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Human prostate carcinoma cells as targets for herpes simplex virus thymidine kinase-mediated suicide gene therapy
S Loimas1, M R Toppinen, T Visakorpi
1A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Finland.
Abstract:
To evaluate human prostate carcinoma cells as targets for herpes simplex virus thymidine kinase (HSV-TK) -mediated gene therapy, we tested the utility of different viral vectors on three human cell lines DU-145, LNCaP, and PC-3. Our viral vectors were carrying a fusion gene of HSV-TK and green fluorescent protein for accurate determination of the gene transfer rate and its contribution to the treatment outcome in each case. We observed that adenoviral and lentiviral vectors were efficient vehicles for all the cell lines, whereas Semliki Forest virus and Sindbis virus vectors yielded only a few percent of transgene-positive cells. Despite sufficient gene transfer rates (25-45%) in the ganciclovir (GCV) sensitivity experiment, only DU-145 cells were efficiently destroyed under clinically relevant GCV concentrations. This was shown to be due to low level of "bystander effect" in PC-3 and LNCaP cells. Our data demonstrate that human prostate tumors can be good targets for adenovirus- or lentivirus-mediated HSV-TK/GCV gene therapy, but each tumor should be investigated for gene transfer rate and bystander effect to warrant a sufficient treatment result.
Insights
Adenovirus and lentivirus vectors efficiently deliver herpes simplex virus thymidine kinase (HSV-TK) gene therapy to prostate cancer cells. However, treatment success depends on the tumor's gene transfer rate and bystander effect for ganciclovir efficacy.
Area of Science:
- Oncology
- Gene Therapy
- Virology
Background:
- Prostate carcinoma is a significant health concern.
- Herpes simplex virus thymidine kinase (HSV-TK) mediated gene therapy offers a potential treatment strategy.
- Evaluating viral vector efficiency and gene transfer is crucial for therapeutic success.
Purpose of the Study:
- To assess the efficacy of different viral vectors for HSV-TK gene therapy in human prostate carcinoma cell lines.
- To determine gene transfer rates and their impact on treatment outcomes.
- To investigate the role of the bystander effect in HSV-TK/ganciclovir therapy.
Main Methods:
- Utilized adenoviral, lentiviral, Semliki Forest virus, and Sindbis virus vectors.
- Vectors carried a fusion gene of HSV-TK and green fluorescent protein (GFP).
- Tested ganciclovir (GCV) sensitivity in DU-145, LNCaP, and PC-3 cell lines.
Main Results:
- Adenoviral and lentiviral vectors showed high gene transfer efficiency across all cell lines.
- Semliki Forest virus and Sindbis virus vectors resulted in low transgene expression.
- DU-145 cells were effectively destroyed by GCV, unlike PC-3 and LNCaP cells, due to a limited bystander effect.
Conclusions:
- Human prostate tumors are viable targets for adenovirus- or lentivirus-mediated HSV-TK/GCV gene therapy.
- Individual tumor assessment of gene transfer rate and bystander effect is essential for optimizing treatment outcomes.
- The bystander effect significantly influences the overall efficacy of HSV-TK/GCV gene therapy in prostate cancer.
