on line version CAN-10-2349.pdf (3.07 MB)
Download file

Use of Macrophages to Target Therapeutic Adenovirus to Human Prostate Tumors

Download (3.07 MB)
journal contribution
posted on 27.04.2011, 13:34 authored 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, 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.

History

Citation

Cancer Research, 2011, 71 (5), pp. 1805-1815.

Published in

Cancer Research

Publisher

American Association for Cancer Research

issn

0008-5472

Copyright date

2011

Available date

27/04/2011

Publisher version

http://cancerres.aacrjournals.org/content/71/5/1805

Language

en

Usage metrics

Categories

Keywords

Exports