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Relative Activity of Structural Analogues of Amsacrine against Human Leukemia Cell Lines Containing Amsacrine-sensitive or -resistant Forms of Topoisomerase II: Use of Computer Simulations in New Drug Development¹

Department of Medical Oncology, Division of Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [L. A. Z., P. S., J. M., E. A., M. H.]; The Institute for Molecular Design, Department of Chemistry, the University of Houston, Houston, Texas 77204 [M. J. M.]; and Cancer Research Laboratory, University of Auckland Medical School, Auckland, New Zealand[B. C. B.]

Anilino analogues of amsacrine showed increased activity against amsacrine (AMSA)-resistant cell lines when compared with the parent compound, but the mechanisms of amsacrine resistance in these lines were unknown (Finlay, G. J., Baguley, B. C., Snow, K., and Judd, W., J. Natl. Cancer Inst., 82: 662–667, 1990). We tested the cytotoxic and DNA-cleaving activities of two amsacrine analogues which were derivatives of 9-anilinoacridine (1'-methylcarbamate and 1'-benzenesulfonamide) against an amsacrine-resistant human leukemia cell line (HL-60/AMSA) whose resistance is due to an amsacrine-resistant topoisomerase II. Neither agent could overcome the amsacrine resistance of HL-60/AMSA. Neither agent could induce HL-60/AMSA topoisomerase II-mediated cleavage of DNA in an isolated biochemical system, although at high concentrations the two analogues could inhibit HL-60/AMSA topoisomerase II-mediated DNA strand passage. Both analogues were at least as active, if not more active, than amsacrine against amsacrine-sensitive HL-60 and its topoisomerase II. Comparison of the cellular and biochemical results with those from computer simulation of the energy-minimized structures of amsacrine, its inactive isomer o-AMSA, and the two new active analogues suggests the following possibilities: (a) the positioning of the potential topoisomerase II-binding site (1'-anilino group) of the two new drugs resembles the positioning of this site in amsacrine; (b) the HL-60 topoisomerase II has a binding site which interacts with amsacrine and the two anilino analogues but not with o-AMSA, an analogue with altered positioning of the methoxy group; (c) the HL-60/AMSA topoisomerase II interacts with reduced affinity with amsacrine and the two anilino analogues, although HL-60/AMSA topoisomerase II still interacts with the structurally distinct topoisomerase II-reactive nonintercalator, etoposide; (d) because of their higher DNA binding affinity or the greater possible positions of their side groups in comparison to amsacrine, the two analogues can, at high concentrations, inhibit the strand-passing activity of HL-60/AMSA topoisomerase II.

¹ This study was supported by USPHS Research Grant CA40090 (to L.A.Z.), by Grant CH-324D from the American Cancer Society (to L.A.Z.), by grants to Professor J. A. McCammon from the Robert A. Welch Foundation, the Texas Advanced Research Program, and HNSX Supercomputers, and by the Auckland Division of the Cancer Society of New Zealand and the Medical Research Council of New Zealand (to B.C.B.). M.J.M. is supported, in part, by HNSX supercomputers.

² To whom correspondence should be addressed, at Box 52, 1515 Holcombe Blvd., Houston, TX 77030.

Received 5/24/91. Accepted 10/ 2/91.