DECREASED CYTO-TOXICITY OF CIS-DIAMMINEDICHLOROPLATINUM(II) BY ALPHA-DIFLUOROMETHYLORNITHINE DEPLETION OF POLYAMINES IN 9L RAT-BRAIN TUMOR-CELLS INVITRO

  • 1 January 1982
    • journal article
    • research article
    • Vol. 42  (4) , 1296-1299
Abstract
Before treatment with the cytotoxic drug cis-dichlorodiammineplatinum(II) (cis-platinum), 9L rat brain gliosarcoma cells grown in vitro were depleted of intracellular polyamines by .alpha.-difluoromethylornithine (DFMO; 10 mM, 48 h), an enzyme-activated, irreversible inhibitor of the polyamine-synthetic enzyme ornithine decarboxylase. In contrast to studies that showed that the cytotoxicity of 1,3-bis (2-chloroethyl)-1-nitrosourea as measured by colony-forming efficiency is enhanced by DFMO depletion of intracellular polyamines, the cytotoxicity of cis-platinum was significantly decreased in polyamine-depleted 9L cells. At 10, 1 and 0.1% survival levels, the dose modification factors were 2.0-2.1. Addition of exogenous putrescine to polyamine-depleted 9L cells 24 h before treatment with cis-platinum partially reversed this phenomenon. When 9L cells were treated either with DFMO and cis-platinum or with DFMO, putrescine and cis-platinum for 1 h, a time period that is too short for DFMO to affect intracellular polyamine levels, the cytotoxicity of cis-platinum was decreased, but to a significantly lesser extent than by the 48-h DFMO pretreatment. Putrescine alone did not alter the cytotoxic effect of cis-platinum when administered either 24 or 1 h before treatment. DFMO appears to affect cis-platinum cytotoxicity by 2 different mechanisms, the 1st mediated through polyamine depletion and the 2nd through a direct interaction with cis-platinum.