The interaction between nuclear topoisomerase II activity from human leukemia cells, exogenous DNA, and 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) or 4-(4,6-O-ethylidene-beta-D-glucopyranoside) (VP-16) indicates the sensitivity of the cells to the drugs.
The presumptive intracellular target of the anti-leukemia agents 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and 4-(4,6-O-ethylidene-beta-D-glucopyranoside) (VP-16) is the enzyme topoisomerase II. We found that 350 mM NaCl extracts of nuclei from HL-60 and HL-60/AMSA, an m-AMSA resistant HL-60 subline, contained equivalent topoisomerase II activity. However, the ability of m-AMSA to stimulate cleavage of exogenous DNA and to stimulate crosslinking of exogenous DNA with protein, processes which are topoisomerase II-mediated, was greatly reduced in the HL-60/AMSA extracts compared to the HL-60 extracts. HL-60 and HL-60/AMSA were almost equally sensitive to the cytotoxic effects of VP-16 and differences in VP-16-stimulated, topoisomerase II-mediated exogenous DNA cleavage and protein crosslinking between HL-60 and HL-60/AMSA extracts were much less than the differences in m-AMSA-stimulated exogenous DNA cleavage and protein crosslinking. Thus, the interaction between topoisomerase II activity, exogenous DNA, and m-AMSA or VP-16 indicated the susceptibility HL-60 and HL-60/ AMSA to the cytotoxic effects of the drugs. A similar correlation may exist in explanted leukemia cells from patients with acute myelogenous leukemia.
D000677:Amsacrine / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology*; D003421:Crithidia; D004247:DNA / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute; D011034:Podophyllotoxin / Q000494:pharmacology*
D000677:Amsacrine; D004247:DNA; D004250:DNA Topoisomerases, Type II; D011034:Podophyllotoxin