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Suicide gene therapy for plasma cell tumors
M S Dilber1, M R Abedi, B Björkstrand
1Department of Medicine, Karolinska Institute at Huddinge Hospital, Sweden.
Abstract:
Suicide gene therapy for plasma cell tumors was attempted in severe combined immunodeficient (SCID) mice injected with human myeloma cell lines. Initially, a ganciclovir-induced bystander effect was observed in vitro using myeloma cells transduced with a herpes simplex thymidine kinase (HSVtk) gene. Transduced cells injected subcutaneously (SC) into SCID mice could be eradicated by the administration of ganciclovir (GCV). Furthermore, an in vivo bystander effect was noticed when mice received mixtures of HSVtk-positive and nontransduced cells. Unexpectedly, a "distant bystander" effect was observed as tumors in regions inoculated with only nontransduced cells were significantly smaller and had increased frequency of apoptotic figures and decreased mitotic frequency in GCV-treated mice transplanted with HSVtk-positive cells at a different region compared with control mice.
Insights
Suicide gene therapy using herpes simplex thymidine kinase (HSVtk) and ganciclovir (GCV) eradicated myeloma tumors in mice. A surprising distant bystander effect was observed, impacting non-treated tumors.
Area of Science:
- Oncology
- Gene Therapy
- Cancer Research
Background:
- Plasma cell tumors, like multiple myeloma, are challenging to treat.
- Suicide gene therapy offers a novel therapeutic strategy.
- The herpes simplex thymidine kinase (HSVtk)/ganciclovir (GCV) system is a well-studied suicide gene therapy approach.
Purpose of the Study:
- To evaluate the efficacy of HSVtk/GCV suicide gene therapy against human myeloma cell lines in severe combined immunodeficient (SCID) mice.
- To investigate the in vitro and in vivo bystander effects of this gene therapy approach.
- To explore the potential for a "distant bystander" effect.
Main Methods:
- Human myeloma cell lines were transduced with the HSVtk gene.
- In vitro studies assessed ganciclovir-induced cytotoxicity.
- SCID mice were injected with either transduced cells, mixtures of transduced and non-transduced cells, or cells at different locations to assess in vivo and distant bystander effects.
- Tumor growth, apoptosis, and mitotic frequency were analyzed.
Main Results:
- Ganciclovir effectively eradicated HSVtk-transduced myeloma cells in vitro.
- Subcutaneous injection of HSVtk-transduced cells in SCID mice led to tumor eradication upon ganciclovir administration.
- A significant in vivo bystander effect was observed when mixtures of transduced and non-transduced cells were present.
- A notable "distant bystander" effect was documented, with significant tumor reduction and increased apoptosis in non-transduced tumors located separately from the treated site.
Conclusions:
- HSVtk/GCV suicide gene therapy is effective against human myeloma xenografts in SCID mice.
- The therapy demonstrates both direct cytotoxic and significant bystander effects, including a distant bystander effect.
- These findings support the potential of suicide gene therapy for treating plasma cell tumors, warranting further investigation.