Abstract
BackgroundIn a phase I study of angiotensin-(1–7) [Ang-(1–7)], clinical benefit was associated with reduction in plasma placental growth factor (PlGF) concentrations. The current study examines Ang-(1–7) induced changes in biomarkers according to cancer type and investigates mechanisms of action engaged in vitro.MethodsPlasma biomarkers were measured prior to Ang-(1–7) administration as well as 1, 2, 3, 4, and 6 hours after treatment. Tests for interaction were performed to determine the impact of cancer type on angiogenic hormone levels. If a positive interaction was detected, treatment-induced biomarker changes for individual cancer types were assessed. To investigate mechanisms of action, in vitro growth assays were performed using a murine endothelioma cell line (EOMA). PCR arrays were performed to identify and statistically validate genes that were altered by Ang-(1–7) treatment in these cells.ResultsTests for interaction controlled for dose cohort and clinical response indicated a significant impact of cancer type on post-treatment VEGF and PlGF levels. Following treatment, PlGF levels decreased over time in patients with sarcoma (P = .007). Treatment of EOMA cells with increasing doses of Ang-(1–7) led to significant growth suppression at doses as low as 100 nM. PCR arrays identified 18 genes that appeared to have altered expression after Ang-(1–7) treatment. Replicate analyses confirmed significant changes in 8 genes including reduction in PlGF (P = .04) and hypoxia inducible factor 1α (HIF-1α) expression (P < .001).ConclusionsAng-(1–7) has clinical and pre-clinical activity for vascular sarcomas that is linked to reduced HIF-1α and PlGF expression.
Highlights
In a phase I study of angiotensin-(1–7) [Ang-(1–7)], clinical benefit was associated with reduction in plasma placental growth factor (PlGF) concentrations
Murine xenograft models have demonstrated that Ang-(1–7) exerts anti-angiogenic effects in a variety of cancer types [7,8]
The group of patients with clinical benefit demonstrated a reduction in plasma levels of the PlGF over time following treatment
Summary
In a phase I study of angiotensin-(1–7) [Ang-(1–7)], clinical benefit was associated with reduction in plasma placental growth factor (PlGF) concentrations. Murine xenograft models have demonstrated that Ang-(1–7) exerts anti-angiogenic effects in a variety of cancer types [7,8]. While this drug has shown a broad spectrum of. A phase I study was conducted to examine the tolerability and activity of Ang-(1–7) for the treatment of patients with advanced solid tumors refractory to standard therapy [9]. The group of patients with clinical benefit demonstrated a reduction in plasma levels of the PlGF over time following treatment. PlGF levels did not significantly change over time in the group of patients without clinical benefit. Levels of VEGF did not significantly change over time in either group [9]
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