Bicalutamide-activated oncolytic adenovirus for the adjuvant therapy of high-risk prostate cancer
| Autor: | Theodore L. DeWeese, Ronald Rodriguez, Shawn E. Lupold, Wasim H. Chowdhury, Tamara Jane Johnson, Naser Uddin Hoti, Chunyan Liu, Ying Li, Yonggang Zhang |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Male
Cancer Research Fiber-IRES-GFP viruses Genetic enhancement medicine.medical_treatment Virus Replication Tosyl Compounds Mice Prostate cancer 0302 clinical medicine Viral Envelope Proteins Adenovirus Anilides Promoter Regions Genetic Oncolytic Virotherapy Mice Inbred BALB C 0303 health sciences Radiation Combined Modality Therapy 3. Good health Oncolytic Viruses Receptors Androgen 030220 oncology & carcinogenesis Molecular Medicine E1A-ARC685Y medicine.drug Oncolytic adenovirus Bicalutamide Cell Survival Anti-Androgen Mice Nude CRAd Biology Article Adenoviridae 03 medical and health sciences Cell Line Tumor Nitriles medicine Adjuvant therapy Animals Humans Molecular Biology 030304 developmental biology Prostatic Neoplasms Androgen Antagonists medicine.disease Virology Androgen receptor Radiation therapy HEK293 Cells Amino Acid Substitution Viral replication Neoplasm Transplantation |
| Zdroj: | Cancer gene therapy |
| ISSN: | 1476-5500 0929-1903 |
| DOI: | 10.1038/cgt.2013.34 |
| Popis: | Conditionally replicating adenoviruses (CRAds) utilize tissue specific promoters to control the expression of the early genes, E1A and E1B, to preferentially replicate and lyse tumor cells (oncolysis). Previous CRAds used in prostate cancer gene therapy require androgens to activate prostate specific promoters and induce viral replication. Unfortunately, these CRAds have reduced activity in patients on androgen suppressive therapy. We describe a novel prostate specific CRAd generated by fusing the E1A gene to the androgen receptor (AR) cDNA with a point mutation in codon 685 (C685Y). The E1A-AR fusion neutralizes the previously described mutual inhibition of E1A & AR, and the C685Y point mutation alters specificity of steroid ligand binding to the AR, such that both androgens and non-steroidal anti-androgens can activate viral replication. We demonstrate that the mutated E1A-AR retained the ability to function in regulating AR responsive genes and E1A responsive viral genes. In combination therapy of virus, bicalutamide (anti-androgen) and radiation, a profound impact on cell death by viral oncolysis was seen both in vitro and tumor xenografts. To our knowledge, this is the first gene therapy engineered to be enhanced by anti-androgens, and a particularly attractive adjuvant strategy for intensity modulated radiation therapy (IMRT) of high-risk prostate cancers. |
| Databáze: | OpenAIRE |
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