1. ^*Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine and Department of Dermatology, University of Würzburg, Germany
2. ^†Department of Dermatology, Otto-von-Guericke-University, Magdeburg, Germany
3. ^‡Department of Dermatology, University Medical Center Benjamin Franklin, Berlin, Germany

Correspondence: Michael P. Schön, MD, Rudolf-Virchow-Center, DFG Research Center for Experimental Biomedicine and Department of Dermatology and Venereology, Julius-Maximilians-University, Versbacher Str. 9, 97078 Würzburg, Germany. Email: michael.schoen@virchow.uni-wuerzburg.de

Received 23 September 2003; Revised 18 December 2003; Accepted 6 January 2003; Published online 5 May 2004.

Abstract

Bypassing molecular mechanisms of apoptosis deficiency may be of great utility for the successful treatment of malignant tumors. We have discovered that imiquimod, a small-molecule immunomodulator, exerts rather tumor-selective direct pro-apoptotic activity in vivo and in vitro towards cutaneous metastases of malignant melanoma, an aggressive skin tumor. This pro-apoptotic activity was not detectable with resiquimod, a closely related structural analogue whose pro-inflammatory activity is even greater than that of imiquimod. Unresponsiveness of some melanoma metastases to imiquimod in vivo corresponded to resistance towards imiquimod-induced apoptosis in vivo and in vitro. At the molecular level, the pro-apoptotic activity of imiquimod was independent of membrane-bound death receptors, but depended on Bcl-2 expression as demonstrated by overexpression of Bcl-2 in melanoma cells. Imiquimod is the first topical compound with the potential to bypass molecular mechanisms of apoptosis deficiency, a concept that may be relevant for other tumors as well.