Bcl-2 antisense oligonucleotides chemosensitize human gastric cancer in a SCID mouse xenotransplantation model.
We used Bcl-2 antisense oligonucleotides (G3139) to chemosensitize human gastric cancer by downregulation of Bcl-2 expression in vivo. Oligonucleotides and cisplatin were administered systemically in a human gastric cancer SCID mouse model, and Bcl-2 expression, apoptosis, tumor size, and survival were assessed. Used alone, G3139 treatment led to downregulation of Bcl-2 and moderate tumor reduction compared to saline control. G3139 combined with cisplatin treatment markedly enhanced the antitumor effect of cisplatin (70% tumor size reduction vs. cisplatin alone), associated with increased apoptosis measured in tumor biopsy specimens. Combined treatment with G3139 and cisplatin prolonged survival of the tumor-bearing SCID mice by more than 50% without adding significant drug-related toxicity. Treatment with Bcl-2 antisense oligonucleotides is thus a promising novel approach to enhance antitumor activity of cisplatin or other drugs used in gastric cancer therapy and warrants further evaluation in clinical trials.
Wacheck
V
V
Department of Clinical Pharmacology, Section of Experimental Oncology/Molecular Pharmacology, University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
Heere-Ress
E
E
Halaschek-Wiener
J
J
Lucas
T
T
Meyer
H
H
Eichler
H G
HG
Jansen
B
B
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002945:Cisplatin / Q000627:therapeutic use*; D016373:DNA, Antisense / Q000494:pharmacology*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D016373:DNA, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D002945:Cisplatin