Synergistic antileukemic effect of two polyamine synthesis inhibitors. Host survival and cell-cycle kinetic analysis.
alpha-Difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase, was used alone and in combination with multiple doses of methylglyoxal-bis(guanylhydrazone) (MGBG) to treat mice with systemic L1210 leukemia. Used as a single agent (administered p.o. as a 3% solution in tap water), DFMO exerted a weak therapeutic effect against this tumor. The therapeutic effect of MGBG (administered i.p. at 50 mg/kg/day) was only slightly better. However, 1-3 days of pretreatment with DFMO strongly potentiated the effect of MGBG treatment. Thus, mice treated with the combination exhibited an increase in life span of up to 138%. The prolonged survival of leukemic mice treated with a combination of DFMO and MGBG was associated with inhibition of polyamine synthesis and a marked decrease in the spermidine and spermine content of the tumor cells as compared to untreated controls. As a consequence, there was a continuous decrease in the S- and G2-phase fractions with a concomitant increase in G1. Used singly, DFMO and MGBG had no significant effect on the cell-cycle distribution. The effects of the combination of DFMO and MGBG on the cell-cycle distribution are consistent with the contention that polyamine deficiency primarily interferes with initiation of DNA synthesis. However, the possibility that selective S-phase kill partly contributes to this change in cell-cycle distribution cannot be excluded.
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D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D004357:Drug Synergism; D000518:Eflornithine; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008935:Mitoguazone / Q000008:administration & dosage / Q000494:pharmacology*; D009952:Ornithine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000096:biosynthesis*
D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D009952:Ornithine; D012437:Adenosylmethionine Decarboxylase; D008935:Mitoguazone; D000518:Eflornithine