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Bcl-2 antisense oligonucleotides chemosensitize human gastric cancer in a SCID mouse xenotransplantation model
V Wacheck1, E Heere-Ress, J Halaschek-Wiener
1Department of Clinical Pharmacology, Section of Experimental Oncology/Molecular Pharmacology, University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
Abstract:
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.
Insights
Bcl-2 antisense oligonucleotides (G3139) enhance cisplatin chemotherapy in gastric cancer models. This combination therapy reduces tumor size and prolongs survival by increasing apoptosis, showing promise for clinical trials.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Gastric cancer remains a significant global health challenge.
- Chemotherapy resistance is a major obstacle in treating gastric cancer.
- Bcl-2 protein is often overexpressed in cancer cells, inhibiting apoptosis.
Purpose of the Study:
- To investigate the efficacy of Bcl-2 antisense oligonucleotides (G3139) in chemosensitizing human gastric cancer.
- To evaluate the combined effect of G3139 and cisplatin in a preclinical gastric cancer model.
Main Methods:
- A human gastric cancer SCID mouse model was established.
- Systemic administration of G3139 and cisplatin, alone and in combination.
- Assessment of Bcl-2 expression, apoptosis, tumor size, and survival.
Main Results:
- G3139 alone downregulated Bcl-2 and moderately reduced tumor size.
- Combination therapy with G3139 and cisplatin significantly enhanced antitumor effects (70% tumor reduction vs. cisplatin alone).
- Increased apoptosis and over 50% prolonged survival were observed with combined treatment, without significant toxicity.
Conclusions:
- Bcl-2 antisense oligonucleotides (G3139) show potential as a novel approach to overcome cisplatin resistance in gastric cancer.
- Combined G3139 and cisplatin therapy demonstrates significant antitumor activity and improved survival in preclinical models.
- This strategy warrants further investigation in clinical trials for gastric cancer treatment.
