Replication-selective virotherapy for cancer: Biological principles, risk management and future directions

Kirn, David H.; Martuza, Robert L.; Zwiebel, James A.

doi:10.1038/89901

Cited by 457 publications

(350 citation statements)

References 57 publications

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“…11 In clinical trials, the response rate for tumors in patients treated with combinations improved compared to tumors in patients treated with chemotherapy alone. 13 There are several possible mechanisms underlying the synergy between virotherapy and chemotherapy. We have observed that Ad downregulates the expression of multidrug-resistant proteins like MRP in vitro (data not shown).…”

Section: Discussionmentioning

confidence: 99%

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Antitumor efficacy and tumor-selective replication with a single intravenous injection of OAS403, an oncolytic adenovirus dependent on two prevalent alterations in human cancer

et al. 2004

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A potentially promising treatment of metastatic cancer is the systemic delivery of oncolytic adenoviruses. This requires engineering viruses which selectively replicate in tumors. We have constructed such an oncolytic adenovirus, OAS403, in which two early region genes are under the control of tumor-selective promoters that play a role in two key pathways involved in tumorigenesis. The early region E1A is controlled by the promoter for the E2F-1 gene, a transcription factor that primarily upregulates genes for cell growth. The E4 region is under control of the promoter for human telomerase reverse transcriptase, a gene upregulated in most cancer cells. OAS403 was evaluated in vitro on a panel of human cells and found to elicit tumor-selective cell killing. Also, OAS403 was less toxic in human hepatocyte cultures, as well as in vivo when compared to an oncolytic virus that lacked selective E4 control. A single intravenous injection of 3 Â 10 12 vp/kg in a Hep3B xenograft mouse tumor model led to significant antitumor efficacy. Additionally, systemic administration in a pre-established LNCaP prostate tumor model resulted in over 80% complete tumor regressions at a tolerable dose. Vector genome copy number was measured in tumors and livers at various times following tail vein injection and showed a selective time-dependent increase in tumors but not livers over 29 days. Furthermore, efficacy was significantly improved when OAS403 treatment was combined with doxorubicin. This virus holds promise for the treatment of a broad range of human cancers including metastatic disease.

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Section: Discussionmentioning

confidence: 99%

“…2,[6][7][8][9] Clinical trial data also suggest the utility of oncolytic Ads for the treatment of cancer. [10][11][12][13][14] Previously, we described the oncolytic Ad called Ar6pAE2fF, in which the E2F-1 promoter controls expression of E1A. 4 This oncolytic Ad was safe and efficacious when delivered intratumorally.…”

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confidence: 99%

Antitumor efficacy and tumor-selective replication with a single intravenous injection of OAS403, an oncolytic adenovirus dependent on two prevalent alterations in human cancer

et al. 2004

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“…Other human DNA viruses have been used to kill tumor cells (for a recent review of this topic, please see Kirn et al 65 ). The E1b-mutant adenovirus ONYX-015 was recently shown in clinical trials to have antitumor activity, especially when administered in combination with chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Viral oncoapoptosis of human tumor cells

Aubert

Blaho

2003

Gene Ther

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Many cancer cells refractory to radiation treatment and chemotherapy proliferate because of loss of intrinsic programmed cell death (apoptosis) regulation. Consequently, the resolution of these cancers are many times outside the management capabilities of conventional therapeutics. We now report that replication-defective D27 herpes simplex virus (rd D27) triggers apoptosis in three representative transformed human cell lines. Susceptibility to virus-induced cell death is dependent on the abundance and distribution of modified p53 protein in the tumor cells indicating specific targeting of the treatment. Primary human and mouse fibroblast cells that produce modified p53 are resistant to rd D27 killing but not to apoptosis induced by nonviral environmental factors. These results suggest that induction of apoptosis by nonreplicating virus is a feasible genetic therapy approach for killing human cancer cells. Our findings may have important implications in designing novel virus-based anticancer strategies in appropriate animal model systems.

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“…1 As the g 1 34.5 gene is responsible for the neurovirulence of HSV-1, g 1 34.5 gene-deficient mutants are considered to be useful as vectors for oncolytic therapy. 2,3 However, it was reported that they exerted only limited antitumor activity on their own.…”

Section: Introductionmentioning

confidence: 99%

The effects of trichostatin A on the oncolytic ability of herpes simplex virus for oral squamous cell carcinoma cells

et al. 2008

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Combining the use of a chemotherapeutic agent with oncolytic virotherapy is a useful way to increase the efficiency of the treatment of cancer. The effect of the histone diacetylase (HDAC) inhibitor trichostatin A (TSA) on the antitumor activity of a herpes simplex virus type-1 (HSV-1) mutant was examined in oral squamous cell carcinoma (SCC) cells. Immunoblotting analysis and immunoflourescence staining revealed that a cytoplasmic nuclear factor-kB (NF-kB) component, p65, translocated into the nucleus after infection with g 1 34.5 gene-deficient HSV-1 R849, indicating that R849 activated NF-kB. TSA induced acetylation of p65 and increased the amount of p65 in the nucleus of oral SCC cells. Treatment of R849-infected cells with TSA also increased the amount of nuclear p65 and binding of NF-kB to its DNA-binding site and an NF-kB inhibitor SN50 diminished the increase in nuclear p65. In the presence of TSA, the production of virus and the expression of LacZ integrated into R849 and glycoprotein D, but not ICP0, ICP6 and thymidine kinase, were increased. The viability of cells treated with a combination of R849 and TSA was lower than that of those treated with R849 only. After treatment with TSA, expression of the cell cycle kinase inhibitor p21 was upregulated and the cell cycle was arrested at G1. These results indicate that TSA enhanced the replication of the HSV-1 mutant through the activation of NF-kB and induced cell cycle arrest at G1 to inhibit cell growth. TSA can be used as an enhancing agent for oncolytic virotherapy for oral SCC with g 1 34.5 gene-deficient HSV-1.

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Replication-selective virotherapy for cancer: Biological principles, risk management and future directions

Cited by 457 publications

References 57 publications

Antitumor efficacy and tumor-selective replication with a single intravenous injection of OAS403, an oncolytic adenovirus dependent on two prevalent alterations in human cancer

Antitumor efficacy and tumor-selective replication with a single intravenous injection of OAS403, an oncolytic adenovirus dependent on two prevalent alterations in human cancer

Viral oncoapoptosis of human tumor cells

The effects of trichostatin A on the oncolytic ability of herpes simplex virus for oral squamous cell carcinoma cells

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