15-Deoxyspergualin, an antiproliferative agent for human and mouse leukemia cells shows inhibitory effects on the synthetic pathway of polyamines.
The mechanism of the antitumor action of 15-deoxyspergualin (DSG) was investigated. DSG inhibited spermidine synthase noncompetitively with putrescine, spermine synthase competitively with spermidine and polyamine oxidase in vitro. Induction of ornithine decarboxylase (ODC) activity observed after subculture of human leukemia cells was blocked by the addition of DSG to the culture medium. In DSG-treated leukemia cells, putrescine, spermidine and spermine levels were markedly depressed. The synthesis of protein was also greatly diminished in these polyamine-depleted leukemic cells, whereas the depressions of DNA and RNA syntheses were minimum. In in vivo experiments, DSG depressed polyamine levels in P388 leukemic ascites cells, and prolonged the survival times of mice bearing the leukemia cells. These results suggest that inhibition of polyamine and protein biosyntheses by DSG is substantially responsible for its antitumor action on the tumor cells.
Hibasami
H
H
College of Medical Sciences, Mie University, Japan.
Tsukada
T
T
Suzuki
R
R
Takano
K
K
Takaji
S
S
Takeuchi
T
T
Shirakawa
S
S
Murata
T
T
Nakashima
K
K
D000123:Acetyltransferases / Q000037:antagonists & inhibitors; D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002286:Carcinoma, Ehrlich Tumor / Q000201:enzymology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D007938:Leukemia; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D065108:Ornithine Decarboxylase Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors; D011073:Polyamines / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013097:Spermine Synthase / Q000037:antagonists & inhibitors*; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D012437:Adenosylmethionine Decarboxylase; D000903:Antibiotics, Antineoplastic; D006146:Guanidines; D009363:Neoplasm Proteins; D065108:Ornithine Decarboxylase Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D012334:RNA, Neoplasm; D013097:Spermine Synthase; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase; C037258:gusperimus