518A2 Melanoma cells are protected by G3139 and other antineoplastic agents against the cytotoxic effects of DTIC

Luba Benimetskaya, Paul Miller, C. A. Stein

Research output: Contribution to journalArticle

Abstract

G3139 is an antisense Bcl-2 phosphorothioate oligonucleotide that has been combined with DTIC in a phase III clinical trial in melanoma. However, its actual mechanism of action in melanoma is controversial. Treatment of 518A2 melanoma cells with either G3139 or G4126 (a two-base mismatch) and then with light-activated DTIC caused these cells (but not SK-Mel-30 or 346.1 cells) to be protected against the cytotoxic effects of DTIC. This cytoprotection was not recapitulated with a phosphodiester congener of G3139 nor with a small interfering RNA (siRNA) also targeted to the Bcl-2 mRNA. Administering the drugs in reverse order also did not produce cytoprotection, and an 18-mer phosphorothioate homopolymer of thymidine was also inactive. Subsequently, it was discovered that gemcitibine and cis-platinum also induced cytoprotection to DTIC in this cell line, suggesting that the cytoprotection is a stress response to chemical proapoptotic stress. Cytoprotection was completely inhibited by O6-benzylguanine, an inhibitor of O6-guanosine alkyltransferase (OGAT) activity. However, a direct assay of OGAT activity demonstrated that 518A2 melanoma cells are essentially completely devoid of it, either basally or induced. The cytoprotection may thus be caused by a chemical stress-induced increase in mismatch repair activity.

Original languageEnglish (US)
Pages (from-to)206-214
Number of pages9
JournalOligonucleotides
Volume15
Issue number3
DOIs
StatePublished - Oct 10 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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