Armoring CRAds with p21/Waf-1 shRNAs: the next generation of oncolytic adenoviruses.

Abstract

Conditionally replicating adenoviruses (CRAds) represent a promising modality for the treatment of neoplastic diseases, including Prostate Cancer. Selectively replicating viruses can be generated by placing a tissue or cancer-specific promoter upstream of one or more of the viral genes required for replication (for example, E1A, E1B). We have previously reported multiple cellular processes that can attenuate viral replication, which in turn compromises viral oncolysis and tumor kill. In this study, we investigated the importance of the cyclin-dependent kinase inhibitor p21/Waf-1, on viral replication and tumor growth. To our knowledge, this is the first report describing the importance of p21/Waf-1shRNA on the induction of an androgen responsive element (ARE) based promoter driving the E1A gene. As a proof of concept, the study emphasizes the use of RNA interference technology to overcome promoter weaknesses for tissue-specific oncolytic viruses, as well as the cellular inhibitor pathways on viral life cycle. Using RNA interference against p21/Waf-1, we were able to show an increase in viral replication and viral oncolysis of prostate cancer cells. Similarly, CRAd viruses that carry p21/Waf-1 shRNA (Ad5-RV004.21) were able to prevent tumor outgrowth that resulted in a marked increase in the mean survival time of tumor-bearing mice compared with CRAd without p21/Waf-1 shRNA (Ad5-RV004). In studies combining Ad5-RV004.21 with Adriamycin, a suprar-additive effect was observed only in CRAds that harbor shRNA against p21/Waf-1. Taken together, these findings of enhanced viral replication in prostate cancer cells by using RNA interference against the cdk inhibitor p21/Waf-1 have significant implications in the development of prostate-specific CRAd therapies.

• Authors: N Höti, W H Chowdhury, S Mustafa, J Ribas, M Castanares, T Johnson, M Liu, S E Lupold, R Rodriguez
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 17 Issue 8 Pg. 585-97 (Aug 2010) ISSN: 1476-5500 [Electronic] England
• PMID: 20448671 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• RNA, Small Interfering
• Receptors, Androgen
• Doxorubicin

Topics

• Adenoviridae (genetics, metabolism, physiology)
• Animals
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p21 (genetics)
• Down-Regulation
• Doxorubicin (pharmacology)
• Gene Knockdown Techniques
• Gene Silencing
• Genetic Vectors (genetics, metabolism, physiology)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Oncolytic Viruses (genetics, metabolism)
• Prostatic Neoplasms (genetics, metabolism, therapy, virology)
• RNA Interference
• RNA, Small Interfering (administration & dosage, genetics)
• Receptors, Androgen (biosynthesis, genetics)
• Virus Replication (genetics, physiology)