Antitumor activity of norspermidine, a structural homologue of the natural polyamine spermidine.
The structural specificities of the natural polyamines putrescine (Put), spermidine (Spd) and spermine (Spm) for cell growth are rather stringent, suggesting that appropriate structural analogues of these polycations could serve as potential antineoplastic agents via polyamine antagonism. Norspermidine (Nspd), a homologue of spermidine, had significant antitumor activity against L1210 leukemia, 3LL carcinoma and EL4 lymphoma in mice. The observed antitumor activity of the compound was potentiated by administration of a - difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase. DFMO treatment alone, or in combination with Nspd reduced tumoral Put and Spd levels by greater than 50% in all three tumor models. In animals receiving both Nspd and DFMO, Nspd accumulation in the tumor cells was increased by 50% or more compared to cells from animals receiving Nspd only. Co-administration of Spd, but not Put, abolished the antitumor activity of L1210 observed with DFMO and Nspd treatment, and also reduced the tumoral accumulation of Nspd. These results indicate that appropriate structural analogues of the natural polyamines may be useful as antineoplastic agents.
D012437:Adenosylmethionine Decarboxylase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000518:Eflornithine / Q000494:pharmacology; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000201:enzymology; D008175:Lung Neoplasms / Q000188:drug therapy*; D008223:Lymphoma / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011700:Putrescine / Q000494:pharmacology; D013095:Spermidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; C006760:norspermidine; D009955:Ornithine Decarboxylase; D012437:Adenosylmethionine Decarboxylase; D013095:Spermidine; D011700:Putrescine; D000518:Eflornithine