The combination of HSV-tk and endostatin gene therapy eradicates orthotopic human renal cell carcinomas in nude mice

Abstract

Background and methods: Gene therapy may offer a new tool for the treatment of renal cell carcinoma ( RCC ). We have tested a combination of cytotoxic and antiangiogenic gene therapy for wild -type orthotopic human RCC xenografts in nude mice using intratumoral adenovirus -mediated herpes simplex virus thymidine kinase ( HSV -tk ) and endostatin ( ES ) gene therapy. In vivo magnetic resonance imaging, morphometry, immunocytochemistry, and survival were used to evaluate the treatment effect. Adenovirus -mediated marker gene transfers ( GFP ) were used as controls. Results: In vivo transduction efficiency, measured using GFP gene transfer, was 27 ± 7%. The combination gene therapy with HSV -tk and ES adenoviruses resulted in a significant antitumor effect ( P < .01 ) compared to single HSV -tk ( n.s. ) or ES ( n.s. ). In the survival study, all tumors with single gene therapy using HSV -tk, ES, and marker gene adenoviruses showed progression in magnetic resonance imaging. In contrast, the majority of the tumors in the combination treatment group remained dormant or were eradicated ( 57% ). Survival of these mice equaled healthy nude mice, and was significantly prolonged ( P < .0001 ) compared to HSV -tk ( P < .028 ) and ES ( n.s. ) groups. Conclusions: It is concluded that the inhibition of angiogenesis using ES gene transfer together with the cytotoxic HSV -tk gene therapy results in a significantly improved treatment effect in RCC compared to the single gene treatments.

Electrogene therapy using endostatin, with or without suicide gene therapy, suppresses murine mammary tumor growth and metastasis

“…Experimental combination therapy with endostatin has exhibited some successful synergistic effects on primary tumor growth, [42][43][44] correlating with the results of our study. However, the present experimental models did not focus on any antimetastatic effects that might have been evident.…”

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.…”

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] .…”