Hypoxia-mediated tumour targeting

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

“…twice daily for 5 days resulted in the regression of VEGF-HSVtk-lung tumors, although there was no direct evidence that GCV-mediated toxicity was due to hypoxia-regulated overexpression of HSVtk (Koshikawa et al, 2000). Interestingly, another study showed that the use of a hypoxia-responsive promoter can also reduce the normal tissue toxicity of HSVtk/GCV gene therapy (Binley et al, 2003). Mice bearing human breast carcinoma MDA-MB468 xenografts transduced with an adenovirus containing the HSVtk CDS under the control of the constitutive cytomegalovirus (CMV) showed significant weight loss and increased hepatic cellular injury and death, when treated with 25 mg/kg daily GCV (Binley et al, 2003).…”

“…Interestingly, another study showed that the use of a hypoxia-responsive promoter can also reduce the normal tissue toxicity of HSVtk/GCV gene therapy (Binley et al, 2003). Mice bearing human breast carcinoma MDA-MB468 xenografts transduced with an adenovirus containing the HSVtk CDS under the control of the constitutive cytomegalovirus (CMV) showed significant weight loss and increased hepatic cellular injury and death, when treated with 25 mg/kg daily GCV (Binley et al, 2003). On the other hand, when the CMV promoter was replaced with the OBHRE promoter (containing a murine PGK-1 HRE trimer upstream of the minimal SV40 promoter; Boast et al, 1999), transgene expression was limited to the tumor areas and neither weight loss nor liver abnormalities were observed (Binley et al, 2003).…”

“…Mice bearing human breast carcinoma MDA-MB468 xenografts transduced with an adenovirus containing the HSVtk CDS under the control of the constitutive cytomegalovirus (CMV) showed significant weight loss and increased hepatic cellular injury and death, when treated with 25 mg/kg daily GCV (Binley et al, 2003). On the other hand, when the CMV promoter was replaced with the OBHRE promoter (containing a murine PGK-1 HRE trimer upstream of the minimal SV40 promoter; Boast et al, 1999), transgene expression was limited to the tumor areas and neither weight loss nor liver abnormalities were observed (Binley et al, 2003). The low basal activity of the OBHRE promoter did not compromise its therapeutic potential, as shown with the CYP 2B6/CP GDEPT system (Boast et al, 1999).…”

Gene therapy targeting to tumor endothelium

“…59 Another adenovirus expressing HSV-TK under the control of an optimized hypoxia responsive promoter (OBHRE) derived from phosphoglycerate kinase 1 promoter is well tolerated in liver after intravenous administration contrary to administration of Ad.CMV-TK/GCV. 60 In addition, an adenoviral vector simultaneously expressing both cytosine deaminase (CD) and HSV-TK genes under the transcriptional control of KDR promoter showed that this combined CD/TK therapy is more effective at killing HUVEC than with either treatment alone. 61 Von Willebrand factor (vWf) promoter has also been employed to drive the transcription of HSV-TK, showing endothelial selectivity, but with low activity.…”

“…63 Finally, an adenovirus expressing cytochrome P450-CYP2B6 regulated by the optimized hypoxia responsive promoter together with cyclophosphamide showed an ability to delay tumor growth. 60 Endothelial transcription of pro-apoptotic proteins Destroying tumor vasculature with pro-apoptotic genes can be selectively achieved with the use of tumor vascular- Abbreviations: CD, cytosine deaminase; GDEPT, gene-directed enzyme-prodrug therapy; GFP, green fluorescent protein; HSV-TK, thymidine kinase; NTR, nitroreductase; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor; VSV, vesiculoviruses. associated promoters.…”