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[Possibility and future problems of gene therapy for gastric cancer]
N Matsukura1, M Onda, T Shimada
1First Department of Surgery, Nippon Medical School, Tokyo, Japan.
Abstract:
Recently, stage-oriented surgery has been performed for gastric cancer, but a new strategy is necessary for stage IV gastric cancer. The first target of gene therapy for gastric cancer was for stage IV patients with-widespread lymph node metastases and/or peritoneal dissemination. We reported on suicide gene therapy in experimental gastric cancer induced by ENNG in the dog, and the results showed that in situ gene transfer of a suicide gene (Ad. CAGHSV-TK) followed by prodrug (GCV) treatment may be applicable not only to the primary gastric tumor, but also to lymph node metastasis. Next, we assessed the efficacy of in situ gene therapy with Ad. CAGHSV-TK/GCV in gastric cancer induced by MNNG in rats, and followed the histopathological changes in the gastric cancer and HSV-TK gene in peripheral blood for 30 days. The results showed that: 1) apoptosis preceded tissue degeneration; 2) histopathological efficacy requires 30 days after suicide gene therapy; and 3) the HSV-TK gene persisted for 30 days. Based on these studies, we speculated that combination treatment with endoscopy is possible for all early gastric cancer, i.e., endoscopic mucosal resection of the primary tumor plus suicide gene therapy for sentinel lymph node metastasis. New possible strategies for peritoneal dissemination are: 1) tumor dormancy therapy with adeno-associated virus (AAV); and 2) combination gene therapy with suicide genes plus gene transfer to provide immunotherapy.
Insights
New suicide gene therapy strategies show promise for advanced gastric cancer. This approach, involving in situ gene transfer and prodrug treatment, effectively targets primary tumors and metastases, offering hope for stage IV patients.
Area of Science:
- Oncology
- Gene Therapy
- Gastroenterology
Context:
- Stage-oriented surgery is standard for gastric cancer, but advanced (stage IV) disease requires novel therapeutic strategies.
- Gene therapy has been explored for stage IV gastric cancer, particularly for widespread lymph node metastases and peritoneal dissemination.
- Previous research targeted gene therapy for gastric cancer, with initial efforts focusing on stage IV patients.
Purpose:
- To evaluate the efficacy of in situ suicide gene therapy (Ad.CAGHSV-TK/GCV) for gastric cancer, including primary tumors and lymph node metastases.
- To assess the histopathological changes and gene persistence following suicide gene therapy in a rat model of gastric cancer.
- To explore potential new strategies for treating peritoneal dissemination in gastric cancer.
Summary:
- In situ gene transfer of the Ad.CAGHSV-TK suicide gene followed by ganciclovir (GCV) prodrug treatment demonstrated efficacy against primary gastric tumors and lymph node metastases in canine models.
- In rat models, suicide gene therapy induced apoptosis preceding tissue degeneration, with histopathological efficacy observed 30 days post-treatment.
- The HSV-TK gene persisted in peripheral blood for 30 days, indicating sustained therapeutic potential.
- The study suggests combining endoscopic mucosal resection with suicide gene therapy for early gastric cancer and sentinel lymph node metastasis.
- Future strategies for peritoneal dissemination include tumor dormancy therapy using adeno-associated virus (AAV) and combination gene therapy for immunotherapy.
Impact:
- Provides evidence for the potential application of suicide gene therapy in treating primary gastric tumors and lymph node metastases.
- Establishes a timeline for histopathological efficacy and gene persistence, crucial for treatment planning.
- Suggests innovative combination approaches for early-stage gastric cancer and advanced peritoneal dissemination.
- Highlights the potential of gene therapy as a therapeutic modality for challenging gastric cancer cases.