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Kinetic Effects of Sangivamycin in Sarcoma 180 in Vitro

Laboratory of Medicinal Chemistry and Biology [P. S. R., R. I. G.] and Clinical Pharmacology Branch [R. E. C., S. E. S.], Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20205

The lethal and sublethal effects of sangivamycin (SGM) were studied in sarcoma 180 in vitro in relation to drug concentration and duration of drug exposure. SGM lethality was found to be dependent on both drug concentration and duration of drug exposure. Pronounced effects on cell survival were observed only when SGM exposure was prolonged; with prolonged drug exposure, small increments in SGM concentration resulted in large increases in cell killing. Long-phase cells were more susceptible to the lethal effects of SGM than were early-plateauphase cells. Measurements of incorporation of [³H]thymidine and [³H]uridine into the acid-insoluble cell fraction demonstrated inhibition of both DNA and RNA synthesis by SGM which was also dependent on drug concentration and duration of drug exposure, reflecting the lethality characteristics of SGM. As SGM concentration was increased, DNA synthesis was inhibited more rapidly than was RNA synthesis. Flow cytometry demonstrated a concentration- and time-dependent accumulation of cells in the late S and G₂-M region of the DNA histogram. Our findings indicate that maximum lethality is obtained by prolongation of SGM exposure, and they suggest that pharmacokinetic studies may be important for determining regimens which provide such exposure in humans.

¹ Present address: Department of Medicine, The Medical College of Wisconsin, Section of Hematology-Oncology, 8700 W. Wisconsin Ave., Milwaukee, Wis. 53226. To whom requests for reprints should be addressed.

Received 4/24/80. Accepted 2/ 4/81.

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