Abstract
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). 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 x4, followed by DDP given i.p. at a dose of 3.3 mg/kg/day x3 and ODN c-myc i.v. at 0.5 mg/day x7, 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. 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 LM-bearing 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. 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.
Highlights
As increasingly evident, therapies based on the combination of conventional cytotoxic agents and targeted agents can result in an improvement of current cancer management
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
We have previously shown that the combination of cis-diammine dichloroplatinum with c-myc antisense oligonucleotides (ODN c-myc), increases the cytotoxic activity of DDP by inhibiting cells to progress through the cell cycle
Summary
Therapies based on the combination of conventional cytotoxic agents and targeted agents can result in an improvement of current cancer management. Among the increasing number of target-specific drugs currently under investigation, antisense oligonucleotides (ODN) capable of interfering with tumor cell growth or apoptotic signaling as well as cancer cell invasiveness and metastatization, seem promising for combination therapy in view of their lack of toxicity [1]. We have previously shown that the combination of cis-diammine dichloroplatinum (cisplatin, DDP) with c-myc antisense oligonucleotides (ODN c-myc), increases the cytotoxic activity of DDP by inhibiting cells to progress through the cell cycle. We have shown that c-myc antisense oligonucleotides are able to overcome DDP resistance in a human melanoma cell line intrinsically resistant to this compound [3]
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