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DNA Breakage by Tallysomycin¹

Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030 [J. E. S., S. T. C.], and Bristol Laboratories, Syracuse, New York 13201 [S. T. C.]

Tallysomycin, a third generation bleomycin analog was found to be more potent than bleomycin in the Walker 256 carcinosarcoma and the P-388 leukemia tumor systems and against a variety of bacteria and fungl. The mechanism of action of tallysomycin appears to be similar to that of bleomycin. Both drugs induced strand scission of isolated purified DNA and intracellular DNA. Breakage of DNA was determined by using three systems: PM-2 DNA fluorescence assay, agarose gel electrophoresis of PM-2 DNA, and alkaline sucrose density gradient sedimentation of Novikoff hepatoma cellular DNA. The optimum pH (9.5), the reducing agent concentration (25 mM 2-mercaptoethanol), and the incubation temperature (30–37°) were equivalent for both drugs for degradation of PM-2 DNA. Moreover, agarose gel electrophoresis demonstrated that both drugs induced both single- and double-strand breaks. However, tallysomycin had significantly less DNA breakage activity than had bleomycin.

Treatment of Novikoff hepatoma ascites cells in vitro with bleomycin or tallysomycin resulted in degradation of intracellular DNA demonstrated by alkaline sucrose density gradient centrifugation. However, tallysomycin was less potent in this system than was bleomycin. Since the difference in DNA breakage activity cannot be explained on the basis of trace metal (iron) contamination because tallysomycin had a greater iron concentration than had bleomycin, other factors are probably involved in the increased antitumor potency of tallysomycin than intrinsic DNA breakage activity.

¹ This work was supported in part by Bristol Laboratories.

² Recipient of American Cancer Society Grant ACS IN-27Q and the Pharmaceutical Manufacturers Association Research Starter Grant.

³ Recipient of NIH Grant CA-10893-10.

Received 4/10/78. Accepted 7/18/78.