Systemic delivery of antiangiogenic adenovirus AdmATF induces liver resistance to metastasis and prolongs survival of mice

Systemic administration of AdS-based recombinant adenovirus leads to prefer ential transduction of the liver. Using this property, we have assessed the potential of venous viral injection to deliver a recombinant antiangiogeni c adenovirus to treat cancer dissemination and improve survival. The result s demonstrate that venous injection of adenovirus AdmATF, which encodes a s ecretable mouse ATF (amino-terminal fragment of urokinase) known to inhibit angiogenesis, suppressed angiogenesis induced by colon cancer metastasis g rowth in mice liver and improved survival. Nude mice were injected intraven ously with 5 X 10(9) PFU of AdmATF and subsequently challenged after a 3-da y interval by:intrasplenically injected human colon carcinoma cells (LS174T , 3 X 10(6)) that home to liver. Microscopic inspection revealed that, with in the AdmATF-pretreated mice (n = 8), the size and number of liver-metasta sized nodules on day 30 were remarkably reduced (80% in number, p < 0.05) c ompared with control mice (n = 7) pretreated in parallel with a control ade novirus. Metastatic growth-related liver weight gain was also inhibited up to 90%, AdmATF-specific capability that offers liver resistance to the appa rition and growth of liver metastasis was shown to correlate with the inhib ition of peritumoral and intratumoral angiogenesis (reduced by 79%,p < 0.01 as shown by anti-vWF immunostaining of liver sections) and a twofold incre ase in tumor necrotic area and an eightfold increase in apoptotic tumor cel l number. This protective effect was still observed when the mice were chal lenged 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 mi ce, 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-eff icacy, although transient, in this experimental mice model strongly advocat es the plausibility of transforming the liver into a dissemination resistan t organ by antiangiogenic gene therapy through systemic delivery approach.