Persistent distension and enhanced diffusive extravasation of tumor vessels improved uniform tumor targeting of radioimmunoconjugate in mice administered with angiotensin II and kininase inhibitor.

Induced hypertension with angiotensin II (AT-II) and the inhibition of kininase with enalapril maleate may increase the tumor targeting of radiolabeled monoclonal antibodies (MAbs). We previously found that short-period infusion of 2.0 microg/kg/min of AT-II enhanced tumor targeting of MAb without an impact on normal tissue distribution. In this study, we aimed to optimize the manipulation with these agents, and examine the possible mechanism of their effects on MAb distribution. Effect of the manipulation on tissue circulation was assessed in mice bearing colon cancer xenografts by 201Tl and 99mTc-human serum albumin (HSA) as markers of tissue blood flow and tissue blood volume and/or vascular permeability. A dose finding study of enalapril ranging from 3 to 300 microg showed that 30 microg of enalapril in combination with AT-II infusion produced the best improvement in tumor uptake of 99Tc-HSA without altering 201Tl distribution, suggesting that the increase of vascular permeability was caused by enalapril. AT-II infusion for longer than 1 h affected renal blood flow and caused subcutaneous edema. Tumor uptake of (111)In-A7, a murine IgG1, was 1.62-fold improved 72 h postinjection (P < 0.001) and intratumoral distribution became uniform with 2.0 microg/kg/min of AT-II for 1 h and 30 microg of enalapril. Vessels in manipulated tumors were distended even 48 h after the cessation of AT-II infusion. In conclusion, it was suggested that persistent distension of tumor vessels and the increase of diffusive extravasation of MAb caused by short-period-induced hypertension and inhibition of bradykinin degradation produced favorable effect for the MAb distribution in tumors.