Double suicide gene therapy using a replication defective herpes simplex virus vector reveals reciprocal interference in a malignant glioma model

Moriuchi, Shusuke; Wolfe, Darren; Tamura, Masakazu; Yoshimine, Toshiki; Miura, Flávio Key; Cohen, Justus B.; Glorioso, Joseph C.

doi:10.1038/sj.gt.3301693

Cited by 55 publications

(35 citation statements)

References 18 publications

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“…28 The absence of an effective treatment and the extremely poor prognosis of this disease necessitate new therapeutic options such as gene therapy. [29][30][31] Since replication-defective vectors have to date failed to achieve a high degree of tumor transduction, replication-competent virus vectors appear to be attractive therapeutic agents for cancer. [32][33][34][35][36] Since the first description of a virus that was engineered to replicate selectively in dividing cells 14 years ago, 15 the field of viral therapy for cancer has significantly expanded, and at least 10 different viral species have entered clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Enhanced therapeutic efficacy of G207 for the treatment of glioma through Musashi1 promoter retargeting of γ34.5-mediated virulence

et al. 2005

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G207 is a conditionally replicating derivative of herpes simplex virus type1 (HSV-1) engineered with deletions of both ICP34.5 loci and a lacZ insertion disabling the ICP6 gene. G207 exhibits an efficient oncolytic activity in vitro and in vivo, yet minimal toxicity in normal tissue, and is now in clinical trial for malignant glioma. According to the results of clinical trials, however, although G207 was proved to be safe, the efficacy was not so impressive. Deletion of the ICP34.5 gene coding for virulence made G207 extremely safe, but it markedly reduced the cytotoxicity mediated by HSV-1. To enhance the therapeutic efficacy of G207 without diminishing its safety, we used a defective vector containing Musashi1 promoter/ICP34.5, with G207 as helper virus. P/musashi1 was functional selectively in human glioma cell lines (U87MG, U251, T98G) in this study and dvM345 showed a much higher therapeutic efficacy both in culture and in the in vivo glioma model, than G207 alone, without diminishing its favorable toxicity profile. These results suggest that transcriptional regulation of ICP34.5 by P/musashi1 can be used to target HSV-1 virulence toward gliomas while maintaining the desirable neuroattenuated phenotype.

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Section: Discussionmentioning

confidence: 99%

Enhanced therapeutic efficacy of G207 for the treatment of glioma through Musashi1 promoter retargeting of γ34.5-mediated virulence

et al. 2005

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“…A recent study tested a nonreplicating HSV-1 vector carrying two suicide genes, Escherichia coli cytosine deaminase (CD) and HSV-1 TK, followed by exposure with their reciprocal prodrugs (5-FC and GCV), in the 9L gliosarcoma model in vitro and in vivo. 108 This double suicide gene therapy was shown to be inferior to single gene treatments, suggesting that HSV-1 TK and CD are mutually counteractive in the prodrug-dependent killing of glioma cells. Although a conclusive explanation for this observation is not yet available, this result raises the possibility that single suicide gene systems employing HSV-TK or CD may be preferable over combinations of the two.…”

Section: Generation Of Replication-defective Herpes Simplex Virus Typmentioning

confidence: 99%

Herpes simplex virus 1 (HSV-1) for cancer treatment

2006

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Cancer remains a serious threat to human health, causing over 500 000 deaths each year in US alone, exceeded only by heart diseases. Many new technologies are being developed to fight cancer, among which are gene therapies and oncolytic virotherapies. Herpes simplex virus type 1 (HSV-1) is a neurotropic DNA virus with many favorable properties both as a delivery vector for cancer therapeutic genes and as a backbone for oncolytic viruses. Herpes simplex virus type 1 is highly infectious, so HSV-1 vectors are efficient vehicles for the delivery of exogenous genetic materials to cells. The inherent cytotoxicity of this virus, if harnessed and made to be selective by genetic manipulations, makes this virus a good candidate for developing viral oncolytic approach. Furthermore, its large genome size, ability to infect cells with a high degree of efficiency, and the presence of an inherent replication controlling mechanism, the thymidine kinase gene, add to its potential capabilities. This review briefly summarizes the biology of HSV-1, examines various strategies that have been used to genetically modify the virus, and discusses preclinical as well as clinical results of the HSV-1-derived vectors in cancer treatment.

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“…2,6,14,15 Also, to enhance efficacy of CD/5-FC molecular chemotherapy, several strategies have been developed, including irradiation of the tumor, 6,16-18 use of vectors encoding the bCD:uracil phosphoribosyltransferase fusion gene, 6,19,20 or a combination of bCDwt/5-FC and herpes simplex virus thymidine kinase/ganciclovir suicide gene therapy. [21][22][23] Since one of the major limitations in current cancer gene therapy is the poor efficacy of in vivo gene transfer, successful application of a suicide gene will depend on its bystander killing effect. In the CD/5-FC system, the bystander effect is caused by the passive diffusion of 5-FU into the extracellular milieu and its diffusion into the adjacent cells, which requires Enzyme/prodrug therapy of glioma SA Kaliberov et al no gap junctions.…”

Section: Discussionmentioning

confidence: 99%

Mutation of Escherichia coli cytosine deaminase significantly enhances molecular chemotherapy of human glioma

et al. 2007

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Combined treatment using adenoviral (Ad)-directed enzyme/ prodrug therapy and radiation therapy has the potential to become a powerful method of cancer therapy. We have developed an Ad vector encoding a mutant bacterial cytosine deaminase (bCD) gene (AdbCD-D314A), which has a higher affinity for cytosine than wild-type bCD (bCDwt). The purpose of this study was to evaluate cytotoxicity in vitro and therapeutic efficacy in vivo of the combination of AdbCD-D314A with the prodrug 5-fluorocytosine (5-FC) and ionizing radiation against human glioma. The present study demonstrates that AdbCD-D314A infection resulted in increased 5-FC-mediated cell killing, compared with AdbCDwt. Furthermore, a significant increase in cytotoxicity following AdbCD-D314A and radiation treatment of glioma cells in vitro was demonstrated as compared to AdbCDwt. Animal studies showed significant inhibition of subcutaneous or intracranial tumor growth of D54MG glioma xenografts by the combination of AdbCD-D314A/5-FC with ionizing radiation as compared with either agent alone, and with AdbCDwt/5-FC plus radiation. The results suggest that the combination of AdbCD-D314A/5-FC with radiation produces markedly increased cytotoxic effects in cancer cells in vitro and in vivo. These data indicate that combined treatment with this novel mutant enzyme/prodrug therapy and radiotherapy provides a promising approach for cancer therapy.

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Double suicide gene therapy using a replication defective herpes simplex virus vector reveals reciprocal interference in a malignant glioma model

Abstract: Herpes simplex virus thymidine kinase (HSV-TK) and

Cited by 55 publications

References 18 publications

Enhanced therapeutic efficacy of G207 for the treatment of glioma through Musashi1 promoter retargeting of γ34.5-mediated virulence

Enhanced therapeutic efficacy of G207 for the treatment of glioma through Musashi1 promoter retargeting of γ34.5-mediated virulence

Herpes simplex virus 1 (HSV-1) for cancer treatment

Mutation of Escherichia coli cytosine deaminase significantly enhances molecular chemotherapy of human glioma

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