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Endostatin lowers blood pressure via nitric oxide and prevents hypertension associated with VEGF inhibition.


ABSTRACT: 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.

SUBMITTER: Sunshine SB 

PROVIDER: S-EPMC3396467 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Endostatin lowers blood pressure via nitric oxide and prevents hypertension associated with VEGF inhibition.

Sunshine Sarah B SB   Dallabrida Susan M SM   Durand Ellen E   Ismail Nesreen S NS   Bazinet Lauren L   Birsner Amy E AE   Sohn Regina R   Ikeda Sadakatsu S   Pu William T WT   Kulke Matthew H MH   Javaherian Kashi K   Zurakowski David D   Folkman Judah M JM   Rupnick Maria M  

Proceedings of the National Academy of Sciences of the United States of America 20120625 28


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 effe  ...[more]

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