Comparative molecular pharmacology in leukemic L1210 cells of the anthracene anticancer drugs mitoxantrone and bisantrene.
1,4-Dihydroxy-5,8-bis(2-[(2-hydroxyethyl)aminoethyl]amino)-9, 10-anthracenedione (mitoxantrone) and 9,10-anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazol-2y)hydrazone] dihydrochloride (bisantrene) were evaluated for their abilities to cause cytotoxicity and interact with cellular DNA using leukemic L1210 cells. On a molar basis mitoxantrone has been found to be 7-fold more toxic than bisantrene. Using a nucleoid sedimentation technique, bisantrene caused changes in DNA supercoiling which were characteristic of an intercalating drug, but mitoxantrone did not induce these changes. Both drugs were found to interact with cellular DNA with tight but noncovalent binding. Both drugs also induced protein-associated double- and single-strand DNA breaks, but with mitoxantrone only some of the DNA single-strand breaks were protein associated, whereas with bisantrene all the DNA single-strand breaks were protein associated. The cytotoxicity produced by bisantrene at a given frequency of protein-associated DNA strand breaks was low. However, with mitoxantrone at an equivalent DNA strand break frequency, the cytotoxicity was high. Treatment of isolated L1210 nuclei with either drug did not result in DNA single-strand breaks. It can be concluded that bisantrene binds DNA in whole cells by an intercalative mechanism, whereas mitoxantrone binds DNA by a nonintercalative, electrostatic interaction and induces non-protein-associated DNA strand breaks.
D000818:Animals; D000873:Anthracenes / Q000378:metabolism / Q000494:pharmacology; D000880:Anthraquinones / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D004277:DNA, Single-Stranded; D004278:DNA, Superhelical / Q000032:analysis; D007939:Leukemia L1210 / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008942:Mitoxantrone
D000873:Anthracenes; D000880:Anthraquinones; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004277:DNA, Single-Stranded; D004278:DNA, Superhelical; C031404:bisantrene; D008942:Mitoxantrone