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The Role of DNA Damage and Inhibition of Poly(ADP-ribosyl)ation in Loss of Clonogenicity of Murine L929 Fibroblasts, Caused by Photodynamically Induced Oxidative Stress¹

Department of Medical Biochemistry, Sylvius Laboratory, State University Leiden, P.O. Box 9503, 2300 RA Leiden, the Netherlands [L. C. P., J. W. M. L., T. M. A. R. D., J. V.], and Department of Pathology, State University Leiden, Leiden, the Netherlands [J. H. V., C. J. C.]

Reactive oxygen species are used to eradicate malignant cells in photodynamic therapy as well as in other cancer therapies. Despite many efforts, the pathways leading to cellular damage and cell killing due to the action of these species are poorly understood. In previous studies with hematoporphyrin derivative-sensitized L929 murine fibroblasts, the only parameter for which a relation with photodynamically induced reproductive cell death could not be excluded was inhibition of DNA excision repair. The present results show that loss of clonogenicity of these cells in fact is related to a series of effects, including the development of slight, irreperable DNA damage, a virtually complete inhibition of poly(ADP-ribosyl)ation activation, a transient elevation of the intracellular calcium concentration and, after a lag time of about 8 h, DNA fragmentation caused by endonuclease activity. This conclusion is supported by the observation that photodynamic treatment inhibited the repair of X-ray-induced DNA strand breaks and suppressed X-ray- and methyl methanesulfonate-induced enhancement of poly(ADP-ribosyl)ation. Our experimental results further suggest that in this cell line the photodynamically induced inhibition of enhanced poly(ADP-ribosyl)ation could well be involved in inhibition of repair of DNA strand breaks and in activation of endonuclease activity.

¹ This work was supported by Dutch Cancer Society Grant IKW 89-01.

² To whom requests for reprints should be addressed.

Received 5/12/94. Accepted 8/30/94.

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