Antitumor Efficacy of bcl-2 and c-myc Antisense Oligonucleotides in Combination with Cisplatin in Human Melanoma Xenografts: Relevance of the Administration Sequence

Abstract

Purpose: bcl-2 and c-myc oncogenes are frequently overexpressed in different human tumors, including melanoma. Here, we evaluate the combined efficacy of two antisense oligonucleotides targeting bcl-2 mRNA (ODN bcl-2) and c-myc mRNA (ODN c-myc) in combination with cis-diammine dichloroplatinum (cisplatin, DDP) on three human melanoma lines (LM, NG, and M20).Experimental Design: Two different sequences were designed to treat tumor-bearing mice: in the first one, ODN bcl-2 at a dose of 0.2 mg/day      4, followed by DDP given i.p. at a dose of 3.3 mg/kg/day      3 and ODN c-myc i.v. at 0.5 mg/ day      7, whereas the other sequence consisted of ODN c-myc given as first agent followed by DDP and ODN bcl-2 at the same doses. Mice received three complete cycles of treatment in 1-week intervals.Results: The treatment sequence with ODN bcl-2/DDP/ ODN c-myc combination completely inhibited growth in NG tumor and induced a 35-day delay in LM tumor growth. In contrast, the M20 tumor growth was unaffected by the combination. A discrete amount of c-Myc and bcl-2 protein expression in both LM and NG tumors was detected, whereas no detectable levels of the two proteins were observed in M20 tumors. Compared with the other combination, the sequence ODN bcl-2/DDP/ODN c-myc produced the most effective results, producing a significant decrease in bcl-2 and c-Myc protein expression, which in turn significantly increased the survival of NG-and LMbearing mice, with 4 mice out of 11 and 1 out of 7 mice being cured, respectively. Finally, this combination increased the apoptotic rate and produced an antiangiogenetic effect.Conclusions: These results show that an antisense approach to the treatment of melanoma xenografts overexpressing either bcl-2 or c-myc oncogenes represents a successful strategy to improve the response to chemotherapy in melanoma, with particular attention to the treatment sequence.

BCL-2 antisense and cisplatin combination treatment of MCF-7 breast cancer cells with or without functional p53

“…Combined treatment of bcl-2 and cisplatin in small-cell lung cancer [20], bladder cancer [49], mesothelioma [50] and alignant melanoma [51] showed greater effect than either one alone. Moreover, preclinical studies demonstrated potentiated antitumor efficacy of bcl-2 antisense combined with cisplatin in gastric carcinoma [52,53] and human melanoma xenografts [54]. The results of our combination treatment corroborated with these findings.…”

The Antisense Transcript SMN-AS1 Regulates SMN Expression and Is a Novel Therapeutic Target for Spinal Muscular Atrophy

“…Our study shows that SMN-AS1 can be a therapeutic target, and also demonstrates the potential of combinatorial ASOs targeting distinct molecular regulators of a single gene. Combining ASOs targeting two different genes with traditional chemotherapy has been proposed for cancer therapeutics (Biroccio et al, 2003; Zupi et al, 2005), but this is the first example to our knowledge of two ASOs used in combination for a neurological disorder. Like others, we found that dosing of multiple ASOs was well tolerated in SMA mice (Hua et al, 2015; Zupi et al, 2005).…”

Defining the mechanism by which IFN-β dowregulates c-myc expression in human melanoma cells: pivotal role for human polynucleotide phosphorylase (hPNPaseold-35)

“…[29][30][31][32] Indeed, antisense inhibition of c-myc significantly inhibited the growth of melanoma cells in in vitro cultures 33 and improved the response to chemotherapy in human melanoma xenografts in nude mice. 34 Type I IFNs have been used as adjuvant therapy for malignant melanoma with significant but limited success and high toxicity. 35 Experimental overexpression of Myc in mouse fibroblasts and myeloblastic cells renders these cells resistant to cell cycle arrest by type I IFNs.…”