IngentaConnect Mcl-1 Antisense Therapy Chemosensitizes Human Melanoma in a SCID ...

Authors: Thallinger, Christiane; Wolschek, Markus F.; Wacheck, Volker¹; Maierhofer, Helmut¹; Günsberg, Patrick¹; Polterauer, Peter²; Pehamberger, Hubert; Monia, Brett P.³; Selzer, Edgar; Wolff, Klaus⁴; Jansen, Burkhard⁴

Source: Journal of Investigative Dermatology, Volume 120, Number 6, June 2003 , pp. 1081-1086(6)

Publisher: Blackwell Publishing

Abstract:

It is well established that high expression of the antiapoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL can significantly contribute to chemoresistance in a number of human malignancies. Much less is known about the role the more recently described Bcl-2 family member Mcl-1 might play in tumor biology and resistance to chemotherapy. Using an antisense strategy, we here address this issue in melanoma, a paradigm of a treatment-resistant malignancy. After in vitro proof of principle supporting an antisense mechanism of action with specific reduction of Mcl-1 protein as a consequence of nuclear uptake of the Mcl-1 antisense oligonucleotides employed, antisense and universal control oligonucleotides were administered systemically in combination with dacarbazine in a human melanoma SCID mouse xenotransplantation model. Dacarbazine, available now for more than three decades, still remains the most active single agent for treatment of advanced melanoma. Mcl-1 antisense oligonucleotides specifically reduced target protein expression as well as the apoptotic threshold of melanoma xenotransplants. Combined Mcl-1 antisense oligonucleotide plus dacarbazine treatment resulted in enhanced tumor cell apoptosis and led to a significantly reduced mean tumor weight (mean 0.16 g, 95% confidence interval 0.08-0.26) compared to the tumor weight in universal control oligonucleotide plus dacarbazine treated animals (mean 0.35 g, 95% confidence interval 0.2-0.44) or saline plus dacarbazine treated animals (mean 0.39 g, 95% confidence interval 0.25-0.53). We thus show that Mcl-1 is an important factor contributing to the chemoresistance of human melanoma in vivo. Antisense therapy against the Mcl-1 gene product, possibly in combination with antisense strategies targeting other antiapoptotic Bcl-2 family members, appears to be a rational and promising approach to help overcome treatment resistance of malignant melanoma.

Keywords: antisense oligonucleotide; apoptosis; chemoresistance; human melanoma; Mcl-1

Document Type: Research article

DOI: 10.1046/j.1523-1747.2003.12252.x

Affiliations: 1: Department of Clinical Pharmacology, Section of Experimental Oncology, 2: Department of Surgery, Division of Vascular Surgery, 3: ISIS Pharmaceuticals Inc., Carlsbad, California, USA; 4: Department of Dermatology, Division of General Dermatology,

Mcl-1 Antisense Therapy Chemosensitizes Human Melanoma in a SCID Mouse Xenotransplantation Model