Skip to main content
Article thumbnail
Location of Repository

Use of Macrophages to Target Therapeutic Adenovirus to Human Prostate Tumors

By Munitta Muthana, Athina Giannoudis, Simon D. Scott, Hsin-Yu Fang, Seth B. Coffelt, Fiona J. Morrow, Craig Murdoch, Julian Burton, Neil Cross, Bernard Burke, Roshna Mistry, Freddie Hamdy, Nicola J. Brown, Lindsay Georgopoulos, Peter Hoskin, Magnus Essand, Claire E. Lewis and Norman J. Maitland


New therapies are required to target hypoxic areas of tumors as these sites are highly resistant to conventional cancer therapies. Monocytes continuously extravasate from the bloodstream into tumors where they differentiate into macrophages and accumulate in hypoxic areas, thereby opening up the possibility of using these cells as vehicles to deliver gene therapy to these otherwise inaccessible sites. We describe a new cell-based method that selectively targets an oncolytic adenovirus to hypoxic areas of prostate tumors. In this approach, macrophages were cotransduced with a hypoxia-regulated E1A/B construct and an E1A-dependent oncolytic adenovirus, whose proliferation is restricted to prostate tumor cells using prostate-specific promoter elements from the TARP, PSA, and PMSA genes. When such cotransduced cells reach an area of extreme hypoxia, the E1A/B proteins are expressed, thereby activating replication of the adenovirus. The virus is subsequently released by the host macrophage and infects neighboring tumor cells. Following systemic injection into mice bearing subcutaneous or orthotopic prostate tumors, cotransduced macrophages migrated into hypoxic tumor areas, upregulated E1A protein, and released multiple copies of adenovirus. The virus then infected neighboring cells but only proliferated and was cytotoxic in prostate tumor cells, resulting in the marked inhibition of tumor growth and reduction of pulmonary metastases. This novel delivery system employs 3 levels of tumor specificity: the natural “homing” of macrophages to hypoxic tumor areas, hypoxia-induced proliferation of the therapeutic adenovirus in host macrophages, and targeted replication of oncolytic virus in prostate tumor cells

Publisher: American Association for Cancer Research
Year: 2011
DOI identifier: 10.1158/0008-5472.CAN-10-2349
OAI identifier:

Suggested articles


  1. A blood-tumor barrier limits gene transfer to experimental liver cancer: the effect of vasoactive compounds. Gene Ther 2000;7:1824- doi
  2. (2002). A DNA-based method to assay total and infectious particle contents and helper virus contamination in high-capacity adenoviral vector preparations. Hum Gene Ther doi
  3. (1991). A mouse model for investigating the molecular pathogenesis of adenovirus pneumonia. doi
  4. A novel hypoxia-inducible factor (HIF) activated oncolytic adenovirus for cancer therapy. doi
  5. Adenoviral infection induces a multi-faceted innate cellular immune response that is mediated by the toll-like receptor pathway in A549 cells. doi
  6. Adenovirus binding to blood factors results in liver cell infection and hepatotoxicity. doi
  7. (2006). An oncolytic conditionally replicating adenovirus for hormone-dependent and hormone-independent prostate cancer. Cancer Gene Ther doi
  8. Brave little world: spheroids doi
  9. Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector. doi
  10. HIF-1, and the pathophysiology of common human diseases. doi
  11. Hypoxia regulates macrophage functions in inflammation. doi
  12. (2011). Impact of human neutralizing antibodies on antitumor efficacy of an oncolytic adenovirus in a murine model. Clin Cancer Res 2004;10:7199-206. American Association for Cancer Research Copyright © doi
  13. Increased therapeutic efficacy of the prostate-specific oncolytic adenovirus Ad[I/PPT-E1A] by reduction of the insulator size and introduction of the full-length E3 region. doi
  14. Oncolytic effects of adenovirus mutant capable of replicating in hypoxic and normoxic regions of solid tumor. doi
  15. (1999). Quantitation of adenovirus DNA and virus particles with the PicoGreen fluorescent Dye. Anal Biochem doi
  16. Quantitation of the number of cells within tumor colonies in semisolid medium and their growth as oblate spheroids.
  17. Targeted cancer gene therapy using a hypoxia inducible factor dependent oncolytic adenovirus armed with interleukin-4. doi
  18. Targeting gene-virotherapy of cancer and its prosperity. doi
  19. The case of oncolytic viruses versus the immune system: waiting on the judgment of Solomon. Hum Gene Ther doi
  20. (2002). The release of inflammatory cytokines from human peripheral blood mononuclear cells in vitro following exposure to adenovirus variants and capsid. Hum Gene Ther doi
  21. (1996). The role of human adenovirus early region 3 proteins (gp19K, 10.4K, 14.5K, and 14.7K) in a murine pneumonia model.
  22. (1997). Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells. doi
  23. transcriptional effectors in primary macrophages experiencing hypoxia. doi

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.