Systemic administration of radiation-potentiated anti-angiogenic gene therapy against primary and metastatic cancer based on transcriptionally controlled HSV-TK

Abstract

Transcription-targeted gene delivery directed against angiogenic endothelial cells is a new approach against advanced cancer.Moreover, the herpes simplex virus-thymidine kinase (HSV-TK) gene coupled with low dose radiotherapy is an efficient and externally controlled cytotoxic system. We have previously demonstrated enhanced endothelial-specific cell expression and killing using the modified murine pre-proendothelin-1 promoter (PPE1-3x) to direct adenoviral expression of a pro-apoptotic gene. The purpose of this study was to create an externally potentiated systemic antiantiangiogenic gene delivery system based on an adenoviral vector expressing HSV-TK under the regulation of PPE1-3X promoter combined with radiotherapy for eradicating metastatic cancer.Ad-PPE1-3x-TK induced endothelial-specific cell killing in-vitro upon introduction of the prodrug ganciclovir (GCV). BALB/c mice bearing a primary CT-26 colon carcinoma tumor showed tumor growth suppression and diminished tumor angiogenesis when the vector was administered intravenously, activated with GCV and potentiated with a single sub-therapeutic and non-toxic radiation dose. Moreover, intravenous administration of the vector, activated with GCV and potentiated with chest aimed radiation, to C57BL/6 mice bearing Lewis lung carcinoma metastases resulted in prolongation of mice survival. PPE1-3x-regulated HSV-TK expression was detected only in lung metastases in contrast to CMV-regulated expression. This novel system may benefit patients with metastatic disease.

Microvascular Modifications in Diabetic Retinopathy

“…Although targeting VEGF imposes risks on the retina, as discussed above, the murine preproendothelin (PPE1) promoter represents an attractive candidate for endothelial-specific targeting of pathologic microvessels associated with PDR [126,127]. Not only does this promoter element aid in widespread vascular disruption and apoptosis in combination with chemotherapy in xenograft rumor models [128], but also the PPE1 sequence can be modified to target gene expression specifically to ischemic tissue [129]. Thus, PPE1 might be appropriate for targeting retinal neovasculature, which is widely participating in angiogenesis and experiencing ischemic conditions.…”

Improving the safety of cell therapy products by suicide gene transfer

“…Suicide genes have also been employed as cytotoxic strategy, in vitro and in vivo models (Huber et al, 1991; Clark et al, 1997; Nor et al, 2002; Nakayama et al, 2005; Hodish et al, 2009; Evans and Dey, 2011; Duarte et al, 2012; Mazor et al, 2012), including combination with replication competent oncolytic viruses (Ahn et al, 2009; Kaur et al, 2009), with some evidence of clinical benefit in solid tumors (Pandha et al, 1999; Freytag et al, 2003, 2007; Nemunaitis et al, 2003; Voges et al, 2003; Li et al, 2007; Xu et al, 2009). …”

Recent Advances in Biological Strategies for Targeted Drug Delivery

“…Systemic administration of a mouse model with this vector resulted in enhanced blood perfusion, improved clinical outcome, and increased capillary density without systemic toxicity [200]. This promoter was also used by the same group to construct an Ad vector to express HSV-thymidine kinase combined with radiotherapy for eradicating metastatic cancer [201]. AAV vector has also been tested for expression of vascular endothelial growth factor (VEGF), an angiogenic factor, specifically in myocardium by using a cardiac myosin light chain 2v (MLC-2v) promoter and the hypoxia-response element (HRE).…”