Chemoprotection by 9-aminoacridine derivatives against the cytotoxicity of topoisomerase II-directed drugs.

The effect of three acridine derivatives, 9-aminoacridine (9AA), 4'-(9-acridinylamino)-methanesulphon-O-anisidide (O-AMSA) and quinacrine were compared in their ability to protect against the cytotoxicity of amsacrine, 9-[[2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino)-N,5-dimethyl-4- acridine-carboxamide (CI-921), N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC), etoposide, mitoxantrone and doxorubicin. Cytotoxicity was measured in vitro by clonogenic survival assay and in vivo by life extension assays. All three acridine derivatives protected a Lewis lung cell line in vitro against CI-921, with 9AA having the highest activity. Cellular uptake of [14C] CI-921 by cultured Lewis lung cells was unaffected by 9AA, and slightly stimulated by O-AMSA and quinacrine. 9AA protected Lewis lung cells in vitro against the cytotoxicity of amsacrine, CI-921, AC and etoposide, partially against mitoxantrone but not against doxorubicin. A similar result was obtained with the human melanoma cell line MM96, where 9AA protected against CI-921 but not against doxorubicin toxicity. 9AA protected P388 leukaemia in vivo against amsacrine, CI-921 and AC cytotoxicity, partially against etoposide but not against mitoxantrone or doxorubicin. 9AA also protected against animal toxicity caused by high dose amsacrine and partially against CI-921 toxicity. It is hypothesized that DNA intercalating chemoprotectors act by restricting the conformational flexibility of the DNA and thus the ability of topoisomerase II to form a 'cleavable complex' in which the DNA is covalently linked to the enzyme.