Temporal Patterns of Novel Circulating Biomarkers in IL-2-mediated Vascular Injury in the Rat

Abstract

Recombinant interleukin-2 (rIL-2) administration in oncology indications is hampered by vascular toxicity, which presents as a vascular leak syndrome. We used this aspect of the toxicity of rIL-2 to evaluate candidate biomarkers of drug-induced vascular injury (DIVI) in rats given 0.36 mg/kg rIL-2 daily. Groups of rats were given either 2 or 5 doses of rIL-2 or 5 doses of rIL-2 followed by a 7-day recovery. The histomorphologic lexicon and grading scheme developed by the Vascular Injury Working Group of the Predictive Safety Testing Consortium of the Critical Path Institute were utilized to enable semiquantitative integration with circulating biomarker levels. The administration of rIL-2 was associated with time-dependent endothelial cell hyperplasia and hypertrophy and perivascular inflammation that correlated with increases in circulating angiopoietin-2, lipocalin-2, monocyte chemotactic protein-1, tissue inhibitor of metalloproteinase-1, vascular endothelial growth factor A, E-selectin, and chemokine (C-X-C motif) ligand-1, and the microRNAs miR-21, miR-132, and miR-155. The dose groups were differentially identified by panels comprising novel candidate biomarkers and traditional hematologic parameters. These results identify biomarkers of the early stages of DIVI prior to the onset of vascular smooth muscle necrosis.

Different expression of miR-29b and VEGFA in glioma

“…MicroRNAs (miRNAs) are short RNA molecules with 18-25 nucleotides in length, which are implicated in post-transcriptional regulation of gene expression (Liu et al 2015a). Currently, it is clear that miRNAs are also present in circulation (e.g., in plasma or serum), and these circulating miRNAs are found to be either encapsulated in membranous microvesicles or associated with RNA-binding proteins or lipoprotein complexes, rendering circulating miRNAs relatively resistant to enzymatic degradation (Keirstead et al 2015, Ovchinnikova et al 2015). An increasing number of studies demonstrate that miRNA expression profiles may be specific to certain types of cancer and tumor-derived miRNAs may be stably detected in the plasma or serum (Ma et al 2013, Xiao et al 2014.…”