Co-expression of herpes simplex virus thymidine kinase and Escherichia coli nitroreductase by an hTERT-driven adenovirus vector in breast cancer cells results in additive anti-tumor effects

Yu, Bin; Yang, Zhan; Xiao, Zhengguo; Wu, Yonege; Zhang, Xizhen; Dong, Qingyu; Kong, Wei; Yu, Xianghui

doi:10.3892/or.2011.1285

Cited by 11 publications

(8 citation statements)

References 19 publications

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“…Recently, we explored the therapeutic potential of HSV1-sr39TK and E.coli NTR-mediated double suicide gene therapy and showed that HSV1-sr39TK-NTR fusion is more efficacious than either system alone. In addition, Yu et al studied the treatment efficiency of HSV1-sr39TK and NTR combinations in an hTERT-driven adenovirus vector against subcutaneously implanted breast cancer cell line, ZR-75-30, basically derived from metastatic breast cancer 29. Significant levels of tumor growth reduction were observed when GCV (3.75 mg/kg) was injected consecutively for 4 days and CB1954 (80 mg/kg) for 2 days 29.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Yu et al studied the treatment efficiency of HSV1-sr39TK and NTR combinations in an hTERT-driven adenovirus vector against subcutaneously implanted breast cancer cell line, ZR-75-30, basically derived from metastatic breast cancer 29. Significant levels of tumor growth reduction were observed when GCV (3.75 mg/kg) was injected consecutively for 4 days and CB1954 (80 mg/kg) for 2 days 29. As HSV1-TK-NTR fusion showed enhanced therapeutic potential, we intended to explore whether HSV1-sr39TK-NTR fusion was able to cure metastatic breast cancer in a mice model of lung-metastatic breast cancer implanted with a triple negative breast cancer cell line, MDA-MB-231 co-expressing HSV1-sr39TK-NTR and Fluc-EGFP fusions.…”

Section: Discussionmentioning

confidence: 99%

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Noninvasive Theranostic Imaging of HSV1-sr39TK-NTR/GCV-CB1954 Dual-Prodrug Therapy in Metastatic Lung Lesions of MDA-MB-231 Triple Negative Breast Cancer in Mice

Sekar¹,

Foygel²,

Ilovich³

et al. 2014

Theranostics

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Metastatic breast cancer is an obdurate cancer type that is not amenable to chemotherapy regimens currently used in clinic. There is a desperate need for alternative therapies to treat this resistant cancer type. Gene-Directed Enzyme Prodrug Therapy (GDEPT) is a superior gene therapy method when compared to chemotherapy and radiotherapy procedures, proven to be effective against many types of cancer in pre-clinical evaluations and clinical trials. Gene therapy that utilizes a single enzyme/prodrug combination targeting a single cellular mechanism needs significant overexpression of delivered therapeutic gene in order to achieve therapy response. Hence, to overcome this obstacle we recently developed a dual therapeutic reporter gene fusion that uses two different prodrugs, targeting two distinct cellular mechanisms in order to achieve effective therapy with a limited expression of delivered transgenes. In addition, imaging therapeutic reporter genes offers additional information that indirectly correlates gene delivery, expression, and functional effectiveness as a theranostic approach. In the present study, we evaluate the therapeutic potential of HSV1-sr39TK-NTR fusion dual suicide gene therapy system that we recently developed, in MDA-MB-231 triple negative breast cancer lung-metastatic lesions in a mouse model. We compared the therapeutic potential of HSV1-sr39TK-NTR fusion with respective dual prodrugs GCV-CB1954 with HSV1-sr39TK/GCV and NTR/CB1954 single enzyme prodrug system in this highly resistant metastatic lesion of the lungs. In vitro optimization of dose and duration of exposure to GCV and CB1954 was performed in MDA-MB-231 cells. Drug combinations of 1 μg/ml GCV and 10 μM CB1954 for 3 days was found to be optimal regimen for induction of significant cell death, as assessed by FACS analysis. In vivo therapeutic evaluation in animal models showed a complete ablation of lung metastatic nodules of MDA-MB-231 triple negative breast cancer cells following two consecutive doses of a combination of GCV (40 mg/kg) and CB1954 (40 mg/kg) administered at 5 day intervals. In contrast, the respective treatment condition in animals expressing HSV1-sr39TK or NTR separately, showed minimal or no effect on tumor reduction as measured by bioluminescence (tumor mass) and [18F]-FHBG microPET (TK expression) imaging. These highlight the strong therapeutic effect of the dual fusion prodrug therapy and its use in theranostic imaging of tumor monitoring in living animals by multimodality molecular imaging.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Noninvasive Theranostic Imaging of HSV1-sr39TK-NTR/GCV-CB1954 Dual-Prodrug Therapy in Metastatic Lung Lesions of MDA-MB-231 Triple Negative Breast Cancer in Mice

