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Regorafenib induces rapid and reversible changes in plasma nitric oxide and endothelin-1

Nilka de Jesus-Gonzalez1, Emily Robinson, Radostin Penchev

  • 1Division of Nephrology, Department of Medicine, Boston Children's Hospital, Massachusetts, USA.

American Journal of Hypertension
|July 13, 2012
PubMed
Abstract

Insights

Regorafenib therapy for gastrointestinal stromal tumors causes hypertension by suppressing nitric oxide (NO) and increasing endothelin-1 (ET-1). These changes are reversible upon drug withdrawal, suggesting a potential biomarker role.

Area of Science:

  • Oncology
  • Pharmacology
  • Cardiovascular Science

Background:

  • Hypertension is a known toxicity of antiangiogenic therapies and a potential biomarker for cancer outcomes.
  • Understanding the mechanisms of this hypertension can improve treatment and identify new biomarkers.
  • Nitric oxide (NO) suppression and endothelin-1 (ET-1) stimulation are implicated in antiangiogenic therapy-induced hypertension.

Purpose of the Study:

  • To evaluate the effects of regorafenib, a broad-spectrum kinase inhibitor, on NO and ET-1 levels.
  • To investigate the role of regorafenib in the development of hypertension.
  • To explore potential mechanisms linking regorafenib to hypertension.

Main Methods:

  • Regorafenib was administered to 32 gastrointestinal stromal tumor patients.
  • Plasma levels of NO and ET-1 were measured at baseline and during therapy.
  • Statistical analysis included Wilcoxon rank-sum and paired t-tests.

Main Results:

  • 63% of subjects developed regorafenib-induced hypertension.
  • Regorafenib suppressed NO by 20% and increased ET-1 by 25% within 2 weeks.
  • These effects were reversible upon drug washout but recurred upon re-administration.

Conclusions:

  • Regorafenib induces a coordinated, reversible suppression of NO and stimulation of ET-1.
  • These findings suggest a potential mechanism for regorafenib-induced hypertension.
  • Further research is needed to determine if NO and ET-1 can predict therapeutic efficacy.

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