Antitumor activity of a novel synthetic polyamine analogue, N,N'-bis-[3-(ethylamino)-propyl]-1-7-heptane diamine: potentiation by polyamine oxidase inhibitors.
The requirement of the natural polyamines, putrescine, spermidine and spermine, for cell growth suggests that appropriate structural analogues of these compounds could serve as potential antiproliferative agents acting via polyamine antagonism. In this investigation, the antiproliferative activity of N, N'-Bis[3-(ethylamino)-propyl]-1-7-heptane diamine (BEPH), a synthetic polyamine analogue, was investigated employing HeLa cells in culture and L1210 leukemia in mice. BEPH inhibited the growth of HeLa cells with an IC50 of 0.25 microM during a four day culture period. This concentration of the compound was cytotoxic to the cells as evidenced by an 80% reduction in cloning efficiency. Only marginal changes in intracellular polyamine concentrations were observed during incubation with 0.25 microM BEPH. In both HeLa cells and L1210 cells in culture, incorporation of radioactive precursors into DNA, RNA and protein were reduced by BEPH. Inhibition of protein synthesis was discernible prior to inhibition of RNA and DNA in these cells. In mice inoculated i.p. with 10(5) L1210 cells on day 0, i.p. administration of 10.0 mg/kg of BEPH qd(X5) beginning on day 1 prolonged the survival time by 84% compared to controls. The same dose of the compound, in combination with 10.0 mg/kg of N,N'-bis-2-3-butadienylputrescine, an inhibitor of the polyamine catabolizing enzyme polyamine oxidase (PAO), produced a 100% cure rate. Similar results were obtained when BEPH was combined with N-methyl-N'-2-3-butadienylputrescine, another PAO inhibitor. Furthermore, animals cured of the leukemia by the combination chemotherapy were resistant to a subsequent challenge with L1210 cells, indicating the development of tumor "immunity". The striking antitumor activity along with the development of tumor immunity indicate that synthetic polyamine analogues have potential for development as antineoplastic agents.
Prakash
N J
NJ
Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Bowlin
T L
TL
Edwards
M L
ML
Sunkara
P S
PS
Sjoerdsma
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015317:Biogenic Polyamines / Q000032:analysis / Q000378:metabolism; D003959:Diamines / Q000494:pharmacology* / Q000627:therapeutic use; D004351:Drug Resistance; D004357:Drug Synergism; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D008297:Male; D051379:Mice; D009696:Nucleic Acids / Q000096:biosynthesis; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors*; D011073:Polyamines / Q000494:pharmacology* / Q000627:therapeutic use; D014176:Protein Biosynthesis; D000097667:Polyamine Oxidase
D000970:Antineoplastic Agents; D015317:Biogenic Polyamines; D003959:Diamines; D009696:Nucleic Acids; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D000097667:Polyamine Oxidase; C066203:N,N'-bis(3-(ethylamino)propyl)-1,7-heptanediamine