CELLS INVITRO

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (10) , 4606-4609
Abstract
Using a colony-forming efficiency assay, the effect was studied of polyamine depletion on the cytotoxicity of 4 nitrosoureas with different capacities to alkylate and/or carbamoylate biomolecules. 9L rat brain tumor cells were treated with 10 mM .alpha.-difluoromethylornithine for 48 h before a 1 h treatment with nitrosoureas. The cytotoxicity of 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose (chlrozotocin), which alkylates and subsequently cross-links DNA, but does not carbamoylate, was significantly increased by depletion of intracellular polyamines; the dose enhancement ratio of 1.3 is identical to that found for 1,3-bis(2-chloroethyl)-1-nitrosourea and 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl-1-nitrosourea in previous studies. Addition of exogenous putrescine to polyamine-depleted 9L cells 24 h before treatment prevented this phenomenon. The cytotoxicity of 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea, which carbamoylates only, was significantly decreased in polyamine-depleted cells. This compound alone reduced intracellular polyamine levels. Polyamine depletion did not affect the cytotoxicity of the monoalkylating nitrosoureas N-ethyl-N-nitrosourea and N-methyl-N-nitrosourea. Thus, polyamine depletion apparently potentiates the cytotoxicity only of chloroethylnitrosoureas that alkylate and cross-link.