title: Antitumor efficacy of bcl-2 and c-myc antisense oligonucleotides in combination with cisplatin in human melanoma xenografts: relevance of the administration sequence.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  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 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.
  
  
  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.
authors.affiliation: Experimental Chemotherapy Laboratory, Pathology Department, and Immunology Laboratory, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy. zupi@ifo.it
authors.forename: Gabriella
authors.initials: G
authors.lastname: Zupi
authors.forename: Marco
authors.initials: M
authors.lastname: Scarsella
authors.forename: Sean C
authors.initials: SC
authors.lastname: Semple
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.forename: Pier G
authors.initials: PG
authors.lastname: Natali
authors.forename: Carlo
authors.initials: C
authors.lastname: Leonetti
mesh_terms: D000818:Animals; D004334:Drug Administration Schedule; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012333:RNA, Messenger; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D016019:Survival Analysis; D014183:Transplantation, Heterologous
chemical_list: C489427:MYC protein, human; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger