Herpes simplex virus thymidine kinase/ganciclovir–induced cell death is enhanced by co-expression of caspase-3 in ovarian carcinoma cells

McNeish, Iain A.; Tenev, Tencho; Bell, Stephen; Marani, Michela; Vassaux, Georges; Lemoine, Nicholas R.

doi:10.1038/sj.cgt.7700305

Cited by 27 publications

(18 citation statements)

References 38 publications

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“…44 Several approaches have been tested to overcome these problems, including coexpression of TK and connexins, 45 -47 enhancement of the catalytic activity of TK, 48 or co -delivery of TK with genes encoding for cytokines increasing the anti -tumoral response, 49 -52 for proteins inhibiting cell cycle progression, 53 for the enzyme guanylate kinase, 54 or for caspase 3. 55 An alternative ( and complementary ) possibility to increase TK suicide gene therapy is to extend its functionality to nonexpressing cells by fusing the enzyme with proteins capable of mediating its extracellular release and uptake. One of these proteins is the VP22 protein of HSV-1, which has been originally shown to be exported from the cytoplasm of expressing cells and subsequently imported into neighboring cells, where it accumulates in the nucleus.…”

Section: Discussionmentioning

confidence: 99%

Transcellular transfer of active HSV-1 thymidine kinase mediated by an 11-amino-acid peptide from HIV-1 Tat

Tasciotti¹,

Zoppé²,

Giacca³

2002

Cancer Gene Ther

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Suicide gene therapy using herpes simplex virus type -1 ( HSV -1 ) thymidine kinase ( TK ) is a widely exploited approach for gene therapy of cancer and other hyperproliferative disorders. Despite its popularity, clinical success has been so far hampered mostly by the relative inefficiency of TK gene transfer and its limited bystander effect. Here we report that fusion of TK to an 11 -amino -acid peptide from the basic domain of the HIV -1 Tat protein ( Tat11 ) imparts cell membrane translocating ability to the enzyme and significantly increases its cytotoxic efficacy. In cells expressing Tat11 -TK, this protein is found extracellularly, associated with cell surface heparan sulfate proteoglycans, and is released into the cell culture medium. Based on its interaction with HSPGs, the protein is then internalized by neighboring, nonexpressing cells, which become susceptible to cell death when treated with the nucleoside analogue acyclovir. As a consequence, co -cultures of wild -type cells with cells expressing Tat11 -TK show increased sensitivity to ACV through a mechanism involving apoptosis. Modification of TK by fusion with Tat11 might constitute an important step for the optimization of TK suicide gene strategy for gene therapy of cellular proliferation.

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Section: Discussionmentioning

confidence: 99%

Transcellular transfer of active HSV-1 thymidine kinase mediated by an 11-amino-acid peptide from HIV-1 Tat

Tasciotti¹,

Zoppé²,

Giacca³

2002

Cancer Gene Ther

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“…dl309 is identical to dl922-947 apart from a WT E1A region. Control viruses adenovirus CMV GFP and adenovirus LM-X are both E1-deleted nonreplicating vectors as previously described (49). For viability assays, 2 × 10 4 cells were infected in serum-free medium at MOI 0.001-1,000 PFU/cell.…”

Section: Methodsmentioning

confidence: 99%

Genomic DNA damage and ATR-Chk1 signaling determine oncolytic adenoviral efficacy in human ovarian cancer cells

