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Enhancement of Oxidative Cell Injury and Antitumor Effects of Localized 44°C Hyperthermia upon Combination with Respiratory Hyperoxia and Xanthine Oxidase¹

Institute of Biological Chemistry and Nutrition, University of Hohenheim, D-70593 Stuttgart, Germany [J. F., H. K. B.]; Institute of Physiology and Pathophysiology, University of Mainz, D-55099 Mainz, Germany [D. K. K., O. T., P. V.]; and Institute of General Pathology, University of Siena, 1-53100 Siena, Italy [A. P.]

The effects of respiratory hyperoxia (RH) and xanthine oxidase (XO) during localized hyperthermia (HT) were investigated by determining markers of oxidative damage to lipids and proteins and tumor growth. Anesthetized rats with s.c. DS-sarcomas underwent one of the following treatments: (a) localized saline-bath HT (60 min, 44°C); (b) HT + RH (100% O₂); and (c) HT + RH + XO (15 units/kg i.v.). Sham-treated animals served as controls. Tumors were investigated for: (a) thiobarbituric acid-reactive substance formation and protein-bound 4-hydroxynonenal, as indicators of lipid peroxidation; (b) reactive oxygen-mediated protein modifications; (c) apoptosis; and (d) tumor volume growth. Upon treatment, increases in thiobarbituric acid-reactive substances, protein-bound 4-hydroxynonenal, protein-associated carbonyl functions, and number of cells undergoing apoptosis were found in tumor tissue, together with an inhibition of tumor growth. When treatment groups were compared, effects in the group HT + RH + XO were generally most pronounced. These findings indicate that the antitumor effect of HT is at least partially mediated through the selective induction of lipid peroxidation and oxidative injury in tumor cells, leading to apoptosis. This effect was enhanced by adding RH or RH + XO, presumably due to enhanced tissue damage following an increased formation of reactive oxygen species, with higher levels of lipid peroxidation and protein oxidation.

¹ Supported by Grant 70–1920 Va 2 from the Deutsche Krebshilfe.

² To whom requests for reprints should be addressed, at the Institute of Biological Chemistry and Nutrition, University of Hohenheim, Fruwirthstr. 12, D-70593 Stuttgart, Germany. Phone: 49-711-459-3613; Fax: 49-711-459-3822; E-mail: frank140@unihohenheim.de.

Received 3/16/98. Accepted 5/22/98.

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