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 language | English (US) |
|---|---|
| Pages (from-to) | 206-214 |
| Number of pages | 9 |
| Journal | Oligonucleotides |
| Volume | 15 |
| Issue number | 3 |
| DOIs | |
| State | Published - 2005 |
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ASJC Scopus subject areas
- Genetics
- Pharmacology
Cite this
518A2 Melanoma cells are protected by G3139 and other antineoplastic agents against the cytotoxic effects of DTIC. / Benimetskaya, Luba; Miller, Paul; Stein, C. A.
In: Oligonucleotides, Vol. 15, No. 3, 2005, p. 206-214.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 518A2 Melanoma cells are protected by G3139 and other antineoplastic agents against the cytotoxic effects of DTIC
AU - Benimetskaya, Luba
AU - Miller, Paul
AU - Stein, C. A.
PY - 2005
Y1 - 2005
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=25844464098&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=25844464098&partnerID=8YFLogxK
U2 - 10.1089/oli.2005.15.206
DO - 10.1089/oli.2005.15.206
M3 - Article
C2 - 16201908
AN - SCOPUS:25844464098
VL - 15
SP - 206
EP - 214
JO - Nucleic Acid Therapeutics
JF - Nucleic Acid Therapeutics
SN - 2159-3337
IS - 3
ER -