An oncolytic viral mutant that delivers the CYP2B1 transgene and augments cyclophosphamide chemotherapy

Chase, Maureen; Ry, Chung; Ea, Chiocca

doi:10.1038/nbt0598-444

Cited by 156 publications

(130 citation statements)

References 23 publications

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“…121 Cancer regression significantly improved with the cytochrome p450 conversion of cyclophosphamide to the active metabolite phosphoramide mustard. 78 Similar results have been produced with the cytosine deaminase transgene. 122 Interestingly, HSV TK activation of acyclovir or ganciclovir in HSV-infected cells inhibits viral replication without affecting tumor growth.…”

Section: Herpes Simplex Virus (Hsv)supporting

confidence: 62%

“…One modification involved inactivation of viral gene ICP6, which encodes the large subunit of ribonucleotide reductase, an enzyme required for viral DNA replication. [77][78][79][80] This enzyme is expressed abundantly in rapidly dividing tumor cells but is sparse in normal cells. As a consequence, the ICP6 gene modified HSV-1 replicates selectively in tumor cells.…”

Section: Herpes Simplex Virus (Hsv)mentioning

confidence: 99%

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Clinical development directions in oncolytic viral therapy

Eager

Nemunaitis

2011

Cancer Gene Ther

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Oncolytic virotherapy is an emerging experimental treatment platform for cancer therapy. Oncolytic viruses are replicativecompetent viruses that are engineered to replicate selectively in cancer cells with specified oncogenic phenotypes. Multiple DNA and RNA viruses have been clinically tested in a variety of tumors. This review will provide a brief description of these novel anticancer biologics and will summarize the results of clinical investigation. To date oncolytic virotherapy has shown to be safe, and has generated clinical responses in tumors that are resistant to chemotherapy or radiotherapy. The major challenge for researchers is to maximize the efficacy of these viral therapeutics, and to establish stable systemic delivery mechanisms.

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Section: Herpes Simplex Virus (Hsv)supporting

confidence: 62%

Section: Herpes Simplex Virus (Hsv)mentioning

confidence: 99%

Clinical development directions in oncolytic viral therapy

Eager

Nemunaitis

2011

Cancer Gene Ther

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“…Other delivery methods reported include retroviral constructs, 26 oncolytic vectors 13,27 and direct implantation of encapsulated CYP-engineered cells. 28,29 However, the ability of adenoviral vectors to infect both dividing and nondividing cells increases the proportion of infected cells.…”

mentioning

confidence: 99%

A virus-directed enzyme prodrug therapy (VDEPT) strategy for lung cancer using a CYP2B6/NADPH-cytochrome P450 reductase fusion protein

Tychopoulos

Corcos

Genne³

et al. 2005

Cancer Gene Ther

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Virus-directed enzyme prodrug therapy (VDEPT) is an emerging strategy against cancer. Our approach is a P450-based VDEPT that consists of using cyclophosphamide (CPA) as a prodrug and a Cytochrome P450 2B6/NADPH cytochrome P450 reductase fusion protein (CYP2B6/RED) as a prodrug-activating enzyme. Due to the heterogenous expression of proteins in tumor cells, basal reductase activity may not be sufficient to supply CYP2B6 with electrons, the fusion protein should enable the expression of both proteins at high levels in tumor cells. CYP/RED fusion proteins have never been previously expressed in mammalian cells, to enable expression the fusion protein was cloned into an adenoviral vector and subsequently several pulmonary tumor cell lines were infected. The CYP2B6/RED fusion protein was detected by Western blot, its mRNA by Northern blot, and its heme incorporation into an active form by spectral analysis. Infection with the fusion gene increased RED activity in microsomes by a factor of 3 compared to the control. After infection and treatment with CPA, in cell lines with low endogenous RED, the fusion protein mediated significantly higher CPA-induced cytotoxicity compared to cells expressing solely CYP2B6. In conclusion, the fusion protein is functional for VDEPT by providing one protein for higher levels of CPA metabolism. Cancer Gene Therapy (2005) Keywords: VDEPT; P450-based gene therapy; cyclophosphamide; lung cancer G ene-directed enzyme prodrug therapy (GDEPT) 1,2 is an emerging strategy used to improve the selectivity of cancer chemotherapy. This is accomplished through tumor-specific activation of noncytotoxic prodrugs to active drugs by drug-metabolizing enzymes. The general scheme consists of transfection of tumor cells with an enzyme responsible for the bioactivation of a noncytotoxic prodrug and treatment with the prodrug: only cells expressing the transfected drug-metabolizing enzyme can metabolize the prodrug into cytotoxic metabolites, leading to cell death. The use of viral vectors for transgene introduction is more specifically referred to as virusdirected enzyme prodrug therapy (VDEPT). Following promising early results of a P450-based GDEPT strategy, 3 using the rat 9L gliosarcoma cell line, cyclophosphamide (CPA) as a prodrug and CYP2B1 as the prodrug activating enzyme, our approach was to improve the strategy by activating CPA with cytochrome P450 2B6 (CYP2B6) 4,5 or a CYP2B6/NADPH cytochrome P450 reductase (RED) fusion protein in order to avoid the frequent problem of low RED expression in tumor cells. This constructed protein is the fusion of two human proteins namely CYP2B6 and the human RED resulting in a single protein able to transfer electrons from NADPH right through to the heme moiety of the protein to enable metabolism of CYP2B6 substrates. In order to achieve high levels of expression in mammalian cells, the proteins were cloned into adenoviral vectors by homologous recombination.CPA belongs to the oxazaphosphorine class of molecules 6,7 and remains a widely used cytotoxic agent f...

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“…This strategy is named gene-directed pro-drug activation therapy and has many examples where it was used with very promising results. One characteristic class of prodrug arming is the expression of the thymidine kinase gene in HSV vector that is able to monophosphorylate ganciclovir, which in turn is converted to triphosphorylated forms that induce cell death by blocking DNA synthesis (Boviatsis et al, 1994;Chase et al, 1998). Several other systems have been described such as the nitroreductase in combination with the pro-drug CB1954 or the cytosine deaminase (CD) with the pro-drug 5-fluorocytosine, which is forming the chemotherapeutic 5-fluorouracil (5-FU) (Chalikonda et al, 2008;Foloppe et al, 2008).…”

Section: Arming Viruses For Cytotoxic Virotherapymentioning

confidence: 99%

Anticancer Gene Transfer for Cancer Gene Therapy

Pazarentzos

Mazarakis

2014

Advances in Experimental Medicine and Biology

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Gene therapy vectors are among the treatments currently used to treat malignant tumors. Gene therapy vectors use a specific therapeutic transgene that causes death in cancer cells. In early attempts at gene therapy, therapeutic transgenes were driven by nonspecific vectors which induced toxicity to normal cells in addition to the cancer cells. Recently, novel cancer specific viral vectors have been developed that target cancer cells leaving normal cells unharmed. Here we review such cancer specific gene therapy systems currently used in the treatment of cancer and discuss the major challenges and future directions in this field.

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An oncolytic viral mutant that delivers the CYP2B1 transgene and augments cyclophosphamide chemotherapy

Cited by 156 publications

References 23 publications

Clinical development directions in oncolytic viral therapy

Clinical development directions in oncolytic viral therapy

A virus-directed enzyme prodrug therapy (VDEPT) strategy for lung cancer using a CYP2B6/NADPH-cytochrome P450 reductase fusion protein

Anticancer Gene Transfer for Cancer Gene Therapy

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