Local inflammation and devascularization — in vivo mechanisms of the “bystander effect” in VPC-mediated HSV-Tk/GCV gene therapy for human malignant glioma

Abstract

Somatic gene therapy with the herpes simplex virus type I thymidine kinase gene/ganciclovir (HSV-Tk/GCV) system and murine retroviral vector producer cells (VPCs) was introduced as a new adjuvant treatment modality to treat tumor bulk and to prevent tumor recurrence in patients harboring malignant glioma. The single-center experience after treatment of 27 patients undergoing tumor resection followed by intracerebral VPC injection for HSV-Tk suicide gene therapy will be presented focused on findings of systematic and close MRI follow-up and a few histological specimens. The data indicate that hemorrhagic necrosis due to endothelial cell transfection mediated vessel necrosis and that local inflammatory immune response occurs frequently after gene therapy. These phenomena seem to be specific because none of the patients of a control group showed any similar features. The prognosis (time to progression, survival) of the patients with "bystander effects" after gene therapy was better, but compared to those patients without bystander effects, they were also privileged by a favorable constellation of prognostic factors. Therefore, the appearance of these neuroradiologic features cannot serve as an indicator for treatment effectiveness and outcome.

Construction and identification of recombinant vectors carrying herpes simplex virus thymidine kinase and cytokine genes expressed in gastric carcinoma cell line SGC7901

“…Gene therapy has become a promising strategy for the treatment of gastric cancer [27][28][29][30][31] , in which the transfer of suicide genes into tumor cells has emerged as an attractive modality for the selective elimination of cancer cells [14][15][16]30,31] . The suicide genes encode non-mammalian enzymes that can convert nontoxic prodrugs into cellular toxic metabolites.…”

“…One of the landmark discoveries for this therapeutic strategy is the transfer of suicide genes, such as HSV-TK, into the tumor cells, which has been shown to exert antitumor efficacy on a variety of cancer cells [8][9][10][11] . The expressed HSV-TK/ganciclovir (GCV) system can not only inhibit the DNA synthesis of the target cells but also produce a bystander effect against tumors [12][13][14][15][16] . However, these effects have been found to be unstable in some of the transfected cells, which may result in a decreased efficiency in the treatment of malignancies.…”

GCV phosphates are transferred between HeLa cells despite lack of bystander cytotoxicity

“…9 Success of this approach in animal tumor models has led to clinical trials in a variety of tumor types. [22][23][24][25] An important feature of this form of enzyme-prodrug therapy is that HSV-TK-expressing cells can cause GCVmediated cytotoxicity in tumor cells that do not express the transgene, a process known as the bystander effect. 10,[26][27][28] Bystander cytotoxicity is critical for the enzyme-prodrug gene therapy strategy because current techniques for gene transfer typically result in fewer than 10% of the cells expressing the transgene.…”

Do there exist synergistic antitumor effects by coexpression of herpes simplex virus thymidine kinase with cytokine genes on human gastric cancer cell line SGC7901?

“…Suicide gene therapy with the herpes simplex virus thymidine kinase (HSV-TK) fragment, the most widely used strategy for the cancer therapeutic study [3] , has been shown to exert antitumor efficacy in various cancer models [4][5][6][7] . However, its efficacy seems not to be fully developed to eliminate tumor cells in some of the investigations [8][9][10][11][12] . Gene therapy with HSV-TK and cytokine genes together may produce a complementary effect, and has become a new insight for the treatment of malignancies [13,14] .…”