518A2 melanoma cells are protected by G3139 and other antineoplastic agents against the cytotoxic effects of DTIC.
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 O(6)-benzylguanine, an inhibitor of O(6)-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.
Benimetskaya
Luba
L
Department of Oncology, Albert Einstein-Montefiore Cancer Center, Montefiore Medical Center, Bronx, NY 10467, USA.
Miller
Paul
P
Stein
C A
CA
D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003606:Dacarbazine / Q000633:toxicity*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology*; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D003841:Deoxycytidine; D006147:Guanine; D003606:Dacarbazine; C408162:oblimersen; D002945:Cisplatin; D000093542:Gemcitabine