Design of DNA intercalators to overcome topoisomerase II-mediated multidrug resistance.

Abstract

Murine P388 (P) leukemia cell lines resistant to amsacrine (P/AMSA), dactinomycin (P/DACT), and doxorubicin (P/DOX) were compared with the parental strain in their sensitivity to a number of derivatives of amsacrine. The P/DACT cell line, which shows the characteristics of a transport-mediated multidrug-resistant cell line, was cross-resistant to vincristine, doxorubicin, etoposide, and a number of acridine-substituted amsacrine derivatives, but was sensitive in vitro and in vivo to amsacrine and its analog CI-921. The P/DOX cell line was cross-resistant to amsacrine but showed a similar pattern of cross-resistance to that of P/DACT in its in vitro response to amsacrine derivatives. In contrast, the P/AMSA line was substantially cross-resistant (from 27- to 146-fold) to all acridine-substituted amsacrine derivatives. However, when the substituents on the anilino side chain of amsacrine were changed, the in vitro cross-resistance of the P/AMSA line could be substantially reduced and even overcome. Derivatives with low cross-resistance ratios were tested in vivo against the P/AMSA leukemia and, in contrast to amsacrine and CI-921, were found to be active. Since the target enzyme for amsacrine action, topoisomerase II, is thought to be structurally modified in the P/AMSA line as well as in some other multidrug-resistant lines, these results suggest the feasibility of tailoring topoisomerase II-directed drugs specifically for the altered enzymes in resistant cells. New drug design approaches are therefore available for overcoming two major types of multidrug resistance.