Bcl-2 antisense oligonucleotides chemosensitize human gastric cancer in a SCID mouse xenotransplantation model

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2001-10, Vol.79 (10), p.587-593
• Main Authors: WACHECK, Volker, HEERE-RESS, Elisabeth, HALASCHEK-WIENER, Julius, LUCAS, Trevor, MEYER, Hildegard, EICHLER, Hans-Georg, JANSEN, Burkhard
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Cisplatin - therapeutic use; Digestive system; DNA, Antisense - pharmacology; Down-Regulation; Female; Humans; In Situ Nick-End Labeling; Investigative techniques, diagnostic techniques (general aspects); Medical sciences; Mice; Mice, SCID; Neoplasm Transplantation; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Proto-Oncogene Proteins c-bcl-2 - drug effects; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Specific Pathogen-Free Organisms; Stomach Neoplasms - drug therapy; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Survival Analysis; Treatment Outcome; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s001090100251

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.