DCE-MRI biomarkers for monitoring an anti-angiogenic triple combination therapy in experimental hypopharynx carcinoma xenografts with immunohistochemical validation

Acta Radiol. 2015 Mar;56(3):294-303. doi: 10.1177/0284185114527444. Epub 2014 Mar 7.

Abstract

Background: Novel anti-angiogenic treatments are increasingly complementing established cancer therapy strategies in head and neck tumors. Contrast-enhanced magnetic resonance imaging (MRI) can be applied for early and non-invasive therapy monitoring by non-invasive quantitative assessment of tumor microcirculation as in vivo imaging biomarkers of therapy response.

Purpose: To monitor the anti-angiogenic effects of a novel combination therapy on experimental head and neck squamous cell carcinomas (HNSCC) with dynamic contrast-enhanced (DCE)-MRI.

Material and methods: Athymic rats (n = 18) with subcutaneous HNSCC xenografts were investigated by DCE-MRI before and after 7 days of a daily triple therapy regimen combining the COX-II-inhibitor celecoxib, the matrix-metalloproteinase-inhibitor GM6001, and the uPA-inhibitor upamostat. Quantitative measurements of tumor blood flow (tBF), tumor blood volume (tBV), and permeability-surface area product (PS) were calculated and validated by immunohistochemistry.

Results: Mean tBF and tBV in triple-therapy animals decreased significantly from day 0 to day 7 (tBF, 41.0 ± 14.2 to 20.4 ± 5.7 mL/100 mL/min; P < 0.01; tBV, 17.7 ± 3.9 to 7.5 ± 3.3%; P < 0.01). No significant effects on PS were observed in either group (P > 0.05). Immunohistochemical analysis showed a significantly lower tumor vascularity in the therapy group than in the control group (CD31), significantly fewer Ki-67+ proliferating tumor cells and significantly more Capase-3+ apoptotic tumor cells (P < 0.05). Significant (P < 0.05) correlations were observed between tBF/tBV and CD31 (tBF, r = 0.84; tBV, r = 0.70), tBV and Ki-67 (r = 0.62), as well as tBF and caspase-3 (r = -0.64).

Conclusion: DCE-MRI may be a suitable tool for the non-invasive monitoring of the anti-vascular effects of this innovative triple therapy regimen with potential for clinical translation.

Keywords: Dynamic; GM6001; celecoxic; contrast-enhanced MRI; hypopharyngeal squamous cell carcinoma; therapy monitoring; upamostat.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Biomarkers, Tumor / analysis*
  • Carcinoma, Squamous Cell / chemistry*
  • Carcinoma, Squamous Cell / drug therapy*
  • Celecoxib
  • Combined Modality Therapy
  • Contrast Media
  • Dipeptides / therapeutic use
  • Disease Models, Animal
  • Hypopharyngeal Neoplasms / chemistry*
  • Hypopharyngeal Neoplasms / drug therapy*
  • Image Enhancement / methods*
  • Immunohistochemistry / methods
  • Magnetic Resonance Imaging / methods
  • Oximes
  • Piperazines / therapeutic use
  • Pyrazoles / therapeutic use
  • Rats
  • Rats, Nude
  • Reproducibility of Results
  • Sulfonamides / therapeutic use
  • Xenograft Model Antitumor Assays / methods

Substances

  • Angiogenesis Inhibitors
  • Biomarkers, Tumor
  • Contrast Media
  • Dipeptides
  • N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide
  • Oximes
  • Piperazines
  • Pyrazoles
  • Sulfonamides
  • Celecoxib
  • upamostat