hTERT promoter induces tumor-specific Bax gene expression and cell killing in syngenic mouse tumor model and prevents systemic toxicity

Gu, Jian; Andreeff, Michael; Roth, Jack A.; Fang, Bingliang

doi:10.1038/sj.gt.3301619

Cited by 81 publications

(68 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While this could be explained by an inability of the human promoter to drive transgene expression in mouse tissues, recent publications have shown that the hTERT promoter was highly active in mouse tumor cell lines but not in normal murine cells. 48,49 Similarly, we observed that AdhTERTp-E1A virus transduction of telomerase-expressing murine cancer cell lines B10.2 and C57 at MOI of 100 or higher resulted in significant killing of both cell types (Wang and Majumdar, unpublished observation). Normal histopathology was observed in liver and spleen samples of mice after systemic administration of AdhTERTp-E1A virus in contrast to the pronounced morphological abnormalities detected in the liver and spleen samples of mice treated with AdCMVp-E1A construct (Fig 6 and data not shown).…”

Section: Discussionmentioning

confidence: 82%

“…22,23 Using replication-deficient adenoviral vectors, direct comparison of hTERTp and CMVp-driven Lac-Z expression in human CD34 þ cells showed that the Ad/hTERTp-lacZ vector was 100-fold less active than the CMV vector in these bone marrow progenitor cell population. 48 Moreover, it is known that stem cells are poorly transduced by adenoviral vectors. These data suggest that the hTERT promoter-driven oncolytic virus may not be toxic to the human bone marrow stem cells.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2004

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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

et al. 2004

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…One approach that we and others have taken for making oncolytic viruses has been to insert tumor-selective promoter elements upstream of critical transcription units including E1a, E1b and E4. [13][14][15][16][17][18] Incorporation of heterologous promoter elements, such as the promoter for prostate-specific antigen, carcinogenic-embryonic antigen, E2F1 and telomerase, has achieved variable levels of tumor-selective replication. The potential clinical utility of viruses using heterologous promoters to provide tumor-selective replication has been limited by nonselective and leaky gene expression, diminished capacity of these vectors to replicate when compared with the wild-type virus and recombination events due to the heterologous promoter sequence.…”

Section: Introductionmentioning

confidence: 99%

Deletion analysis of Ad5 E1a transcriptional control region: impact on tumor-selective expression of E1a and E1b

Hedjran¹,

Shantanu²,

Tony³

2011

Cancer Gene Ther

View full text Add to dashboard Cite

The regulatory sequences upstream of E1a, the first viral protein expressed upon infection of cells with adenovirus, have binding sites for multiple transcription factors including two binding sites for E2f and five binding sites for Pea3. We evaluated the impact of deletions, which remove one or more of these transcription factor-binding sites on the expression of E1a in a panel of tumor cells and non-transformed cells. We demonstrated that specific deletions in the E1a enhancer markedly reduced the expression of E1a in growth-arrested cells while having a minimal impact on the expression of E1a in a panel of tumor cells. In particular, deletion of a 50-bp region located from À305 to À255 upstream of the E1a initiation site resulted in marked reduction of E1a and E1b expression and cytolytic activity in growth-arrested cells, while retaining near wild-type of expression of E1a and E1b and cytolytic activity in tumor cells. This deletion removed two Pea3 sites and one E2f site. The characteristics of this vector, TAV-255, was compared with dl1520 (Onyx-015) and demonstrated restricted cytolytic activity in growth-arrested cells similar to dl1520 and superior cytolytic activity in a panel of tumor cell lines. In this current study, we demonstrate that TAV-255, an E1a enhancer deletion vector, possesses tumor selective expression of both E1a and E1b along with potent tumor-selective oncolytic activity.

show abstract

hTERT promoter induces tumor-specific Bax gene expression and cell killing in syngenic mouse tumor model and prevents systemic toxicity

Abstract: We recently showed that the human telomerase reverse transcriptase (hTERT)

Cited by 81 publications

References 22 publications

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

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

Telomerase-dependent oncolytic adenovirus for cancer treatment

Deletion analysis of Ad5 E1a transcriptional control region: impact on tumor-selective expression of E1a and E1b

Contact Info

Product

Resources

About