Sekar¹,

Foygel²,

Ilovich³

et al. 2014

Theranostics

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“…These approaches include double suicide gene therapy (41), combined suicide gene/immunotherapy (42), combined suicide gene/virotherapy (43) to name but a few. Further refinements in enhancing vector infectivity and in gene transfer imaging could certainly be incorporated into these approaches.…”

Section: Discussionmentioning

confidence: 99%

A Phase I Clinical Trial of Ad5.SSTR/TK.RGD, a Novel Infectivity-Enhanced Bicistronic Adenovirus, in Patients with Recurrent Gynecologic Cancer

Kim

Dmitriev

O’Malley

et al. 2012

Clinical Cancer Research

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Purpose Ad5.SSTR/TK.RGD is an infectivity-enhanced adenovirus expressing a therapeutic thymidine kinase suicide gene and a somatostatin receptor that allows for noninvasive gene transfer imaging. The purpose of this study was to identify the MTD, toxicities, clinical efficacy and biologic effects of Ad5.SSTR/TK.RGD in patients with recurrent gynecologic cancer. Experimental Design Eligible patients were treated intraperitoneally (IP) for 3 days with 1×109 to 1×1012 vp/dose of Ad5.SSTR/TK.RGD followed by intravenous ganciclovir for 14 days. Toxicity and clinical efficacy were assessed utilizing CTC Adverse Events grading and RECIST criteria. Imaging utilizing In-111 pentetreotide was obtained before and after treatment. Tissue samples were obtained to evaluate for gene transfer, generation of wild-type virus, viral shedding and antibody response. Results Twelve patients were treated in three cohorts. The most common vector-related clinical toxicities were grade 1–2 constitutional or pain symptoms, experienced most often in patients treated at the highest dose. MTD was not identified. Five patients demonstrated stable disease; all others experienced progressive disease. One patient with stable disease experienced complete resolution of disease and normalization of CA125 on further follow-up. Imaging detected increased In-111 pentetreotide retention in patients treated at the highest dose. Ancillary studies demonstrated presence of Ad5.SSTR/TK.RGD virus and HSV1-tk expression in ascites samples collected at various time points in most patients treated within the higher dose cohorts. Conclusions This study demonstrates the safety, potential efficacy, and possible gene transfer imaging capacity of Ad5.SSTR/TK.RGD in patients with recurrent gynecologic cancer. Further development of this novel gene therapeutic appears to be warranted.

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“…The Ad2-SEAP and Ad5-SEAP vector was constructed as previously described [7,13]. In these E3 deletion vectors, the E1 region was replaced by the SEAP gene.…”

Section: Methodsmentioning

confidence: 99%

A serological survey of human adenovirus serotype 2 and 5 circulating pediatric populations in Changchun, China, 2011

Wang

Dong

et al. 2012

Virol J

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BackgroundEfficacy of recombinant adenovirus serotype 5 (rAd5) vaccine vectors for human immunodeficiency virus type 1 (HIV-1) and other pathogens have been shown to be limited by high titers of pre-existing Ad5 neutralizing antibodies (NAbs) in the developing world.ResultsUsing a secreted embryonic alkaline phosphatase (SEAP) neutralization assay, 50% serum neutralization titers against rAd2 and rAd5 vectors were measured in samples from 274 infants and young children in northeast China. The pediatric population was found to be 59.6% and 43.3% seropositive for rAd2 and rAd5, respectively. Of all participants, 44.9% had moderate and high (> 200) and 25.6% had high (>1000) Ad2 NAb titers, compared with the corresponding rates of 26.6% and 9.3% against Ad5. Marked age-dependent increases in NAb titers to both Ad serotypes were observed across five age groups, with the exception of infants in the 0-6-month group commonly having relatively high titers due to pre-existing maternal antibodies.ConclusionsOur data suggest that Ad-based therapies may be suitible for children in the 7-12-month age range in this region.

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Co-expression of herpes simplex virus thymidine kinase and Escherichia coli nitroreductase by an hTERT-driven adenovirus vector in breast cancer cells results in additive anti-tumor effects

Cited by 11 publications

References 19 publications

Noninvasive Theranostic Imaging of HSV1-sr39TK-NTR/GCV-CB1954 Dual-Prodrug Therapy in Metastatic Lung Lesions of MDA-MB-231 Triple Negative Breast Cancer in Mice

Noninvasive Theranostic Imaging of HSV1-sr39TK-NTR/GCV-CB1954 Dual-Prodrug Therapy in Metastatic Lung Lesions of MDA-MB-231 Triple Negative Breast Cancer in Mice

A Phase I Clinical Trial of Ad5.SSTR/TK.RGD, a Novel Infectivity-Enhanced Bicistronic Adenovirus, in Patients with Recurrent Gynecologic Cancer

A serological survey of human adenovirus serotype 2 and 5 circulating pediatric populations in Changchun, China, 2011

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