Improved therapeutic effect on malignant glioma with adenoviral suicide gene therapy combined with temozolomide

• Published in: Gene therapy Vol. 20; no. 12; pp. 1165 - 1171
• Main Authors: Stedt, H, Samaranayake, H, Pikkarainen, J, Määttä, A M, Alasaarela, L, Airenne, K, Ylä-Herttuala, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2013; Nature Publishing Group
• Subjects: 692/699/67/1922; 692/700/565/1436; 692/700/565/201; Adenoviruses; Adenoviruses, Human - genetics; Adenoviruses, Human - metabolism; Animals; Antineoplastic Agents, Alkylating - therapeutic use; Antiviral Agents - therapeutic use; Biological products; Biomedical and Life Sciences; Biomedicine; Brain cancer; Brain tumors; Care and treatment; Cell Biology; Chemotherapy; Clinical outcomes; Combined Modality Therapy; Cytotoxicity; Dacarbazine - analogs & derivatives; Dacarbazine - therapeutic use; Drug therapy, Combination; Ganciclovir; Ganciclovir - therapeutic use; Gene Expression; Gene Therapy; Genes, Transgenic, Suicide; Genes, Viral; Genetic Therapy; Genetic Vectors; Glioma; Glioma - drug therapy; Glioma - pathology; Glioma - therapy; Gliomas; Health aspects; Herpes simplex; Herpesvirus 1, Human - genetics; Herpesvirus 1, Human - metabolism; Human Genetics; Humans; Identification and classification; Kinases; Leukopenia; Male; Medical prognosis; Nanotechnology; Neoplasms, Experimental; original-article; Patient outcomes; Rats; Suicide; Suicide genes; Temozolomide; Testing; Thrombocytopenia; Thymidine; Thymidine kinase; Thymidine Kinase - genetics; Thymidine Kinase - metabolism; Treatment Outcome; Tumor Cells, Cultured; Valproic acid; Valproic Acid - therapeutic use; Viral proteins; temozolomide; valproic acid; herpes simplex virus thymidine kinase; MRI; malignant glioma; histone deacetylase inhibitor
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2013.46

Malignant gliomas (MGs) are cancers with poor prognosis and limited therapeutic options. Herpes Simplex virus-1 thymidine kinase expressed from adenoviruses with prodrug ganciclovir (TK/GCV) is the best-characterized suicide gene therapy, whereas temozolomide (TMZ) is the first-line chemotherapy for MG. However, the potential of their combination has not been studied thoroughly. The aim of this study was to evaluate the therapeutic response of this combination and to study whether addition of valproic acid (VPA) could benefit the treatment outcome. Efficacies of different treatments were first studied in vitro in BT4C rat MG cells. Therapeutic assessment in vivo was done in an immunocompetent rat MG model for treatment efficacy and toxicity. In vitro, VPA was able to significantly enhance cytotoxicity and increase adenovirus-mediated transduction efficiency up to sevenfold. In vivo , rats receiving TK/GCV+TMZ had notably smaller tumors and enhanced survival ( P <0.001) in comparison with control rats. However, VPA was not able to further enhance the treatment response in vivo . Leukocytopenia and thrombocytopenia were the major side effects. We conclude that careful optimization of the treatment schedules and doses of individual therapies are necessary to achieve an optimal therapeutic effect with TK/GCV+TMZ combination. No further in vivo benefit with VPA was observed.