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Suppression of Tumor Promoter-induced Oxidative Events and DNA Damage in Vivo by Sarcophytol A: A Possible Mechanism of Antipromotion¹

Departments of Environmental Medicine [H. W., K. F.] and Pathology [K. F.] and Kaplan Comprehensive Cancer Center [K. F.], New York University Medical Center, New York, New York 10016-6451

Sarcophytol A (Sarp A), a nontoxic compound isolated from marine soft coral, inhibits the in vivo effects of tumor promoters. However, the mechanism of its action is unknown. Our studies show that Sarp A suppresses oxidant formation and DNA oxidation in the epidermis of SENCAR mice exposed to 12-O-tetradecanoylphorbol-13-acetate (TPA). In the short-term experiments, mice were topically pretreated with different doses of Sarp A before 6.5 nmol TPA, and the same treatment was repeated 20 h later. Sarp A significantly decreased the TPA-induced infiltration of neutrophils, the levels of myeloperoxidase in the dermis, and the formation of H₂O₂, cis-thymidine glycol, 8-hydroxyl-2'-deoxyguanosine, and 5-hydroxymethyl-2'-deoxyuridine in the epidermis. In the long-term studies, repeated TPA applications (3.2 nmol twice a week for 16 weeks) increased cis-thymidine glycol 2.7-fold, 5-hydroxymethyl-2'-deoxyuridine 3.4-fold, and 8-hydroxyl-2'-deoxyguanosine 3.3-fold in epidermal DNA over the basal levels. Application of 350 nmol Sarp A before each TPA treatment significantly decreased the formation of oxidized DNA bases even below those present in the control mouse skin. Histological examination showed that Sarp A also alleviated the TPA-induced inflammatory response and infiltration of phagocytes. Thus, it is possible that suppression of tumor promotion by Sarp A is due (at least in part) to its inhibitory effects on tumor promoter-mediated migration and activation of phagocytes, oxidant formation, and DNA base oxidation.

¹ This research was supported by USPHS Research Grants CA37858 and CA49798 awarded by the National Cancer Institute and Department of Health and Human Services (its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute), by National Institute of Environmental Health Services Cancer Center Grant ES00260, and by a grant from the Sackler Institute of Graduate Biomedical Sciences.

² Present Address: Department of Environmental Health Sciences, University of Alabama, UAB Station, Birmingham, AL 33294.

³ To whom all requests for reprints should be addressed, at Department of Environmental Medicine, New York University Medical Center, 550 First Avenue, New York, NY 10016-6451.

Received 7/ 1/91. Accepted 2/10/92.

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