Antitumor effect of a new multienzyme inhibitor of polyamine synthetic pathway, methylglyoxal-bis(cyclopentylamidinohydrazone), against human and mouse leukemia cells.
Methylglyoxal-bis(cyclopentylamidinohydrazone) (MGBCP) has been synthesized as a multienzyme inhibitor for the polyamine-synthesizing pathway. This drug inhibited S-adenosylmethionine decarboxylase (EC 4.1.1.50), spermine synthase and spermidine synthase activities, competitively with S-adenosylmethionine, spermidine, and putrescine, respectively. MGBCP inhibited the growth of human leukemia Molt 4B and K 562 cells at 10 to 100 microM concentrations. Spermidine and spermine levels were markedly depressed in these MGBCP-treated leukemic cells, and the synthesis of protein, but not of DNA or RNA, was significantly diminished. In in vivo experiments, MGBCP depleted spermidine and spermine in the P388 leukemic ascites cells, and prolonged the survival time of mice bearing P388 leukemia. The S-adenosylmethionine decarboxylase-stabilizing effect of MGBCP in mouse liver, Molt 4B and K 562 cells was much less than that of the parent inhibitor methylglyoxal-bis(guanylhydrazone). Induction of ornithine decarboxylase activity by MGBCP in the cultured leukemic cells was also much less than that by methylglyoxal-bis(guanylhydrazone).
Hibasami
H
H
Department of Biochemistry, Mie University School of Medicine, Japan.
Maekawa
S
S
Murata
T
T
Nakashima
K
K
D012437:Adenosylmethionine Decarboxylase / Q000032:analysis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015317:Biogenic Polyamines / Q000032:analysis; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008935:Mitoguazone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009955:Ornithine Decarboxylase / Q000032:analysis; D011436:Spermidine Synthase / Q000037:antagonists & inhibitors*; D013097:Spermine Synthase / Q000037:antagonists & inhibitors*; D014166:Transferases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D015317:Biogenic Polyamines; C059234:methylglyoxal bis(cyclopentylamidinohydrazone); D014166:Transferases; D011436:Spermidine Synthase; D013097:Spermine Synthase; D009955:Ornithine Decarboxylase; D012437:Adenosylmethionine Decarboxylase; D008935:Mitoguazone