title: Use of macrophages to target therapeutic adenovirus to human prostate tumors.
abstract: 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.
authors.affiliation: Department of Infection & Immunity, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Munitta
authors.initials: M
authors.lastname: Muthana
authors.forename: Athina
authors.initials: A
authors.lastname: Giannoudis
authors.forename: Simon D
authors.initials: SD
authors.lastname: Scott
authors.forename: Hsin-Yu
authors.initials: HY
authors.lastname: Fang
authors.forename: Seth B
authors.initials: SB
authors.lastname: Coffelt
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Morrow
authors.forename: Craig
authors.initials: C
authors.lastname: Murdoch
authors.forename: Julian
authors.initials: J
authors.lastname: Burton
authors.forename: Neil
authors.initials: N
authors.lastname: Cross
authors.forename: Bernard
authors.initials: B
authors.lastname: Burke
authors.forename: Roshna
authors.initials: R
authors.lastname: Mistry
authors.forename: Freddie
authors.initials: F
authors.lastname: Hamdy
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Brown
authors.forename: Lindsay
authors.initials: L
authors.lastname: Georgopoulos
authors.forename: Peter
authors.initials: P
authors.lastname: Hoskin
authors.forename: Magnus
authors.initials: M
authors.lastname: Essand
authors.forename: Claire E
authors.initials: CE
authors.lastname: Lewis
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Maitland
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D008264:Macrophages / Q000821:virology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000628:therapy*; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D017500:Adenovirus E1A Proteins