Characterization of infectivity-enhanced conditionally replicating adenovectors for prostate cancer radiovirotherapy

Michael J. Oneal, Miguel A. Trujillo, Julia Davydova, Samantha McDonough, Masato Yamamoto, John C. Morris

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Prostate cancer (PCa) is the second most commonly diagnosed and sixth leading cause of cancer death in American men and one for which no curative therapy exists after metastasis. To meet this need for novel therapies, our laboratory has previously generated conditionally replicating adenovirus (CRAd) vectors expressing the sodium iodide symporter (hNIS). This virus transduced PCa cells and induced functional NIS expression, allowing for noninvasive tumor imaging and combination therapy with radioiodide, referred to as radiovirotherapy. We have now generated two new modified vectors to further improve efficacy. Ad5/3PB-ADP-hNIS and Ad5/3PB-hNIS include a hybrid Ad5/3 fiber knob to improve transduction efficiency, and express NIS from the endogenous major late promoter to restrict NIS expression to target cells. Additionally, Ad5/3PB-ADP-hNIS includes the adenovirus death protein (ADP), which hastens the release of viral particles after assembly. These two vectors specifically induce radioisotope uptake, cytopathic effect, and viral replication in androgen receptor-expressing PCa cell lines with Ad5/3PB-ADP-hNIS showing earlier 131I uptake and cytolysis at low multiplicity of infection. SPECT-CT imaging of xenograft tumors infected with Ad5/3PB-hNIS showed steady uptake, whereas infection with Ad5/3PB-ADP-hNIS led to increasing uptake, indicating viral spread. Radiovirotherapy of xenograft LNCaP tumors with Ad5/3PB-ADP-hNIS showed the most significant survival extension versus control tumors (p=0.001), but the benefit of radiovirotherapy was not statistically significant compared with virotherapy alone in this model. These results show the potential of Ad5/3PB-ADP-hNIS as a vector for treatment of prostate cancer.

Original languageEnglish (US)
Pages (from-to)951-959
Number of pages9
JournalHuman gene therapy
Volume23
Issue number9
DOIs
StatePublished - Sep 1 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Fingerprint Dive into the research topics of 'Characterization of infectivity-enhanced conditionally replicating adenovectors for prostate cancer radiovirotherapy'. Together they form a unique fingerprint.

  • Cite this

    Oneal, M. J., Trujillo, M. A., Davydova, J., McDonough, S., Yamamoto, M., & Morris, J. C. (2012). Characterization of infectivity-enhanced conditionally replicating adenovectors for prostate cancer radiovirotherapy. Human gene therapy, 23(9), 951-959. https://doi.org/10.1089/hum.2012.047