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Cellular Pharmacology in Murine and Human Leukemic Cell Lines of Diaziquone (NSC 182986)¹

Division of Developmental Therapeutics, University of Maryland Cancer Center, Baltimore, Maryland 21201 [M. J. E., B. M. F., J. F. S., P. L. G.], and Laboratory of Medical Chemistry and Pharmacology, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20205 [R. D. F., N. R. B.]

We investigated the in vitro interaction with and antitumor effect on several murine and human leukemic cell lines of diaziquone (AZQ). L1210 cells accumulated AZQ from Roswell Park Memorial Institute Medium 1640 with or without newborn calf serum by a temperature-dependent and sodium azide-resistant process. AZQ inhibited, in a dose-dependent fashion, [³H]thymidine incoporation into L1210 cells, but this inhibition was slow to develop, requiring approximately 6 hr to become apparent. The minimal inhibitory concentration of AZQ for this process was 0.05 to 0.25 nmol/ml. AZQ was a much less effective inhibitor of L1210 cell [³H]uridine and [¹⁴C]valine incorporation. In suspension cultures, AZQ inhibited growth of L1210 and HL-60 cells at minimal inhibitory concentrations of 0.5 to 1 nmol/ml. In soft agar cultures, AZQ inhibited HL-60 cell cloning at minimal inhibitory concentrations of 0.1 to 0.3 nmol/ml. AZQ provoked a dose-dependent increase in oxygen consumption when added to intact L1210, HL-60, and K562 cells and was converted to an AZQ anion free radical by these cells. When the aziridine rings of AZQ were opened by acid treatment, the resulting molecule was not accumulated by L1210 cells, did not provoke O₂ consumption, did not form free radicals when added to L1210 cells, and was a much less effective inhibitor of [³H]thymidine incorporation by L1210 cells than was AZQ.

¹ This work was supported in part by USPHS Grant CA 33681 awarded by the National Cancer Institute.

² To whom requests for reprints should be addressed, at Division of Developmental Therapeutics, University of Maryland Cancer Center, 655 West Baltimore Street, Baltimore, MD 21201.

Received 5/ 7/84. Accepted 12/ 4/84.