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Effects of Anthracyclines on Oxygenated and Hypoxic Tumor Cells¹

Department of Pharmacology and Developmental Therapeutics Program, Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510

The cytotoxic effects of anthracyclines and other chemotherapeutic agents were examined in normally aerated and hypoxic Sarcoma 180 and EMT6 tumor cells in vitro. Adriamycin, daunomycin, and mitomycin C were selectively toxic to hypoxic Sarcoma 180 cells. The augmented sensitivity was not the result of an increase in susceptibility of oxygen-deprived cells toward antitumor agents in general. 1,3-Bis(2-chloroethyl)-1-nitrosourea, for example, exhibited equal cytotoxicity toward normally aerated and hypoxic cells, while streptonigrin was selectively toxic toward normally aerated cells. The cellular levels of [³H]daunomycin in both Sarcoma 180 and EMT6 cells were not different under the two conditions of oxygenation, and no greater production of either the alcohol or aglycone metabolites of daunomycin occurred in hypoxic cells, compared with their normally aerated counterparts. In addition, analysis of cellular pellets for residual drug remaining after exhaustive extraction showed no significant difference between normally aerated and hypoxic cells. The effects of reoxygenation of hypoxic cells on their sensitivity to mitomycin C and to Adriamycin were studied in both Sarcoma 180 and EMT6 cells. The enhanced efficacy of mitomycin C as a cytotoxic agent observed under hypoxia was reversed after a 2-hr reoxygenation. In contrast, the augmented toxicity of Adriamycin toward hypoxic cells was not reversible in either cell line after 2 or 4 hr of reoxygenation. The results suggest that neither the formation of a reactive oxygen species nor direct involvement of an alkylating agent generated by drug metabolism is an obligatory step in the cytotoxic action of these anthracyclines.

¹ Supported in part by USPHS Grants CA-02817. CA-24955, and CA-28852 from the National Cancer Institute and by Grants CH-211 and 212 from the American Cancer Society.

² Supported by Postdoctoral Fellowship CA-06177 from the National Cancer Institute. Present address: Department of Pharmacology. The George Washington University School of Medicine, 2300 Eye St., N. W., Washington, D.C. 20037.

³ Present address: Department of Pathology, University of North Carolina School of Medicine, Chapel Hill, N. C. 27514.

⁴ Recipient of Research Career Development Award CA-00684 from the NIH. To whom requests for reprints should be addressed.

Received 11/18/81. Accepted 10/ 4/82.

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