The macrophage - a novel system to deliver gene therapy to pathological hypoxia.
The use of activated macrophages in the treatment of cancer has been largely ineffectual. By 'arming' these cells with the ability to express a therapeutic gene we demonstrate significant advances in the efficacy of this approach. We have used a hypoxia-regulated adenoviral vector to transduce human macrophages with either a reporter or a therapeutic gene encoding human cytochrome P4502B6 (CYP2B6). Infiltration of transduced macrophages into a tumour spheroid results in induction of gene expression. We demonstrate significant tumour cell killing only in the presence of cyclophosphamide via activation by P4502B6 and show that this can be further targeted to tumours through hypoxia regulated gene expression. Gene Therapy (2000) 7, 255-262.
Griffiths
L
L
Oxford BioMedica (UK) Ltd, Oxford, UK.
Binley
K
K
Iqball
S
S
Kan
O
O
Maxwell
P
P
Ratcliffe
P
P
Lewis
C
C
Harris
A
A
Kingsman
S
S
Naylor
S
S
D000256:Adenoviridae / Q000235:genetics*; D001189:Aryl Hydrocarbon Hydroxylases; D015153:Blotting, Western; D003520:Cyclophosphamide / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D000860:Hypoxia / Q000628:therapy*; D008264:Macrophages / Q000502:physiology*; D008863:Microspheres; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism
D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating