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Modulation of the Cell Cycle-dependent Cytotoxicity of Adriamycin and 4-Hydroperoxycyclophosphamide by Novobiocin, an Inhibitor of Mammalian Topoisomerase II¹

Tumor Biology Division, University of Rochester Cancer Center, Rochester, New York 14642

Centrifugal elutriation was used to obtain synchronized cell populations in various cell cycle phases without prior growth-perturbing manipulation. Treatment of these subpopulations with novobiocin (NOVO), a putative inhibitor of the mammalian topoisomerase II enzyme, revealed a unique cell cycle phase-dependent cytotoxicity for this agent. At a concentration of 0.3 mM, NOVO was cytotoxic only to a specific cell subpopulation in the G₁-S phase boundary. Cells in other cell cycle phases were completely unaffected. Additionally, S and G₂M phase cells progressed through the cell cycle relatively unaffected by NOVO but were blocked at the G₁-S boundary.

NOVO treatment protected tumor cells from Adriamycin (ADR)-induced lethality but sensitized them to the toxic action of 4-hydroperoxycyclophosphamide, an alkylating agent. These opposing effects of NOVO were demonstrated in all of the four tumor cell lines investigated: A431 and HEp3 (derived from human squamous cell carcinomas); MLS, a human ovarian cancer cell line; and a Chinese hamster ovary cell line. The degree of protection against ADR was the greatest for S-phase cells, intermediate for cells in early G₁ and M phases, and the least for late G₁ cells. This cell cycle-dependent protection by NOVO, which is identical to the cell cycle-dependent cytotoxicity of ADR, was consistent with the idea that NOVO interfered directly with the cell-killing mechanism of ADR. In contrast, even though the cytotoxic activity of 4-hydroperoxy-cyclophosphamide exhibited significant cell cycle dependency, NOVO enhanced 4-hydroperoxycyclophosphamide lethality equally for all cell cycle phases.

¹ This work is supported by NIH Grant CA-36858 and BRSG Sub S7RR05403-27.

² To whom requests for reprints should be addressed, at Experimental Therapeutics Department, Pharmaceutical Research Institute, Bristol-Myers Squibb Co., 5 Research Parkway, P. O. Box 5100, Wallingford, CT 06492-7660.

Received 1/ 2/91. Accepted 4/21/92.

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