Endostatin lowers blood pressure via nitric oxide and prevents hypertension associated with VEGF inhibition.
Antiangiogenesis therapy has become a vital part of the armamentarium against cancer. Hypertension is a dose-limiting toxicity for VEGF inhibitors. Thus, there is a pressing need to address the associated adverse events so these agents can be better used. The hypertension may be mediated by reduced NO bioavailability resulting from VEGF inhibition. We proposed that the hypertension may be prevented by coadministration with endostatin (ES), an endogenous angiogenesis inhibitor with antitumor effects shown to increase endothelial NO production in vitro. We determined that Fc-conjugated ES promoted NO production in endothelial and smooth muscle cells. ES also lowered blood pressure in normotensive mice and prevented hypertension induced by anti-VEGF antibodies. This effect was associated with higher circulating nitrate levels and was absent in eNOS-knockout mice, implicating a NO-mediated mechanism. Retrospective study of patients treated with ES in a clinical trial revealed a small but significant reduction in blood pressure, suggesting that the findings may translate to the clinic. Coadministration of ES with VEGF inhibitors may offer a unique strategy to prevent drug-related hypertension and enhance antiangiogenic tumor suppression.
Division of Vascular Biology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA. ssunshine@jhmi.edu
Sarah B
SB
Sunshine
Susan M
SM
Dallabrida
Ellen
E
Durand
Nesreen S
NS
Ismail
Lauren
L
Bazinet
Amy E
AE
Birsner
Regina
R
Sohn
Sadakatsu
S
Ikeda
William T
WT
Pu
Matthew H
MH
Kulke
Kashi
K
Javaherian
David
D
Zurakowski
Judah M
JM
Folkman
Maria
M
Rupnick
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000737:chemistry; D001794:Blood Pressure / Q000502:physiology*; D017322:Clinical Trials, Phase II as Topic; D043169:Endostatins / Q000378:metabolism*; D005260:Female; D006321:Heart / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000378:metabolism* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009569:Nitric Oxide / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D000906:Antibodies; D043169:Endostatins; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide