Bystander Killing Effect of Tymidine Kinase Gene-Transduced Adult Bone Marrow Stromal Cells With Ganciclovir on Malignant Glioma Cells

Abstract

Transduction of the suicide gene of Herpes simplex virus thymidine kinase (Hsv-tk) into glioma cells or neural stem cells combined with pro-drug ganciclovir (GCV) treatment has been effective to treat experimental glioma in the rat through the bystander effect. Bone marrow stromal cells (MSCs) in the adult bone marrow have tropism for brain tumors and act as tumor stromal cells. Whether adult MSCs expressing Hsv-tk can also act as effector cells of the bystander killing effect on murine glioma cells was investigated. In vitro study of co-culture between 9L/LacZ (9L) glioma cells and Hsv-tk-transduced MSCs (MSCs/tk(＋)) followed by GCV administration in the culture medium resulted in apparent nuclear morphological changes in the 9L glioma cells surrounding the MSCs/tk(＋). 9L glioma cell survival in the presence of MSCs/tk(＋) and GCV treatment was quantitatively measured and showed significant decrease of 9L glioma cell proliferation with higher MSCs/tk(＋) ratio and GCV concentration. Intracerebral co-inoculation experiments in Fisher rats used 9L glioma cells and either MSCs/tk(＋) or Hsv-tk-non-transduced MSCs (MSCs/tk(-)) followed by intraperitoneal injection of GCV (100 mg/kg, daily for 7 days). The animals co-inoculated with 9L glioma cells and MSCs/tk(＋) showed significant retardation of tumor growth and prolongation of survival time compared with the animals with 9L glioma cells and MSCs/tk(-). Quantitative findings were established of the novel effects of adult MSCs/tk(＋) as effector cells of the bystander killing effect on glioma cells.

Mesenchymal stem cells as therapeutic agents and potential targeted gene delivery vehicle for brain diseases

“…Furthermore, gene-modified MSCs, MSCs-TH and MSCs-GDNF, also resulted in biologically significant functional recovery. The GDNF-transduced MSCs were capable of inducing a pronounced local trophic effect in the denervated striatum as they induced sprouting from the remaining dopaminergic terminals towards the neurotrophic milieu created, while the TH-modified MSCs significantly protected TH-positive cells from neurotoxicity and increases [80] the DA content in the striatum of the rat brain [65][66][67]. All these indicate MSCs as a potential candidate for treatment of diseases of central nervous system.…”

Use of genetically engineered stem cells for glioma therapy

“…Migratory stem cell vectors have been introduced to achieve improved intratumoral distribution of the prodrug-converting enzyme. In vivo preclinical studies confirming the feasibility of this approach for the treatment of glioma have been conducted using NSCs (17,44,83) and MSCs (81,(84)(85)(86)(87)(88)(89)(90) as HSV-tk delivery vehicles. It has also been proven that the 'bystander effect' of HSV-tk/GCV suicide gene therapy does not damage normal brain tissues (91).…”

Frontiers in Suicide Gene Therapy of Cancer

“…The stem cells are being tested for their potential for carrying the suicidal genes also into variety of other tumors [135][136][137][138][139][140][141][142][143][144][145][146][147][148].…”

“…HSV-TK is effectively used in cancer suicide gene therapy by expression in targeted cells to exert intracellular effects outlined above [15][16][17][18][19][22][23][24]. Alternatively, TK is also secreted into the extracellular fluids by genetically engineered cells [135][136][137][138][139][140][141][142][143][144][145][146][147][148]. Thereafter, it is internalized by surrounding cancer cells to cause their death.…”