Effect of pretreatment with alpha-difluoromethylornithine on the selectivity of methylglyoxal bis(guanylhydrazone) for tumor tissue in L1210 leukemic mice.
A number of studies have demonstrated that pretreatment of tumor-bearing animals with the inhibitor of polyamine biosynthesis, alpha-difluoromethylornithine (DFMO), potentiates the antitumor activity of methylglyoxal bis(guanylhydrazone) (MGBG). The present study examines whether this phenomenon is related to a DFMO-mediated increase in the selectivity of MGBG for tumor tissue. Specifically, the effect of DFMO pretreatment on the tissue distribution and content of MGBG was investigated in mice bearing ascites L1210 leukemia. At 3 and 18 h following a single i.v. injection of [14C]MGBG (50 mg/kg), L1210 cells and seven tissues from nonpretreated (control) and DFMO-pretreated (3% by drinking water for 3 days) animals were compared for their [14C]MGBG content. In control mice, the greatest amount of drug was found in L1210 cells, small intestine, and kidney (in decreasing order of magnitude) at both 3 and 18 h. This distribution was not altered following DFMO pretreatment, but the relative MGBG content of other tissues was shifted. On an average, DFMO pretreatment increased the accumulation of MGBG by 30% in normal tissues and 32% in tumor tissues at 3 h and 56% and 69%, respectively, at 18 h. Thus, pretreatment of leukemic mice with DFMO fails to improve the selectivity of MGBG for L1210 cells. It is possible that other tumor systems might demonstrate sufficient DFMO-mediated increases in MGBG uptake to enhance drug selectivity but not without significantly increasing MGBG uptake (and hence toxicity) in normal tissues.
D000818:Animals; D002250:Carbon Radioisotopes; D004359:Drug Therapy, Combination; D000518:Eflornithine; D005260:Female; D006146:Guanidines / Q000378:metabolism*; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D008935:Mitoguazone / Q000008:administration & dosage / Q000378:metabolism*; D009952:Ornithine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
D002250:Carbon Radioisotopes; D006146:Guanidines; D009952:Ornithine; D008935:Mitoguazone; D000518:Eflornithine