Comparison of the effects of treatment with the polyamine analogue N1,N8 bis(ethyl)spermidine (BESpd) or difluoromethylornithine (DFMO) on the Topoisomerase II mediated formation of 4'-(9-acridinylamino) methanesulfon-m-anisidide (m-AMSA) induced cleavable complex in the human lung carcinoma line NCI H157.
The positively charged polyamines putrescine, spermidine, and spermine are thought to be important in the maintenance of chromosomal structure. Polyamine depletion by the ornithine decarboxylase inhibitor, 2-difluoromethyl-ornithine (DFMO) is known to alter the effect of several DNA active agents, presumably resulting from the altered conformation of the polyamine depleted DNA. Here we compare the polyamine depletion effects of DFMO and the spermidine analogue N1,N8 bis(ethyl)spermidine (BESpd) on the formation of Topoisomerase II mediated, 4'-(9-acridinylamino) methanesulfon-m-anisidide (m-AMSA) induced cleavable complex formation in human large cell undifferentiated lung carcinoma NCI H157 cells. This human cell line responds in the normal cytostatic manner to DFMO, whereas it responds in an unusual cytotoxic manner to treatment with BESpd. Here we report that neither DFMO nor BESpd alone affects the formation of cleavable complex. However, both compounds significantly enhance the m-AMSA induced formation of cleavable complex, each by approximately 1.6 fold. These results indicate that both DFMO and BESpd lead to a similar depletion of nuclear polyamines. Additionally, although BESpd closely resembles the natural polyamine spermidine, it appears that it cannot substitute for Spd at the level of DNA.
Denstman
S C
SC
Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Ervin
S J
SJ
Casero
R A
RA
D000677:Amsacrine / Q000494:pharmacology*; D011232:Chemical Precipitation; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism*; D000518:Eflornithine / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D011073:Polyamines / Q000502:physiology; D013095:Spermidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D011073:Polyamines; D000677:Amsacrine; C050659:N(1),N(8)-diethylspermidine; D004250:DNA Topoisomerases, Type II; D013095:Spermidine; D000518:Eflornithine