Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: Implications for clinical trials

Dewey, Ricardo Alfredo; Morrissey, G.; Cowsill, C; Stone, Daniel; Bolognani, Federico; Dodd, N.J.F.; Southgate, Thomas D.; Klatzmann, David; Lassmann, Hans; Castro, María G.; Löwenstein, Pedro R.

doi:10.1038/15207

Cited by 307 publications

(232 citation statements)

References 38 publications

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“…Adenoviral vectors are highly efficient at in vivo transduction and can be concentrated to high titers, thus it is possible to stereotactically inject high titers of viruses directly into the area of brain infiltrated by tumor cells. [17][18][19] In addition to the high efficiency of transduction, adenoviruses mediate high-level transgene expression and pose little risk of insertional mutagenesis.…”

Section: Ecorin Plays Different Roles In Regulating Matrixmentioning

confidence: 99%

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Effects of ectopic decorin in modulating intracranial glioma progression in vivo, in a rat syngeneic model

et al. 2004

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Given the failure of conventional treatments for glioblastoma, gene therapy has gained interest considerable in recent years. Gliomas are associated with a state of immunosuppression, which appears to be partially mediated by an increase in secretion of transforming growth factor-b (TGF-b) from glioma cells. Decorin, a small proteoglycan which can bind to and inactivate TGF-b, has been successfully used as an antitumor strategy on stably transfected tumor cells and has been shown to cause growth suppression in neoplastic cells of various histological origins. In this paper, we investigated the use of gene therapy to deliver the decorin transgene in a site-specific manner in an experimental model of intracranial gliomas. Our aim was to inhibit the glioma-associated immunosuppressive state, and prolong the survival of tumor-bearing rats.We studied the effects of decorin gene transfer in the rat CNS-1 glioma model. To assess the effect of ectopic expression of decorin on glioma progression in vivo, stably transfected CNS-1 cells expressing decorin were implanted into the brain parenchyma of syngeneic Lewis rats. The rats implanted with CNS-1 cells expressing decorin survived significantly longer than those in the control groups which received CNS-1 cells that did not express decorin (Po.0001). We then investigated whether the survival observed with decorin expressing cells could be mimicked in vivo, using recombinant adenoviruses (RAds) expressing the decorin gene under the control of two different promoters: the human immediate-early cytomegalovirus (h-IE-CMV) and the glial fibrillary acidic protein (GFAP). In vivo results showed that administration of RAd expressing the human decorin under the control of h-IE-CMV promoter has a small, but significant effect in prolonging the survival of experimental tumor bearing rats (Po.0001). Our data indicate that ectopic decorin expression has the potential to slow glioma progression in vivo. Our results also indicate that expression of decorin has to be present in all cells which constitute the intracranial tumor mass for the inhibition of tumor growth and prolongation of the life expectancy of tumor-bearing rats to be effective.

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Section: Ecorin Plays Different Roles In Regulating Matrixmentioning

confidence: 99%

“…17,[20][21][22][23] We have assessed this for up to 3 months after CNS-1 tumor implantation in the survivors after gene therapy using RAd/HSV1-TK plus ganciclovir. The reasons for this are two-fold.…”

Section: Ecorin Plays Different Roles In Regulating Matrixmentioning

confidence: 99%

Effects of ectopic decorin in modulating intracranial glioma progression in vivo, in a rat syngeneic model

et al. 2004

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Gentry

Boucher

et al. 2005

Gene Ther

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The role of gap junctional intercellular communication (GJIC) in bystander killing with herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) was evaluated in U251 cells expressing a dominant-negative connexin 43 cDNA (DN14), and in HeLa cells, reportedly devoid of connexin protein. These cell lines both exhibited 0% GJIC when assayed by Lucifer Yellow fluorescent dye microinjection. Bystander cytotoxicity was still apparent in 50:50 cocultures of DN14 and HSV-TK-expressing U251 cells, but not in 50:50 cocultures of HeLa cells. However, the sensitivity of HeLa HSV-TK-expressing cells to GCV decreased nearly 100-fold (IC 90 ¼ 109 mM) when cocultured with bystander cells compared to results in 100% cultures of HSV-TK-expressing cells (IC 90 ¼ 1.2 mM). A more sensitive flow cytometry technique to measure GJIC over 24 h revealed that the DN14 and HeLa cells exhibited detectable levels of communication (29 and 23%, respectively). Transfer of phosphorylated GCV to HeLa bystander cells occurred within 4 h after drug addition, and GCV triphosphate (GCVTP) accumulated to 213784 pmol/10 6 cells after 24 h. In addition, GCVTP levels were decreased in HSV-TK-expressing cells in coculture (867733 pmol/10 6 cells) compared to 100% cultures of HSV-TK-expressing cells (17737188 pmol/10 6 cells). The half-life of GCVTP in the HSV-TK-expressing cells was approximately four times that measured in the bystander cells (12.3 and 3.1 h, respectively). These data suggest that the lack of bystander cytotoxicity in HeLa cocultures is due to low transfer of phosphorylated GCV and a rapid half-life of GCVTP in the bystander cells. Thus, GCV phosphate transfer to non-HSV-TK-expressing bystander cells may mediate either bystander cell killing or sparing of HSV-TK-positive cells, depending upon the cell specific drug metabolism.

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“…On the other hand, a recent study reported widespread chronic brain inflammation, vector distribution, and detection of TK protein in animals cured of experimental gliomas by local injection of replication-incompetent adenoviral TK vectors in combination with systemic GCV treatment. 28 Hence, the occurrence of acute and chronic inflammation and their effects in response to HSV-based TK/GCV therapy are important areas of future investigation.…”

Section: Discussionmentioning

confidence: 99%

HSV vector cytotoxicity is inversely correlated with effective TK/GCV suicide gene therapy of rat gliosarcoma

et al. 2000

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Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: Implications for clinical trials

Cited by 307 publications

References 38 publications

Effects of ectopic decorin in modulating intracranial glioma progression in vivo, in a rat syngeneic model

Effects of ectopic decorin in modulating intracranial glioma progression in vivo, in a rat syngeneic model

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

HSV vector cytotoxicity is inversely correlated with effective TK/GCV suicide gene therapy of rat gliosarcoma

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