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Metastatic Cutaneous Melanoma Promoted by Ultraviolet Radiation in Mice with Transgene-initiated Low Melanoma Susceptibility¹

Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111

An inbred-strain (C57BL/6) transgenic (Tyr-SV40E) mouse model of ultraviolet radiation (UVR)-induced metastatic cutaneous melanoma was produced without the use of chemical carcinogens and without resulting in other skin malignancies. Expression of this transgene occurs specifically in melanocytic-lineage cells. In untreated hemizygous mice of transgenic line 12 there are no skin melanomas, and the oncogenic sequence, which is expressed at a very low level, functions solely as a weak initiating stimulus. UVR [including 65% ultraviolet B (280–320 nm wavelength)] supplied the necessary promoting stimulus leading to melanomas. Of various trial protocols, eight were successful and involved exposure of 112 mice for a limited time on each of 3–10 days starting at 2–3 days of age and totalling 1.1–3.7 J/cm² UVR. Fourteen of these animals developed a total of 15 invasive skin melanomas on the head and body, arising between 37–115 weeks of age and, therefore, often after a relatively long latency. The tumors were melanotic and in five of the mice they yielded macrometastases in regional and distant sites. The single most favorable protocol (1.9 J/cm² total UVR, at 0.38 J/cm²/day for 5 days starting at 3 days of age) led to the highest incidence of melanoma (5 of 19 mice) and one of the lowest mortality rates (2 of 19). No melanomas occurred in UVR-treated non-transgenic C57BL/6 controls. Benign skin keratoacanthomas arose and often regressed in treated transgenic as well as nontransgenic mice. This new transgenic mouse model introduces many novel possibilities for experimental analysis of the melanoma-promoting mechanisms of UVR and also of the ability of specific genetic changes to impede or facilitate the UVR effect.

¹ This work was supported by American Cancer Society Research Grant NP-917 and a Johnson & Johnson Focused Giving Grant (to B. M.) and by NIH Grant CA-06927 to the Fox Chase Cancer Center.

² To whom requests for reprints should be addressed, at Institute for Cancer Research, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111.

Received 5/22/98. Accepted 7/30/98.

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