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Relationship of Adriamycin Concentrations to the DNA Lesions Induced in Hypoxic and Euoxic L1210 Cells¹

Departments of Radiology [M. P., S. K.] and Medicine [M. L., R. S.], New York University School of Medicine, New York, New York 10016; and Sidney Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [M. I., V. K. K.]

Exponentially growing L1210 mouse leukemia cells were incubated with Adriamycin (ADR) under hypoxic (95% N₂:5% CO₂) or euoxic conditions (95% air:5% CO₂) for 1 hr at 37° at a drug concentration ranging from 2.8 x 10^-8 to 2.8 x 10^-4 M, i.e., from levels attained clinically by bolus delivery to the high levels used as an i.p. drug dwell or experimentally, in in vitro conditions. High-pressure liquid chromatography analyses showed diminishing efficiency in drug uptake by the cells as the dose was increased. There were no significant differences between hypoxic and euoxic cells in drug uptake and metabolism. The frequency of DNA protein-associated single-strand breaks and DNA-protein cross-links per 10⁶ nucleotides, detected by the alkaline elution technique, increased with the dose in the range of 2.8 x 10^-8 to 2.8 x 10^-6 M in both euoxic and hypoxic cells and declined thereafter. However, the number of DNA lesions relative to a normalized drug level declined steadily, starting with the 2.8 x 10^-7 M concentration. Concentrations >2.8 x 10^-6 M of ADR induced still another type of lesion, direct DNA strand breaks, only in euoxic cells. The results indicate that a common mechanism of interaction between drug and DNA is present in hypoxic and in euoxic cells at low ADR, while an O₂-dependent mechanism becomes operational in euoxic cells at high ADR levels.

¹ Supported by Research Grant CH-129A from the American Cancer Society, USPHS Grants CA 32055, CA 19118, CA 28376, and CA 29185 from the National Cancer Institute, NIH, and the Marcia Slater Society for Research in Leukemia.

² To whom requests for reprints should be addressed, at Department of Radiology, New York University School of Medicine, 550 First Avenue, New York, N. Y. 10016.

Received 12/ 6/82. Accepted 4/22/83.

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