The telomerase reverse transcriptase promoter drives efficacious tumor suicide gene therapy while preventing hepatotoxicity encountered with constitutive promoters

Majumdar, Anish Sen; Hughes, Douglas E.; Lichtsteiner, Serge; Wang, Z; Lebkowski, Jane; Vasserot, Alain P.

doi:10.1038/sj.gt.3301421

Cited by 108 publications

(86 citation statements)

References 39 publications

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“…Unlike humans, in which the expression of hTERT is limited to a small number of normal tissues, 25 mTERT expression is widely expressed at low levels in many adult tissues. 52 Despite the difference in expression pattern, adenoviral vectors using the hTERT promoter to drive LacZ or HSV-thymidine kinase genes had undetectable transgene expression in the livers of mice, 28,30,33 suggesting that activity of the hTERT promoter is low in normal mouse liver. This was not attributable to the inability of the hTERT promoter to use the mouse transcriptional machinery, since LacZ expression was seen in the mouse lung carcinoma cell line M109.…”

Section: Discussionmentioning

confidence: 99%

“…[23][24][25][26][27][28] Furthermore, the hTERT promoter has been shown to confer tumor-selective expression of the linked gene in plasmids and Ad constructs. [28][29][30][31][32][33] Oncolytic adenoviruses utilizing the hTERT promoter to control Ad early region genes have also been previously described. [34][35][36] By using both the E2F-1 promoter and the hTERT promoter to control different early region genes in the same Ad vector, we have constructed an oncolytic Ad which is active in a broad panel of tumor types and is safe and effective when delivered systemically.…”

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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%

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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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“…The lack of hepatotoxicity has also been reported previously by others using the TERT promoter to direct the expression of Bax or HSV-tk genes in replication-deficient adenovirus vectors. 23,24 Immunohistochemical studies demonstrated that adenovirus fiber positive areas were present only in AdvTERTp-E1A-injected tumors even after 28 days, but not in those treated with dl-312 and solution controls, and that these areas coincided with the necrotic regions in the tumors. These results suggested that the inhibition of tumor growth was mainly because of necrosis associated with adenovirus replication.…”

Section: Discussionmentioning

confidence: 99%

“…21 Furthermore, the TERT promoter has been used to drive Bax as well as thymidine kinase (tk) gene expression for cancer treatment and showed tumor specificity. 23,24 In the present study, we constructed a universal tumor-specific CRAD, the replication of which is under the control of human TERT promoter, and showed its effectiveness and specificity for tumor treatment in an animal model of human hepatocellular carcinoma.…”

Section: Introductionmentioning

confidence: 86%

Telomerase-dependent oncolytic adenovirus for cancer treatment

et al. 2003

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Conditionally replicative adenovirus (CRAD) is an attractive anticancer agent as it can selectively replicate in tumor cells. Expression of telomerase reverse transcriptase (TERT) is a unique tumor cell characteristic, being absent in normal postmitotic cells. Thus, we constructed a TERT promoter regulated CRAD for tumor-specific oncolysis by replacing the endogenous adenovirus E1A promoter with that of human TERT (Adv-TERTp-E1A). We showed that its replication was severely attenuated in TERT-negative cells, but that it replicated almost as efficiently as wild-type adenovirus in TERT-positive cells. Accordingly, Adv-TERTp-E1A conferred cytopathicity to TERT-positive, but not TERT-negative, cells. In vivo replication of Adv-TERTp-E1A after local administration into a xenograft model of human hepatocellular carcinoma in nude mice was demonstrated by an increase in adenovirus titers in tumor extracts by several orders of magnitude between 6 h and 3 days postvector injection. Furthermore, significant inhibition of tumor growth with substantial necrotic tumor areas staining positively for adenovirus was observed with Adv-TERTp-E1A, but not with a control replication-deficient adenovirus. There was also the absence of hepatotoxicity in tumor-bearing animals after intratumoral delivery of the CRAD. The results indicate that the TERT promoter-driven CRAD is capable of tumorselective replication and oncolysis in vitro and in vivo, and can be utilized as an adjuvant treatment agent for cancer.

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“…[32][33][34] We have shown previously that an adenovirus vector containing the HSV-TK gene under the control of a 204 bp hTERT promoter fragment (AdhTERTp-E1A) is cytotoxic to many types of cancer cell lines in vitro when exposed to the prodrug GCV. 35 Intratumoral administration of the AdhTERTp/TK virus plus GCV treatment also inhibited 143B osteosarcoma 35 and BxPC-3 pancreatic tumor growth (Wang and Majumdar, unpublished observation) and increased survival time of the treated animals.…”

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Conditionally replicative adenovirus driven by the human telomerase promoter provides broad-spectrum antitumor activity without liver toxicity

et al. 2004

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The human telomerase reverse transcriptase (hTERT) promoter is known to selectively drive transgene expression in many human cancer cells expressing hTERT, the catalytic component of the telomerase ribonucleoprotein complex. We have created a conditionally replicative adenovirus where the viral E1A gene, which is required for viral replication, is under the control of the hTERT promoter (AdhTERTp-E1A). In vitro studies with AdhTERTp-E1A virus on a variety of normal and tumor cell lines have shown that viral genome replication and productive infection is primarily restricted to telomerase-positive tumor cells. Lytic replication was not observed in normal primary fibroblast and epithelial cell lines tested. In vivo administration of the virus into nude mice bearing human liver or prostate tumor xenografts produced significant tumor reduction and, in some cases, resulted in complete tumor regression. AdhTERTp-E1A virus did not actively express E1A in normal mouse liver, in contrast to a control oncolytic vector in which the CMV promoter (AdCMVp-E1A) was driving the E1A gene. In addition, AdhTERTp-E1A virus produced no apparent toxicity to the liver in systemically injected mice. The hTERT promoter-driven oncolytic virus also produced significantly less toxicity to freshly cultured human hepatocytes. These studies demonstrate that an oncolytic virus driven by the telomerase promoter can be used to effectively kill a wide variety of cancer cell types and has the potential to treat primary and metastatic cancer of diverse origins.

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The telomerase reverse transcriptase promoter drives efficacious tumor suicide gene therapy while preventing hepatotoxicity encountered with constitutive promoters

Cited by 108 publications

References 39 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

Telomerase-dependent oncolytic adenovirus for cancer treatment

Conditionally replicative adenovirus driven by the human telomerase promoter provides broad-spectrum antitumor activity without liver toxicity

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