Bcl-2 antisense oligonucleotides (G3139) inhibit Merkel cell carcinoma growth in SCID mice

Merkel cell carcinoma was first described in 1972 by Toker and is an aggres sive neuroendocrine skin tumor with a high metastatic potential. Merkel cel l carcinoma is thought to derive from the neuroendocrine (Merkel) cells of the skin, although in contrast to fetal and especially adult Merkel cells, Merkel cell carcinomas express high levels of the Bcl-2 oncoprotein. Bcl-2 is capable of blocking programmed cell death and has been shown to play an important role in normal cell turnover, tumor biology, and chemoresistance. High Bcl-2 expression leading to prolonged survival of cells may therefore be of importance in the biological and clinical characteristics of Merkel cell carcinoma. In a SCID mouse xenotransplantation model for human Merkel cell carcinoma, we investigated the influence of the bcl-2 antisense oligon ucleotide G3139 (Genta) on tumor growth in comparison with control oligonuc leotides or cisplatin. Bcl-2 antisense treatment, targeting the first six c odons of the bcl-2 mRNA, resulted in either a dramatic reduction of tumor g rowth or complete remission, whereas reverse sequence and two-base mismatch control oligonucleotides or cisplatin had no significant antitumor effects compared with saline-treated controls. Apoptosis was enhanced 2.4-fold in the bcl-2 antisense treated tumors compared with the saline-treated group, and no other treatment showed a comparable increase in apoptosis. Our findi ngs suggest that bcl-2 antisense treatment may be a novel approach to impro ve treatment outcome of human Merkel cell carcinoma.