Inclusion of the herpes simplex thymidine kinase gene in a replicating adenovirus does not augment antitumor efficacy

Lambright, Eric S.; Amin, Kunjlata M.; Wiewrodt, Rainer; Force, Seth D.; Lanuti, Michael; Propert, Kathleen J.; Litzky, Leslie A.; Kaiser, Larry R.; Albelda, Steven Μ.

doi:10.1038/sj.gt.3301489

Cited by 50 publications

(43 citation statements)

References 26 publications

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“…Overexpression of the death protein, expression of TRAIL or deletion of the E1b-19kD gene, all have been shown to improve viral spread and efficacy of replicating adenoviruses in vitro and in vivo. 20,35,43,52,53 Various suicide genes [54][55][56][57][58] or TNF-a [59][60][61] have also been expressed with replication-competent vectors to improve cell killing, although with mixed results.…”

Section: Discussionmentioning

confidence: 99%

Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53

et al. 2006

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Clinical efficacy of adenovirus-mediated cancer gene therapy has been limited thus far. To improve its oncolytic effect, a replication-competent adenoviral vector was previously constructed to express high levels of p53 at a late time point in the viral life cycle. p53 expression from this vector improved tumor cell killing and viral spread in vitro. However, p53 function is antagonized by cellular mdm2 and adenoviral E1b-55kD, both of which are known to bind to and inactivate p53. Therefore, a new vector (Adp53W23S) that expresses a modified p53 transgene, which does not bind to E1b-55kD and mdm2, was constructed. The modified p53 protein was demonstrated to have a substantially prolonged half-life, and its localization was predominantly nuclear. Viral replication was unaffected by expression of the modified p53 and cancer cell killing was improved in vitro. However, in a xenograft model, efficacy was not significantly different from control virus. In conclusion, expression of a degradation-resistant p53 transgene late in the life cycle of a replication-competent adenovirus improves p53 stability and cancer cell killing in vitro. However, other factors, such as the adenoviral E1b-19kD and E1a proteins, which oppose p53 function, and limitations to viral spread need to be addressed to further improve in vivo efficacy.

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Section: Discussionmentioning

confidence: 99%

Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53

et al. 2006

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“…Some studies have demonstrated that the antitumor efficacy of HSV-TKexpressing oncolytic adenoviruses is augmented by GCV treatment [19][20][21] . On the contrary, other studies have suggested that GCV does not further improve the oncolytic potential of replicating adenoviruses, at least not in vivo [22][23][24][25] . The studies by Raki et al and Wilder et al did not assess whether any differences existed in the tumor weight between the groups.…”

Section: Discussionmentioning

confidence: 85%

“…We presume that the oncolytic effect could not counteract the rapid increase in the number of tumor cells when the tumor volume was >100 mm 3 . Third, in the study by Lambright et al [25] , the time of tumor exposure to oncolytic adenovirus (7 days) was not long enough to allow significant morphological changes to develop. Based on these factors, it is inappropriate to conclude from these studies that HSV-TK/GCV did not enhance the antitumor effects of CRADs .…”

Section: Discussionmentioning

confidence: 99%

“…Second, the time of the first injection was too late in the previous studies. Lambright et al [25] and Morris et al [26] randomized and treated the mice when the mean tumor volume reached ~200 and 250 mm 3 , respectively. In our preliminary experiment, Ad-ETK was injected when the mean subcutaneous tumor volume was ~120 mm 3 , when there was no difference in tumor weight between the Ad-ETK and Ad-ETK/ GCV groups.…”

Section: Discussionmentioning

confidence: 99%

“…r signifies the conformity of data of the method employed, which in this case is the linear correlation coefficient of the median-effect plot. † Combination index (CI) was calculated on the multiple drug effect equation derived by Chou and Talalay [17,18] , using computer software [25] . CI<1, CI=1, and CI>1 indicate synergism, additive effect, and antagonism, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Combination effect of oncolytic adenovirus therapy and herpes simplex virus thymidine kinase/ganciclovir in hepatic carcinoma animal models

Zheng

Yang

et al. 2009

Acta Pharmacol Sin

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Aim: Oncolytic adenovirus, also called conditionally replicating adenovirus (CRAD), can selectively propagate in tumor cells and cause cell lysis. The released viral progeny can infect neighboring cancer cells, initiating a cascade that can lead to the ultimate destruction of the tumor. Suicide gene therapy using herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) offers a potential treatment strategy for cancer and is undergoing preclinical trials for a variety of tumors. We hypothesized that HSV-TK gene therapy combined with oncolytic adenoviral therapy would have an enhanced effect compared with the individual effects of the therapies and is a potential novel therapeutic strategy to treat liver cancer. Methods: To address our hypothesis, a novel CRAD was created, which consisted of a telomerase-dependent oncolytic adenovirus engineered to express E1A and HSV-TK genes (Ad-ETK). The combined effect of Ad-ETK and GCV was assessed both in vitro and in vivo in nude mice bearing HepG2 cell-derived tumors. Expression of the therapeutic genes by the transduced tumor cells was analyzed by RT-PCR and Western blotting. Results: We confirmed that Ad-ETK had antitumorigenic effects on human hepatocellular carcinoma (HCC) both in vitro and in vivo, and the TK/GCV system enhanced oncolytic adenoviral therapy. We confirmed that both E1A and HSV-TK genes were expressed in vivo. Conclusion:The Ad-ETK construct should provide a relatively safe and selective approach to killing cancer cells and should be investigated as an adjuvant therapy for hepatocellular carcinoma.

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Gene and Viral Therapy

Spurrell¹

2007

The Cancer Handbook

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The aim of gene therapy is to treat cancer by the introduction of genes that will sensitize tumour cells to other therapies, replace a mutated gene with a wild‐type copy, or activate an antitumour host immune response. Viruses can be used as vectors for carrying therapeutic transgenes, as well as being oncolytic in their own right. Using viruses to treat tumours derives from the inherent ability of a replicating virus to eventually destroy its host cell. Oncolytic viruses are tumour specific, causing lysis of tumour cells and not normal cells. There are viruses that are naturally tumour specific and viruses that have been engineered to become tumour specific. More recently, there has been increasing interest in the development of non‐viral vectors as gene therapy carriers. The benefits of using non‐viral vectors is that they are less likely to elicit an unwanted immune response, there is no risk of recombination, and they are easier to produce on a large scale. There are two main types of non‐viral gene delivery method—physical and via a chemical carrier. Both viral and non‐viral vectors have entered human phase I and II clinical trials in patients with a variety of solid tumour malignancies.

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Inclusion of the herpes simplex thymidine kinase gene in a replicating adenovirus does not augment antitumor efficacy

Cited by 50 publications

References 26 publications

Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53

Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53

Combination effect of oncolytic adenovirus therapy and herpes simplex virus thymidine kinase/ganciclovir in hepatic carcinoma animal models

Gene and Viral Therapy

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