Comparative antitumor properties in rodents of irreversible inhibitors of L-ornithine decarboxylase, used as such or as prodrugs.
The antitumor properties of (E)-2-(fluoromethyl)dehydroornithine methyl ester (delta-MFMO-ME) and of (E)-2-(fluoromethyl)dehydroornithine ethyl ester (delta-MFMO-EE), the prodrugs of delta-MFMO, an irreversible inhibitor of mammalian L-ornithine decarboxylase (ODC) 14 times more potent than alpha-difluoromethylornithine (DFMO) and equipotent to (2R,5R)-6-heptyne-2,5-diamine (MAP) in vitro, have been investigated in L1210 leukemia- and Lewis lung carcinoma-bearing mice. The anticancer properties of these esters have been compared with those of DFMO and MAP as a function of the dose, the route of administration, and the stage of the lewis lung carcinoma development in mice. The two esters, administered i.p. shortly after cell inoculation at one-fifth the dose of DFMO, prolonged the survival of mice-bearing leukemia to the same extent as DFMO and MAP. When administered orally to leukemia-bearing mice the two esters were equipotent at prolonging survival. The methyl ester appears, however, to be slightly, but not significantly, more effective than the ethyl ester against leukemia when given i.p., maximum prolongation of the mice survival (79%) occurring at 0.5 g/kg methyl ester every 12 h. The two esters achieve at one-sixth to one-twelfth the dose, antitumor effects similar to DFMO in the Lewis lung carcinoma model, the ethyl ester being slightly, but not significantly, more effective than the methyl ester when administered orally. Moreover, the ethyl ester causes greater reduction of tumor growth than DFMO (P less than 0.05) and MAP (P less than 0.01) in this model. Inhibition of tumor growth is correlated with spermidine depletion and an increase of decarboxylated-S-adenosylmethionine, the aminopropyl donor in the spermidine and spermine synthase reactions. All ODC inhibitors, however, lose most of their antitumor properties when administered at late stage of Lewis lung carcinoma development. Finally, this study demonstrates the advantage of using prodrugs of delta-MFMO, an inhibitor of ODC, since they possess longer duration of action, higher potency, and in some cases better antitumor efficiency than the parent direct inhibitor of ODC. Moreover, and as already noticed for DFMO or MAP, no sign of overt toxicity is caused by the highest effective antitumor doses of the esters.
Claverie
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Merrell Dow Research Institute, Strasbourg, France.
Mamont
P S
PS
D000284:Administration, Oral; D000480:Alkynes; D000818:Animals; D003959:Diamines / Q000008:administration & dosage / Q000494:pharmacology; D000518:Eflornithine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D065108:Ornithine Decarboxylase Inhibitors; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology*; D012436:S-Adenosylmethionine / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000473:pathology
D000480:Alkynes; D003959:Diamines; D065108:Ornithine Decarboxylase Inhibitors; D011355:Prodrugs; D012436:S-Adenosylmethionine; C039613:6-heptyne-2,5-diamine; C047399:2-(fluoromethyl)dehydroornithine methyl ester; C060377:2-(fluoromethyl)dehydroornithine ethyl ester; D000518:Eflornithine