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Inhibition of Mammalian DNA Polymerases by Hematoporphyrin Derivative and Photoradiation¹

Department of Biochemistry [J. J. C., A. F. W., R. A. B., R. S. M., S. L. G., R. H.] and The University of Rochester Cancer Center [R. A. B., S. L. G., R. H.], The University of Rochester, School of Medicine and Dentistry, Rochester, New York 14642

Hematoporphyrin derivative (HPD) plus photoradiation caused the inactivation of DNA polymerases from calf thymus and R3230AC rat mammary tumor. Photosensitization of purified DNA polymerase- as well as two forms of DNA polymerase- (I and II) from calf thymus were evaluated. Although all polymerase enzyme forms were inactivated at 70 µg HPD/ml, DNA polymerase- II was the most sensitive, displaying a 90% inactivation under conditions that did not cause significant inactivation of the other polymerase forms. Unlike DNA polymerase-, the -forms have an associated 3'- to 5'-exonuclease activity. The exonuclease associated with DNA polymerase- II was uniquely sensitive to a low level of HPD and light exposure. DNA polymerase- II can be distinguished from other polymerase forms in cell extracts by its relative insensitivity to the polymerase inhibitor N²-(p-n-butylphenyl)deoxyadenosine 5'-triphosphate. In cytosols prepared from calf thymus and R3230AC rat mammary tumors, DNA polymerase- II was preferentially inhibited by HPD plus light. Furthermore, in experiments in which tumor-bearing rats were administered HPD prior to preparation of tumor cytosols, DNA polymerase- II was specifically inactivated by exposure to light. These results are discussed in view of their possible role in cancer therapy, and the potential use of HPD as a specific inhibitory agent of DNA polymerase- II is suggested.

¹ Supported by USPHS Grants CA36856 and GM24441, NIH.

² Supported in part by USPHS Grant T32-GM07102-08, NIH.

³ Recipient of the American Cancer Society Faculty Research Award FRA220. To whom requests for reprints should be addressed, at The Department of Biochemistry, Box 607, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642.

Received 5/14/85. Revised 9/23/85. Accepted 10/ 4/85.