Connell¹,

Shibata²,

Tookman³

et al. 2011

J. Clin. Invest.

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Oncolytic adenoviruses replicate selectively within and lyse malignant cells. As such, they are being developed as anticancer therapeutics. However, the sensitivity of ovarian cancers to adenovirus cytotoxicity varies greatly, even in cells of similar infectivity. Using both the adenovirus E1A-CR2 deletion mutant dl922-947 and WT adenovirus serotype 5 in a panel of human ovarian cancer cell lines that cover a 3-log range of sensitivity, we observed profound overreplication of genomic DNA only in highly sensitive cell lines. This was associated with the presence of extensive genomic DNA damage. Inhibition of ataxia telangiectasia and Rad3-related checkpoint kinase 1 (ATR-Chk1), but not ataxia telangiectasia mutated (ATM), promoted genomic DNA damage and overreplication in resistant and partially sensitive cells. This was accompanied by increased adenovirus cytotoxicity both in vitro and in vivo in tumor-bearing mice. We also demonstrated that Cdc25A was upregulated in highly sensitive ovarian cancer cell lines after adenovirus infection and was stabilized after loss of Chk1 activity. Knockdown of Cdc25A inhibited virus-induced DNA damage in highly sensitive cells and blocked the effects of Chk1 inhibition in resistant cells. Finally, inhibition of Chk1 decreased homologous recombination repair of virus-induced genomic DNA double-strand breaks. Thus, virus-induced host cell DNA damage signaling and repair are key determinants of oncolytic adenoviral activity, and promoting unscheduled DNA synthesis and/or impeding homologous recombination repair could potentiate the effects of oncolytic adenoviruses in the treatment of ovarian cancer.

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“…dl309 is an Ad5 vector with a wild-type E1A region but contains the same E3B deletion as dl922-947. The construction of the E1-deleted control adenoviral vector Ad LM-X has been described elsewhere (17). For cell viability assays, 2 Â 10 4 cells were infected with adenovirus in serum-free medium.…”

Section: Methodsmentioning

confidence: 99%

Activity of the Adenoviral E1A Deletion Mutant dl922-947 in Ovarian Cancer: Comparison with E1A Wild-type Viruses, Bioluminescence Monitoring, and Intraperitoneal Delivery in Icodextrin

et al. 2006

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The adenoviral mutant dl922-947 has potent activity in a variety of tumors. We investigated the efficacy of dl922-947 in ovarian carcinoma; compared its activity to wild-type adenovirus, dl309, and dl1520; and investigated the use of icodextrin to enhance activity in vivo. We also assessed the utility of luciferase bioluminescence imaging to quantify the response of human ovarian carcinoma xenografts to dl922-947. Ovarian carcinoma cell lines were transfected in vitro with dl922-947, adenovirus 5 wild-type (Ad5 WT), dl309, and dl1520 and monitored for S-phase induction, viral protein expression, replication, and overall survival. In vivo, the efficacy of dl922-947 when delivered in PBS or icodextrin to female nude mice bearing IGROV1 xenografts was determined. In vitro, dl922-947 induced lysis with greater efficacy than Ad5 WT, dl309, or dl1520 in all ovarian carcinoma cell lines tested, which was associated with earlier expression of viral proteins and S-phase induction. The lytic effect in immortalized ovarian surface epithelial cells confirmed that cellular retinoblastoma pathway status is a strong determinant of dl922-947 activity. In vivo, i.p. delivery of dl922-947 (5 Â 10 9 particles daily Â 5) increased median survival from 20 to 96 days (P < 0.0001) and delivery in icodextrin-enhanced survival further. However, delayed hepatic toxicity was evident in some dl922-947-treated mice, which was not dependent upon viral replication within tumor cells or the liver. dl922-947 has potency in ovarian carcinoma and i.p. delivery in icodextrin may enhance this activity. Immunocompetent models of ovarian carcinoma are required for further evaluation of hepatotoxicity. (Cancer Res 2006; 66(2): 989-98)

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Herpes simplex virus thymidine kinase/ganciclovir–induced cell death is enhanced by co-expression of caspase-3 in ovarian carcinoma cells

Cited by 27 publications

References 38 publications

Transcellular transfer of active HSV-1 thymidine kinase mediated by an 11-amino-acid peptide from HIV-1 Tat

Transcellular transfer of active HSV-1 thymidine kinase mediated by an 11-amino-acid peptide from HIV-1 Tat

Genomic DNA damage and ATR-Chk1 signaling determine oncolytic adenoviral efficacy in human ovarian cancer cells

Activity of the Adenoviral E1A Deletion Mutant dl922-947 in Ovarian Cancer: Comparison with E1A Wild-type Viruses, Bioluminescence Monitoring, and Intraperitoneal Delivery in Icodextrin

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