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¹ Department of Pathology, Dunedin School of Medicine, University of Otago and ² Oncology Department, Otago District Health Board, Dunedin, New Zealand

Requests for Reprints: Michael R. Eccles, Department of Pathology, Dunedin School of Medicine, P.O. Box 913, Dunedin, New Zealand. Phone: 64-3479-7878; Fax: 64-3479-7136. E-mail: meccles{at}otago.ac.nz

Advanced melanoma is difficult to treat, in part because of greater resistance to therapy compared with other cancer types. The mechanisms underlying this resistance are not well-understood. One factor that is reported to be involved in melanoma cell survival is PAX3, a transcription factor normally expressed during embryonic development, and which is critically required for development of neural crest-derivatives, including skin melanocytes. PAX3 expression is deregulated in primary melanomas and most melanoma cell lines. Here we have investigated whether targeting PAX3 expression in melanoma cell lines together with chemotherapeutic treatment increases susceptibility to therapeutic cell death. Using PAX3-specific antisense oligodeoxynucleotides (PAX3-AS) to treat melanoma cell lines in vitro, we showed dose-dependent reduction of proliferation of melanoma cells, and induction of apoptosis compared with control treatments. Induction of apoptosis was accompanied by the induction of active caspase-3 in UACC62 and M14 cells, and p53 protein in UACC62 cells. Treatment of melanoma cells with cisplatin induces DNA damage and cytotoxicity, which is thought to be via p53-dependent and -independent mechanisms. Treatment of either p53 mutant (M14) or wild-type (UACC62) melanoma cells with cisplatin, and varying doses of PAX3-AS, resulted in percentages of cells undergoing apoptosis equivalent to the sum of the individual treatments, irrespective of mutation status [e.g., UACC62, 43.8% (1 µmol/L PAX3-AS), 30.1% (20 µmol/L cisplatin), 69.6% (PAX3-AS + cisplatin); M14, 12.6% (1 µmol/L PAX3-AS), 41.5% (40 µmol/L cisplatin), 50.2% (PAX3-AS + cisplatin)]. These data suggest that treatment of melanoma cells with PAX3-AS complements cytotoxicity induced by cisplatin.

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³ Unpublished data.

Received 9/20/04; revised 3/13/05; accepted 3/29/05.