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Relationship between Mezerein-mediated Biological Responses and Phorbol Ester Receptor Occupancy

Interdisciplinary Programs in Health [S. J.] and the Laboratory of Toxicology, Harvard School of Public Health [M. A. S., A. H. T.], and the Department of Pharmacology, Harvard Medical School, Boston, Massachusetts 02115 [P. M. B., A. H. T.]

The phorbol ester analog, mezerein, is a weak complete and Stage 1 tumor promoter; however, it is as potent as the most active phorbol esters as a second stage promoter and inflammatory agent. Therefore, mezerein is a useful compound for studying responses associated with Stage 1 or Stage 2 promotion. In this paper, we show that in G-292 osteosarcoma cells in culture, mezerein is 25-fold more potent in causing a decrease in binding of epidermal growth factor to its specific cellular receptor than in inducing prostaglandin E₂ production. This differential potency for these two actions was not noted for other phorbol esters. Our findings indicate that mezerein interacts with the major phorbol dibutyrate receptor to increase prostaglandin E₂ production and also either with a distinct cellular target with a higher affinity or the same target with increased efficacy to cause a decrease in the binding of epidermal growth factor. These human osteosarcoma cells thus provide a model system to facilitate analysis of phorbol ester receptor heterogeneity.

¹ Fellow of the Interdisciplinary Programs in Health, which was funded in part by grants from the Exxon Education Foundation and the Environmental Protection Agency (Cooperative Agreement CR 807809). Present address: Laboratory of Cellular Carcinogenesis and Tumor Promotion, Building 37, National Cancer Institute, Bethesda, Md.

² Recipient of a National Research Service Award (AM 06011).

³ Supported by a grant from the American Cancer Society (BC 345).

⁴ Supported in part by grants from the NIH (AM 11011, AM 10206, and ES 00002).

Received 7/ 6/82. Accepted 9/29/82.

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