Decreased cytotoxicity of aziridinylbenzoquinone caused by polyamine depletion in 9L rat brain tumor cells in vitro.
The in vitro cytotoxicity of aziridinylbenzoquinone (AZQ) used either alone or after induced intracellular polyamine depletion in 9L rat brain tumor cells was studied using a colony-forming efficiency assay. Used alone, AZQ was cytotoxic to 9L cells; however, depletion of intracellular putrescine and spermidine levels by treatment with 1 mM alpha-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, for 72 hr decreased significantly the cytotoxicity of AZQ. Dose modification factors were 1.9 and 1.8 at 10 and 1% survival levels, respectively. Decreased cytotoxicity could be almost completely prevented by addition of putrescine to polyamine-depleted cells 24 hr before AZQ treatment. Although AZQ alone was cytotoxic against 9L cells, metabolic activation by the S-9 rat liver microsomal fraction increased greatly the observed cytotoxicity. However, even with microsomal activation, pretreatment of cells with 1 mM alpha-difluoromethylornithine for 48 hr produced a significant decrease in AZQ cytotoxicity; dose modification factors were 2.4 and 2.2 at 10 and 1% survival levels, respectively. Addition of putrescine to polyamine-depleted cells 24 hr before AZQ treatment prevented the decrease in cytotoxicity. Pretreatment of 9L cells for 48 hr with 40 microM methylglyoxal bis(guanylhydrazone), a polyamine biosynthesis inhibitor that competitively inhibits S-adenosylmethionine decarboxylase, caused a decrease in the cytotoxicity of AZQ administered without microsomal activation. The dose modification factor was 1.6 at both 10 and 1% survival levels.
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001388:Aziridines / Q000633:toxicity*; D001389:Azirines / Q000633:toxicity*; D016227:Benzoquinones; D001932:Brain Neoplasms / Q000503:physiopathology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D053138:Cyclohexenes; D000518:Eflornithine; D007700:Kinetics; D009952:Ornithine / Q000031:analogs & derivatives / Q000633:toxicity; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism*; D051381:Rats
D000970:Antineoplastic Agents; D001388:Aziridines; D001389:Azirines; D016227:Benzoquinones; D053138:Cyclohexenes; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; C006052:2,5-bis(1-aziridinyl)-3,6-bis(2-methoxyethoxy)-4-benzoquinone; D009952:Ornithine; D000518:Eflornithine