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Retrovirally transmitted gene therapy for gastric carcinoma using herpes simplex virus thymidine kinase gene
K Yoshida1, H Kawami, Y Yamaguchi
1Department of Surgery, Hiroshima University, Japan.
Background:
Herpes simplex thymidine kinase (HTK) is known to phosphorylate ganciclovir (GCV). Phosphorylated GCV is incorporated into genomic DNA, which leads to inhibition of cell growth and cell death in the replicating cells. Recently, much attention has been drawn to the use of retrovirally mediated gene therapy using HTK as a new therapeutic approach for brain tumors. However, little is known about this phenomenon in gastrointestinal carcinomas.
Methods:
The authors transfected the HTK gene packaged in retroviral vector into TMK-1 gastric carcinoma cells (TMK-HTK cells). Sensitivity of TMK-HTK cells to GCV was examined in vitro. Moreover, TMK-HTK cells were transduced into nude mice subcutaneously, and the effects of GCV therapy was examined at the concentration of 20 mg/kg daily for 14 days.
Results:
TMK-HTK cells were sensitive to GCV at the concentration of 0.1 to 100 micrograms/ml in a dose- and time-dependent manner in vitro. Moreover, 12 of 13 TMK-HTK tumors, which were transduced into nude mice subcutaneously, shrunk from the average diameter of 6.5 mm.
Conclusion:
The results indicate that retrovirally transmitted gene therapy with GCV may provide a new therapeutic approach for treatment of gastric carcinomas.
Insights
Retrovirally mediated gene therapy using herpes simplex thymidine kinase (HTK) and ganciclovir (GCV) shows promise for treating gastric cancer. This approach effectively inhibited tumor growth in preclinical models, suggesting a potential new therapeutic strategy.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Herpes simplex thymidine kinase (HTK) phosphorylates ganciclovir (GCV), leading to DNA incorporation and cell death in replicating cells.
- Retroviral gene therapy utilizing HTK is a developing treatment for brain tumors, but its efficacy in gastrointestinal carcinomas is largely unexplored.
Purpose of the Study:
- To investigate the potential of retrovirally mediated gene therapy with HTK and GCV for treating gastric carcinomas.
Main Methods:
- HTK gene was introduced into TMK-1 gastric carcinoma cells using a retroviral vector (TMK-HTK cells).
- In vitro sensitivity of TMK-HTK cells to GCV was assessed.
- Subcutaneous xenografts of TMK-HTK cells in nude mice were treated with GCV (20 mg/kg daily for 14 days).
Main Results:
- TMK-HTK cells demonstrated sensitivity to GCV in a dose- and time-dependent manner in vitro.
- Significant tumor regression was observed, with 12 out of 13 TMK-HTK tumors shrinking from an average diameter of 6.5 mm.
Conclusions:
- Retrovirally delivered gene therapy combined with GCV presents a promising new therapeutic avenue for gastric carcinoma treatment.