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Local Vascular Changes Induced by the Cocarcinogen, Phorbol Myristate Acetate¹

Departments of Pathology and Environmental Medicine, New York University School of Medicine, New York, New York 10016

One µg of phorbol myristate acetate, an active tumor-promoting agent from croton oil, produces a severe, local vascular reaction in skin (ear) of CF₁ and STS mice. The response is characterized by hyperemia and edema formation which can be quantitatively monitored by measuring uptake of circulating ¹²⁵I-labeled bovine serum albumin. Microscopic detection of sites of endothelial injury in mice receiving i.v. carbon suspension shows the reaction to be primarily limited to venules. These microvascular changes are accompanied by mast cell degranulation in the affected tissues. Reactions develop about 1 hr after phorbol ester application, persist through 6 to 8 hr, and appear to be lessening in intensity by 24 hr. High doses (50 µg) of 7,12-dimethylbenz(a)anthracene induce similar vascular changes, although of much lower intensity and after a longer delay interval. Antagonists of histamine, serotonin, and kinins produce mild, transient suppression of the local vascular response to the phorbol ester. Hydrocortisone and salicylate are without effect on this component of the tissue reaction. Local application of tosyl phenylalanine chloromethyl ketone, a protease inhibitor previously shown to suppress tumor promotion, affords a more sustained protection against the inflammatory activity of the phorbol ester.

¹ The work reported herein was supported in part by USPHS Research Grants HE 08192 and K3-GM-6461 and American Cancer Society Research Grant IN-14K.

Received 4/ 1/70. Accepted 6/16/70.

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