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Mechanism of Spermidine Cytotoxicity at 37°C and 43°C in Chinese Hamster Ovary Cells¹

Departments of Medicine [K. J. H.], Radiology [A. J. M., W. A. N.], and Physiology/Biophysics [K. J. H., A. J. M., W. A. N.], University of Arkansas for Medical Sciences, and VA Medical Center, Little Rock, Arkansas 72205

Spermidine (SPD) cytotoxicity is mediated largely through SPD oxidation by serum amine oxidases at both 37°C and 43°C. Alkaline sucrose gradient data suggest random induction of DNA strand breaks. A dose response with time at 37°C or 43°C (constant SPD) or with SPD concentration (constant time at 43°C) was observed in terms of both DNA strand breaks and cell survival. The generation of peroxide was demonstrated in the absence of cells by the addition of SPD to medium containing 10% fetal bovine serum. Toxicity of SPD was reduced in saline, with catalase-thiourea and aminoguanidine, and enhanced by prior depletion of glutathione.

Thermotolerance induced 16 h previously did not protect against SPD toxicity, suggesting that the reactive species from spermidine oxidation and heat damage do not produce related subcellular lesions.

¹ The study was supported by USPHS Grants CA-33405 and CA-35689 awarded by the National Cancer Institute, Department of Health and Human Services, and Veterans Administration Merit Review funds. Research was carried out at the John L. McClellan Memorial Veterans Medical Center. A preliminary report of this work was presented at the 33rd Annual Meeting of the Radiation Research Society, Los Angeles, CA, May 5 to 9, 1985 (1).

² To whom requests for reprints should be addressed, at Medical Research Service 151/7, VA Medical Center, 4300 West 7th Street, Little Rock, AR 72205.

Received 6/ 6/85. Revised 9/17/85. Accepted 10/ 2/85.

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