Systemic Delivery of Antiangiogenic Adenovirus AdmATF Induces Liver Resistance to Metastasis and Prolongs Survival of Mice

Abstract

Systemic administration of Ad5-based recombinant adenovirus leads to preferential transduction of the liver. Using this property, we have assessed the potential of venous viral injection to deliver a recombinant antiangiogenic adenovirus to treat cancer dissemination and improve survival. The results demonstrate that venous injection of adenovirus AdmATF, which encodes a secretable mouse ATF (amino-terminal fragment of urokinase) known to inhibit angiogenesis, suppressed angiogenesis induced by colon cancer metastasis growth in mice liver and improved survival. Nude mice were injected intravenously with 5 X 10(9) PFU of AdmATF and subsequently challenged after a 3-day interval by intrasplenically injected human colon carcinoma cells (LS174T, 3 x 10(6)) that home to liver. Microscopic inspection revealed that, within the AdmATF-pretreated mice (n = 8), the size and number of liver-metastasized nodules on day 30 were remarkably reduced (80% in number, p < 0.05) compared with control mice (n = 7) pretreated in parallel with a control adenovirus. Metastatic growth-related liver weight gain was also inhibited up to 90%. AdmATF-specific capability that offers liver resistance to the apparition and growth of liver metastasis was shown to correlate with the inhibition of peritumoral and intratumoral angiogenesis (reduced by 79%, p < 0.01 as shown by anti-vWF immunostaining of liver sections) and a twofold increase in tumor necrotic area and an eightfold increase in apoptotic tumor cell number. This protective effect was still observed when the mice were challenged 10 days after venous AdmATF injection (visible metastasis nodules: 6.3+/-3.1, n = 7 for control mice versus 2.7+/-2.9, n = 10 for treated mice, p < 0.05). More importantly, the mean survival has been prolonged from 45.1 days (n = 9) to 83.3 days (n = 10, p < 0.05). Altogether, the high efficacy, although transient, in this experimental mice model strongly advocates the plausibility of transforming the liver into a dissemination resistant organ by antiangiogenic gene therapy through systemic delivery approach.

In vivo adenovirus-mediated delivery of a uPA/uPAR antagonist reduces retinal neovascularization in a mouse model of retinopathy

“…A recombinant adenovirus encoding the noncatalytic ATF of mouse uPA prevents lung carcinoma metastasis 10 and protects mice in a liver metastasis model of human colon carcinoma. 11 A marked reduction in tumoral neovascularization was observed in these experiments.…”

“…The angiostatic activities of ATF and endostatin have already been described in numerous tumor models. 10,11,13,15 This is the first time that AFT has been shown to have angiostatic activity in a model of retinal neovascularization. We showed that that local gene transfer and the expression of ATFHSA reduce retinal neovascularization by 78.1%.…”

“…11 The construction of Ad ATFHSA is described in detail by Apparailly et al 20 Briefly, these vectors are DE1-DE3 recombinant adenoviruses expressing the murine ATF or endostatin gene coupled to the HSA gene under the control of the cytomegalovirus (CMV) promoter. After recombinational cloning in E. coli, 29 the recombinant adenoviral genome was excised and used to transfect 293 cells by the Lipofectamine Plus-based procedure (Life Technologies), thus yielding Ad ATFHSA and Ad EndoHSA.…”

Adenovirus-mediated gene transfer of urokinase plasminogen inhibitor inhibits angiogenesis in experimental arthritis

“…A recombinant adenovirus encoding the non-catalytic ATF of mouse uPA has been previously shown to prevent lung carcinoma metastasis 15 and to protect mice in a liver metastasis model of human colon carcinoma. 16 In these experiments, a marked reduction in the tumoral neovascularization was observed. Because ATF binds to uPAR on cell surfaces, it disrupts the interaction of uPA to its receptor (uPAR) and inhibits uPA/uPAR-dependent angiogenesis process by preventing plasminogen conversion into plasmin, and subsequent activation of the proteolytic cascade required for extracellular matrix degradation and cell invasion.…”

A gene transfer comparative study of HSA-conjugated antiangiogenic factors in a transgenic mouse model of metastatic ocular cancer

“…[20][21][22][23][24][25][26] The above-mentioned studies provide important information on the relative potency of a number of antiangiogenic gene products previously shown to possess antitumor activity. 10,11,13,14,[27][28][29][30][31] However, there is a dearth of information on the antitumor activity of Can. Our objective was to determine the sensitivity of an intraocular HSA-fused angiostatic factors block metastasis E Frau et al been suboptimal.…”