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Inhibition of Photocarcinogenesis by Platelet-Activating Factor or Serotonin Receptor Antagonists

Department of Immunology and the Center for Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Stephen E. Ullrich, Department of Immunology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-563-3264; Fax: 713-563-3280; E-mail: sullrich{at}mdanderson.org.

Key Words: UV radiation • skin cancer • inflammation • apoptosis • therapy

The UV radiation in sunlight is the primary cause of nonmelanoma skin cancer. Moreover, UV exposure induces immune suppression. Early steps in the cascade of events leading to immune suppression are the binding of UV-induced platelet-activating factor (PAF) to its receptor and the binding of cis-urocanic acid, a photoreceptor for UVB radiation, to the serotonin (5-HT_2A) receptor. Here, we tested the hypothesis that blocking the binding of PAF and 5-HT_2A to their receptors would also block skin cancer induction. Hairless mice were injected with PAF or serotonin receptor antagonists and then exposed to solar-simulated UV radiation. We noted a significant and substantial decrease in skin cancer incidence in mice treated with the PAF or 5-HT_2A receptor antagonists. Also, the PAF and/or serotonin receptor antagonists blocked skin cancer progression. The PAF and serotonin receptor antagonists worked in a synergistic fashion to block skin cancer induction. We also measured the effect that injecting PAF and 5-HT_2A receptor antagonists had on UV-induced skin damage after a single UV exposure. We noted a significant decrease in UV-induced hypertrophy, sunburn cell formation, and apoptosis when the mice were injected with PAF and/or 5-HT_2A receptor antagonists. These data indicate that treating UV-irradiated mice with PAF and 5-HT_2A receptor antagonists blocks skin cancer induction in vivo, in part by reversing UV-induced damage to the skin and by preventing the induction of immune suppression. [Cancer Res 2008;68(10):3978–84]

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