TY - JOUR
T1 - Use of macrophages to target therapeutic adenovirus to human prostate tumors
AU - Muthana, Munitta
AU - Giannoudis, Athina
AU - Scott, Simon D
AU - Fang, Hsin-Yu
AU - Coffelt, Seth B
AU - Morrow, Fiona J
AU - Murdoch, Craig
AU - Burton, Julian
AU - Cross, Neil
AU - Burke, Bernard
AU - Mistry, Roshna
AU - Hamdy, Freddie
AU - Brown, Nicola J
AU - Georgopoulos, Lindsay
AU - Hoskin, Peter
AU - Essand, Magnus
AU - Lewis, Claire E
AU - Maitland, Norman J
N1 - ©2011 AACR.
PY - 2011/3/1
Y1 - 2011/3/1
N2 - 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.
AB - 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.
KW - Adenoviridae/genetics
KW - Adenovirus E1A Proteins/genetics
KW - Animals
KW - Cell Hypoxia/physiology
KW - Electrophoresis, Polyacrylamide Gel
KW - Humans
KW - Macrophages/virology
KW - Male
KW - Mice
KW - Mice, Nude
KW - Oncolytic Virotherapy/methods
KW - Oncolytic Viruses/genetics
KW - Prostatic Neoplasms/therapy
KW - Transduction, Genetic
KW - Xenograft Model Antitumor Assays
U2 - 10.1158/0008-5472.CAN-10-2349
DO - 10.1158/0008-5472.CAN-10-2349
M3 - Article
C2 - 21233334
SN - 1535-7163
VL - 71
SP - 1805
EP - 1815
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 5
ER -