Antitumor activity of combined endostatin and thymidine kinase gene therapy in C6 glioma models

Abstract

The combination of Endostatin (ES) and Herpes Simplex Virus thymidine kinase (HSV‐TK) gene therapy is known to have antitumor activity in bladder cancer. The potential effect of ES and TK therapy in glioma has not yet been investigated. In this study, pTK‐internal ribosome entry site (IRES), pIRES‐ES, and pTK‐IRES‐ES plasmids were constructed; pIRES empty vector served as the negative control. The recombinant constructs were transfected into human umbilical vein endothelial cells (HUVECs) ECV304 and C6 rat glioma cell line. Ganciclovir (GCV) was used to induce cell death in transfected C6 cells. We found that ECV304 cells expressing either ES or TK‐ES showed reduced proliferation, decreased migration capacity, and increased apoptosis, as compared to untransfected cells or controls. pTK‐IRES‐ES/GCV or pTK‐IRES/GCV significantly suppressed cell proliferation and induced cell apoptosis in C6 cells, as compared to the control. In addition, the administration of pIRES‐ES, pTK‐IRES/GCV, or pTK‐IRES‐ES/GCV therapy improved animal activity and behavior; was associated with prolonged animal survival, and a lower microvessel density (MVD) value in tumor tissues of C6 glioma rats. In comparison to others, dual gene therapy in form of pTK‐IRES‐ES/GCV had a significant antitumor activity against C6 glioma. These findings indicate combined TK and ES gene therapy was associated with a superior antitumor efficacy as compared to single gene therapy in C6 glioma.

Novel Semi-Replicative Retroviral Vector Mediated Double Suicide Gene Transfer Enhances Antitumor Effects in Patient-Derived Glioblastoma Models

“…We confirmed the versatility of our sp-RRV-mediated double suicide gene transfer system by investigating the preclinical antitumor efficacy and bystander effects of the combined vectors, spRRVe-sEF1α- TK and sRRVgp-sEF1α- CD , in seven patient-derived GSCs, each of which possessed unique properties (e.g., growth rates and genomic profiles). Our method synergistically halted cell division and induced cancer cell death, anti-angiogenesis, and TAM depletion in orthotopic patient-derived glioblastoma xenografts, which were consistent with the previously reported antitumor activities of the TK/GCV and CD/5-FC systems [8,9,14,23,38,48]. Similarly, recent studies have demonstrated that the fusion of TK and CD with GCV and 5-FC synergistically improves therapeutic efficacy via the enhancement of cytotoxicity and bystander effects [30,34,49].…”

Extracellular Matrix, a Hard Player in Angiogenesis

“…The fragment also inhibits FGF-2 and VEGF-induced EC proliferation and migration [86,87]. Relying on its anti-angiogenic properties, endostatin displays potent anti-tumoral effects [88,89,90,91]. Remarkably, the treatment with the recombinant fragment induces vessel normalization and, as a consequence an improved chemotherapy efficacy [92].…”

Detection of lentiviral suicide gene therapy in C6 rat glioma using hyperpolarised [1‐13C]pyruvate

“…For example, herpes simplex virus‐1 thymidine kinase (HSV‐TK) is the most comprehensively studied suicide gene therapy against malignant glioma . HSV‐TK catalyses the phosphorylation of nucleoside analog ganciclovir (GCV), converting it into a toxic metabolite which inhibits DNA replication and cell proliferation, thus inducing cell apoptosis . The developing therapy regimen requires supporting diagnostic methods that can efficiently evaluate early treatment responses.…”