1. ¹Department of Pharmacology, Canji, Inc., 3525 John Hopkins Court, San Diego, CA 92121, USA
2. ²Department of Biotech Development, Schering–Plough Research Institute, Union, NJ 07083, USA
3. ³Department of Process Science, Canji, Inc., 3525 John Hopkins Court, San Diego, CA 92121, USA
4. ⁴Department of Molecular Biology, Canji, Inc., 3525 John Hopkins Court, San Diego, CA 92121, USA
5. ⁵Department of Cell Biology & Immunology, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, The Netherlands

Correspondence: Drake LaFace, Fax: +1 858 597 0237. E-mail: drake.laface@spcorp.com

Received 17 June 2004; Accepted 8 March 2005.

Abstract

Intravascular administration of recombinant adenovirus (rAd) in cancer patients has been well tolerated. However, dose-limiting hemodynamic responses associated with suppression of cardiac output have been observed at doses of 7.5 10¹³ particles. While analysis of hemodynamic responses induced by small-molecule pharmaceuticals is well established, little is known about the cardiovascular effects of rAd. Telemetric cardiovascular (CV) monitoring in mice was utilized to measure hemodynamic events following intravascular rAd administration. Electrocardiogram analysis revealed a block in the SA node 3–4 min postinfusion, resulting in secondary pacemaking initiated at the AV node. This was associated with acute bradycardia, reduced blood pressure, and hypothermia followed by gradual recovery. Adenovirus-primed murine sera with high neutralizing antibody (nAb) titers could inhibit CV responses, whereas human sera with equivalent nAb titers induced by natural infection were, surprisingly, not inhibitory. Interestingly, repeat dosing within 2–4 h of the primary injection resulted in desensitization, resembling tachyphylaxis, for subsequent CV responses. Last, depletion of Kupffer cells prior to rAd infusion precluded induction of CV responses. These inhibitory effects suggest that rAd interactions with certain cells of the reticular endothelial system are associated with induction of CV responses. Significantly, these studies may provide insight into management of acute adverse effects following rAd systemic delivery, enabling a broadening of therapeutic index.