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Amsacrine-induced Lesions in DNA and Their Modulation by Novobiocin and 2,4-Dinitrophenol¹

Department of Radiology and Radiation Biology, Colorado State University, Fort Collins, Colorado 80523

The cancer chemotherapeutic agent amsacrine, 4'-(9-acridinylamino)-methanesulfon-m-anisidide (mAMSA), is thought to effect cytotoxicity by inhibiting the ATP-dependent enzyme topoisomerase II in the act of its duplex strand-passing action. Upon protein denaturation, the arrested "cleavable complex" that results gives rise to double- and single-strand breaks (dsbs and ssbs) and DNA-protein cross-links (dpcs). Simultaneous cotreatments with 2,4-dinitrophenol (DNP) or novobiocin (novo) abrogates mAMSA cytotoxicity in Chinese hamster cells (H. Utsumi et al., Cancer Res., 50: 2577–2581, 1990). Pulsed-field gel electrophoresis was used to estimate dsbs, velocity sedimentation in alkaline sucrose gradients for ssbs, and alkaline elution without protease digestion for dpcs. Although cotreatment with DNP or novo modulated somewhat the yield of DNA lesions due to mAMSA, quantitatively these changes did not correlate at all with, and therefore could not account for, the reduced lethality that resulted from cotreatments. For example, DNP cotreatment markedly increased the yields of dsbs, ssbs, and dpcs, even though cell killing was appreciably reduced. Furthermore, neither DNP nor novo cotreatment affected the rate, or the completeness of, the repair of mAMSA-induced DNA damage, and neither cotreatment lowered total cellular ATP. Hence, the arresting of the cleavable complex by mAMSA, made evident by lesions in DNA, did not correlate with cytotoxicity. However, cotreatment with either DNP or novo resulted in an enhanced recovery of the mAMSA-induced inhibition of replicative DNA synthesis. Because DNP and novo (transiently) slow down DNA synthesis, it is proposed that these compounds abrogate mAMSA killing of S phase cells by reducing the disorganization of the processing of replicated DNA by topoisomerase II.

¹ Supported by the Department of Health and Human Services, USPHS, via Grant CA 47497 from the National Cancer Institute.

² Present address: Radiation Biology Center, Kyoto University, Kyoto 606, Japan.

³ Present address: 3518 Westminister Ct., Fort Collins, CO 80526.

⁴ Present address: Department of Veterinary Radiology, Nihon University, Tokyo 154, Japan.

⁵ To whom requests for reprints should be addressed, at Department of Radiology and Radiation Biology, Colorado State University, Fort Collins, CO 80523.

Received 7/30/90. Accepted 10/29/90.

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