Characterization of hemodynamic events following intravascular infusion of recombinant adenovirus reveals possible solutions for mitigating cardiovascular responses.
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 x 10(13) 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.
Machemer
Todd
T
Department of Pharmacology, Canji, Inc., 3525 John Hopkins Court, San Diego, CA 92121, USA.
Engler
Heidrun
H
Tsai
Van
V
Lee
Seoju
S
Cannon-Carlson
Susan
S
Voloch
Marcio
M
Schluep
Thomas
T
Ravindran
Sundari
S
Vellekamp
Gary
G
Brin
Elena
E
Cornell
Douglas
D
Sutjipto
Suganto
S
Wen
Shu Fen
SF
Horn
Mark
M
Van Rooijen
Nico
N
Maneval
Dan
D
Hutchins
Beth
B
LaFace
Drake
D
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung; D002302:Cardiac Output / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects; D004562:Electrocardiography; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000494:pharmacology* / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D009980:Influenza A virus; D007728:Kupffer Cells / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D001616:beta-Galactosidase / Q000627:therapeutic use*
D001616:beta-Galactosidase