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Increased Generation of Lipid-derived and Ascorbate Free Radicals by L1210 Cells Exposed to the Ether Lipid Edelfosine¹

Department of Medicine [B. A. W., C. P. B.] and the Electron Spin Resonance Facility [G. R. B.], The University of Iowa College of Medicine, Iowa City, Iowa 52242

Using the spin trap -(4-pyridyl-1-oxide)-N-tert-butyInitrone, we have detected a lipid-derived carbon-centered free radical generated from intact L1210 lymphoblastic leukemia cells that were exposed to 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (edelfosine or ET-18-OCH₃) and oxidative stress. The spectral characteristics, including hyperfine splitting constants of a^N = 15.61G and a^H = 2.65G, were consistent with the spin trapping of an alkyl radical. Radical detection required iron and prior enrichment of cellular components with the polyunsaturated fatty acid docosahexaenoic acid; unmodified cells failed to generate detectable free radical. Ascorbate further enhanced radical generation. The detection of lipid-derived free radicals when intact cells are exposed to edelfosine provides further evidence that oxidative stress may play an important role in the cytotoxic mechanism of this class of anticancer drug.

¹ This investigation was supported by Grants CA31526 awarded by the National Cancer Institute, Department of Health and Human Services. Data analysis utilized the Clinfo system, Grant RR59 from the General Clinical Research Centers Program, Division of Research Resources, NIH.

Received 11/12/92. Accepted 12/30/92.

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