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Isolation and Flow Cytometric Analysis of Glioma-infiltrating Peripheral Blood Mononuclear Cells
Published on: November 28, 2015
Increased invasion of malignant gliomas after 15-LO-1 and HSV-tk/ganciclovir combination gene therapy
A Pacholska1, T Wirth, H Samaranayake
1Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
Abstract:
Recent clinical trials for malignant glioma have drawn attention to the potential therapeutic efficacy of herpes simplex virus-thymidine kinase (HSV-tk) suicide gene therapy. Nevertheless, because of the nature of these tumors, it is believed that no single treatment alone is able to combat this fatal disease. Combination therapies may provide a solution to further improve therapies against malignant gliomas. We have recently demonstrated that 15-lipoxygenase-1 (15-LO-1) is able to inhibit tumor angiogenesis as well as enhance apoptosis in tumors. As a result, we studied the potential additive/synergistic effects of 15-LO-1 gene therapy when combined with HSV-tk gene therapy for the treatment of malignant gliomas. For that, BT4C malignant glioma cells were implanted into BDIX male rats. Fourteen days after tumor cell implantation, animals were transduced using adenoviral vectors either with HSV-tk alone or in combination with 15-LO-1. The results show that the combination gene therapy neither improved inhibition of tumor growth nor did it show any benefit on survival. Instead, a profound effect on the migratory properties of the tumor cells was found, resulting in decreased survival. Similar to conventional therapies, the combination of two therapeutic genes may result in unexpected side effects, not seen when given alone.
Insights
Combining herpes simplex virus-thymidine kinase (HSV-tk) gene therapy with 15-lipoxygenase-1 (15-LO-1) gene therapy did not improve malignant glioma treatment. This combination therapy unexpectedly decreased survival by enhancing tumor cell migration.
Area of Science:
- Oncology
- Gene Therapy
- Cancer Research
Background:
- Malignant gliomas are aggressive brain tumors requiring novel therapeutic strategies.
- Herpes simplex virus-thymidine kinase (HSV-tk) suicide gene therapy shows potential but is often insufficient alone.
- 15-lipoxygenase-1 (15-LO-1) has demonstrated anti-tumorigenic properties, including inhibiting angiogenesis and promoting apoptosis.
Purpose of the Study:
- To investigate the potential additive or synergistic effects of combining 15-LO-1 gene therapy with HSV-tk gene therapy for malignant glioma treatment.
- To evaluate the impact of this combination therapy on tumor growth, apoptosis, angiogenesis, and animal survival.
Main Methods:
- BT4C malignant glioma cells were implanted into BDIX male rats.
- Adenoviral vectors were used to deliver either HSV-tk alone or in combination with 15-LO-1 to tumor-bearing rats 14 days post-implantation.
- Tumor growth, survival rates, and tumor cell migratory properties were assessed.
Main Results:
- The combination of HSV-tk and 15-LO-1 gene therapy did not enhance tumor growth inhibition or improve survival rates compared to single-gene therapy.
- A significant increase in tumor cell migration was observed in the combination therapy group, leading to reduced survival.
- Unexpected adverse effects were noted with the combination therapy, not observed with individual gene treatments.
Conclusions:
- Combination gene therapy using HSV-tk and 15-LO-1 is not effective for treating malignant gliomas and may be detrimental.
- The combination therapy negatively impacts tumor cell behavior, specifically increasing migration and decreasing survival.
- Further research is needed to understand the complex interactions and potential risks of combining gene therapies for cancer treatment.
