C-MYC ANTISENSE OLIGODEOXYNUCLEOTIDES ENHANCE THE EFFICACY OF CISPLATIN IN MELANOMA CHEMOTHERAPY IN-VITRO AND IN NUDE-MICE

This study was designed to assess the efficacy of a new antimelanoma t herapeutic strategy that relies on the use of a c-myc antisense 15-mer phosphorothioate oligodeoxynucleotide ([S]ODN), in combination with c isplatin (cis-diamminedichloroplatinum; DDP), which is currently used in the clinical management of melanoma patients, Proliferation and col ony formation of melanoma cells were both inhibited by the DDP/c-myc a ntisense [S]ODN combination to a greater extent than that observed wit h either agent alone, Inhibition was most effective when DDP was follo wed by c-myc antisense [S]ODNs, Cell cycle flow cytometric analysis of cells exposed to the two agents either alone or in combination demons trated that (a) c-myc antisense [S]ODNs induced an accumulation of cel ls in S phase and apoptosis in a fraction of the cells, detectable at day 5 after the beginning of treatment; (b) DDP induced a block in G(2 )-M phase detectable at day 1, which was partially recovered, and apop tosis similar in extent to that induced by c-myc antisense [S]ODNs; an d (c) DDP and c-myc antisense [S]ODNs together induced arrest in G(2)- M phase, which was maximum at day 3, i.e., delayed as compared to the block induced by DDP, The combination induced a higher percentage of a poptosis, evident at day 3 from the start of treatment, that correlate d with a marked reduction in Bcl-2 expression, Mice bearing human mela noma xenografts and treated sequentially with DDP and c-myc antisense [S]ODNs shelved a higher inhibition of tumor growth, reduction in the number of lung metastases, and increase in life span compared with tho se treated with either agent alone, Together, these data lend support to the development of anticancer therapies involving oncogene-targeted antisense ODNs and conventional antineoplastic drug.