Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015)

Ries, Stefan; Brandts, Christian; Chung, Alicia S.; Biederer, Carola; Hann, Byron; Lipner, Ettie M.; McCormick, Frank; Korn, W. Michael

doi:10.1038/80466

Cited by 165 publications

(114 citation statements)

References 33 publications

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“…In a recent study, we were able to explain some of these observations. We found that lack of p14ARF expression in tumours with wild-type p53 disrupts the p53 signalling pathway leading to high and uncontrolled Mdm2 protein activities and, therefore, facilitates ONYX-015 replication (Ries et al, 2000). Through deregulation of Mdm2, p53 is inhibited from exerting its protective effects after adenoviral infection.…”

Section: Effects Of Onyx-015 On Tumour Cells In Vitromentioning

confidence: 91%

“…This protective effect of p14ARF is p53 dependent. Re-introduction of p14ARF did not prevent replication of ONYX-015 in an isogenic cell line, in which the wild-type p53 gene has been deleted by homologous recombination (Ries et al, 2000). Thus, genetic lesions affecting molecular factors within the p53 pathway other than mutations of p53 itself can render cells permissive for ONYX-015.…”

Section: Effects Of Onyx-015 On Tumour Cells In Vitromentioning

confidence: 93%

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ONYX-015: mechanisms of action and clinical potential of a replication-selective adenovirus

2002

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Accumulated knowledge in the molecular processes of tumour development combined with the availability of genetically modified viruses resemble the basis for new promising cancer therapeutics. The main advantages of employing replicationcompetent viruses are achievement of tumour selective killing and amplification of their oncolytic potential within the tumour mass. In this review, we describe the development of ONYX-015, one of the first and most advanced replication-competent viruses for cancer therapy. We discuss the molecular biology of this therapeutic approach and the interesting results obtained with this virus in clinical trials.

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Section: Effects Of Onyx-015 On Tumour Cells In Vitromentioning

confidence: 91%

Section: Effects Of Onyx-015 On Tumour Cells In Vitromentioning

confidence: 93%

ONYX-015: mechanisms of action and clinical potential of a replication-selective adenovirus

2002

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“…However, several reports have indicated that ONYX-15 can replicate in cancer cells independently of the p53 status. 7,8 Clinical trials with ONYX-15 have demonstrated good safety profiles and therapeutic effects on tumors. 9,10 A replication-competent E1B-attenuated adenovirus similar to ONYX-15 that contains a cytosine deaminase/herpes simplex virus-1 thymidine kinase fusion gene (called Ad5-CD/TKrep) was used in a phase I trial for localized prostate cancer with demonstrated safety and therapeutic effects.…”

Section: Introductionmentioning

confidence: 99%

An oncolytic conditionally replicating adenovirus for hormone-dependent and hormone-independent prostate cancer

et al. 2005

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The use of conditionally replicating adenoviruses offers an attractive complementary treatment strategy for localized prostate cancer. We have produced a replicating adenovirus, Ad[I/PPT-E1A], where E1A gene expression is controlled by a recombinant regulatory sequence designated PPT. The PPT sequence comprises a PSA enhancer, a PSMA enhancer and a T-cell receptor g-chain alternate reading frame protein promoter, and it is shielded from transcriptional interference from adenoviral backbone sequences by an H19 insulator. Ad[I/PPT-E1A] yields prostate-specific E1A protein expression, viral replication and cytolysis in vitro. Furthermore, Ad[I/PPT-E1A] considerably regresses the growth of subcutaneous LNCaP prostate cancer tumors in nude mice. Importantly, the viral replication and cytolytic effect of Ad[I/PPT-E1A] are independent of the testosterone levels in the prostate cancer cells. This may be beneficial in a clinical setting since many prostate cancer patients are treated with androgen withdrawal. In conclusion, Ad[I/PPT-E1A] may prove to be useful in the treatment of localized prostate cancer.

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“…Other research groups questioned the nature of this selectivity, showing that ONYX-015 (dl1520), the prototype of this group of vectors, replicates well in certain cell lines that express p53. [17][18][19][20] Shortly thereafter, Ries et al 21 pointed out that it is a defect in the pathway of p53 signaling and not only necessarily mutant p53 itself that is required for replication of these vectors.…”

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confidence: 99%

Radiation increases the activity of oncolytic adenovirus cancer gene therapy vectors that overexpress the ADP (E3-11.6K) protein

et al. 2003

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We have described three potential adenovirus type 5 (Ad5)-based replication-competent cancer gene therapy vectors named KD1, KD3, and VRX-007. All three vectors overexpress an Ad5 protein named Adenovirus Death Protein (ADP, also named E3-11.6 K protein). ADP is required for efficient lysis of Ad5-infected cells and spread of virus from cell to cell, and thus its overexpression increases the oncolytic activity of the vectors. KD1 and KD3 contain mutations in the Ad5 E1A gene that knock out binding of the E1A proteins to cellular p300/CBP and pRB; these mutations allow KD1 and KD3 to grow well in cancer cells but not in normal cells. VRX-007 has wild-type E1A. Here we report that radiation increases the oncolytic activity of KD1, KD3, and VRX-007. This increased activity was observed in cultured cells, and it was not because of radiation-induced replication of the vectors. The combination of radiation plus KD3 suppressed the growth of A549 lung adenocarcinoma xenografts in nude mice more efficiently than radiation alone or KD3 alone. The combination of ADP-overexpressing vectors and radiation may have potential in treating cancer.

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Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015)

Cited by 165 publications

References 33 publications

ONYX-015: mechanisms of action and clinical potential of a replication-selective adenovirus

ONYX-015: mechanisms of action and clinical potential of a replication-selective adenovirus

An oncolytic conditionally replicating adenovirus for hormone-dependent and hormone-independent prostate cancer

Radiation increases the activity of oncolytic adenovirus cancer gene therapy vectors that overexpress the ADP (E3-11.6K) protein

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