Regorafenib effects on human colon carcinoma xenografts monitored by dynamic contrast-enhanced computed tomography with immunohistochemical validation

PLoS One. 2013 Sep 30;8(9):e76009. doi: 10.1371/journal.pone.0076009. eCollection 2013.

Abstract

Objective: To investigate dynamic contrast-enhanced computed tomography for monitoring the effects of regorafenib on experimental colon carcinomas in rats by quantitative assessments of tumor microcirculation parameters with immunohistochemical validation.

Materials and methods: Colon carcinoma xenografts (HT-29) implanted subcutaneously in female athymic rats (n = 15) were imaged at baseline and after a one-week treatment with regorafenib by dynamic contrast-enhanced computed tomography (128-slice dual-source computed tomography). The therapy group (n = 7) received regorafenib daily (10 mg/kg bodyweight). Quantitative parameters of tumor microcirculation (plasma flow, mL/100 mL/min), endothelial permeability (PS, mL/100 mL/min), and tumor vascularity (plasma volume, %) were calculated using a 2-compartment uptake model. Dynamic contrast-enhanced computed tomography parameters were validated with immunohistochemical assessments of tumor microvascular density (CD-31), tumor cell apoptosis (TUNEL), and proliferation (Ki-67).

Results: Regorafenib suppressed tumor vascularity (15.7±5.3 to 5.5±3.5%; p<0.05) and tumor perfusion (12.8±2.3 to 8.8±2.9 mL/100 mL/min; p = 0.063). Significantly lower microvascular density was observed in the therapy group (CD-31; 48±10 vs. 113±25, p<0.05). In regorafenib-treated tumors, significantly more apoptotic cells (TUNEL; 11844±2927 vs. 5097±3463, p<0.05) were observed. Dynamic contrast-enhanced computed tomography tumor perfusion and tumor vascularity correlated significantly (p<0.05) with microvascular density (CD-31; r = 0.84 and 0.66) and inversely with apoptosis (TUNEL; r = -0.66 and -0.71).

Conclusions: Regorafenib significantly suppressed tumor vascularity (plasma volume) quantified by dynamic contrast-enhanced computed tomography in experimental colon carcinomas in rats with good-to-moderate correlations to an immunohistochemical gold standard. Tumor response biomarkers assessed by dynamic contrast-enhanced computed tomography may be a promising future approach to a more personalized and targeted cancer therapy.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Capillary Permeability / drug effects
  • Carcinoma / drug therapy*
  • Colonic Neoplasms / drug therapy*
  • Drug Monitoring / methods*
  • Female
  • Heterografts / drug effects*
  • Humans
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Microcirculation / drug effects
  • Phenylurea Compounds / pharmacology*
  • Pyridines / pharmacology*
  • Rats
  • Tomography, X-Ray Computed / methods

Substances

  • Phenylurea Compounds
  • Pyridines
  • regorafenib

Grants and funding

This study was supported by the German Federal Ministry of Education and Research (BMBF, www.bmbf.de) Excellence Cluster M4 (01EX1021X) (www.m4.de) and a research grant from Bayer HealthCare (healthcare.bayer.de). Funding solely concerned the animals and materials used in this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.