Cilengitide-induced temporal variations in transvascular transfer parameters of tumor vasculature in a rat glioma model: identifying potential MRI biomarkers of acute effects

• Published in: PloS one 2013-12, Vol.8 (12), p.e84493-e84493
• Main Authors: Nagaraja, Tavarekere N, Aryal, Madhava P, Brown, Stephen L, Bagher-Ebadian, Hassan, Mikkelsen, Tom, Yang, James J, Panda, Swayamprava, Keenan, Kelly A, Cabral, Glauber, Ewing, James R
• Format: Article
• Language: English
• Subjects: Acute effects; Analysis of Variance; Anesthesiology; Angiogenesis; Animals; Bioindicators; Biomarkers; Blood; Blood Vessels - drug effects; Blood Vessels - physiopathology; Blood-brain barrier; Blood-vessels; Brain; Brain cancer; Brain tumors; Cancer therapies; Capillary Permeability - drug effects; Chemotherapy, Adjuvant; Concentration (composition); Contrast media; Drugs; Edema; Glioma; Glioma - blood supply; Glioma - drug therapy; Glioma - radiotherapy; Gliomas; Hospitals; Immunohistochemistry; Implantation; Laboratory animals; Magnetic Resonance Imaging; Neurology; NMR; Nuclear magnetic resonance; Parameter identification; Peptides; Perfusion; Permeability; Pharmacology; Physics; Potentiation; Radiation therapy; Rats; Rats, Nude; Sensitivity analysis; Snake Venoms - pharmacology; Temporal variations; Time Factors; Tumors; Von Willebrand factor
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0084493

Increased efficacy of radiotherapy (RT) 4-8 h after Cilengitide treatment has been reported. We hypothesized that the effects of Cilengitide on tumor transvascular transfer parameters might underlie, and thus predict, this potentiation. Athymic rats with orthotopic U251 glioma were studied at ~21 days after implantation using dynamic contrast-enhanced (DCE)-MRI. Vascular parameters, viz: plasma volume fraction (v(p)), forward volume transfer constant (K(trans)) and interstitial volume fraction (v(e)) of a contrast agent, were determined in tumor vasculature once before, and again in cohorts 2, 4, 8, 12 and 24 h after Cilengitide administration (4 mg/kg; N = 31; 6-7 per cohort). Perfusion-fixed brain sections were stained for von Willebrand factor to visualize vascular segments. A comparison of pre- and post-treatment parameters showed that the differences between MR indices before and after Cilengitide treatment pivoted around the 8 h time point, with 2 and 4 h groups showing increases, 12 and 24 h groups showing decreases, and values at the 8 h time point close to the baseline. The vascular parameter differences between group of 2 and 4 h and group of 12 and 24 h were significant for K(trans) (p = 0.0001 and v(e) (p = 0,0271). Vascular staining showed little variation with time after Cilengitide. The vascular normalization occurring 8 h after Cilengitide treatment coincided with similar previous reports of increased treatment efficacy when RT followed Cilengitide by 8 h. Pharmacological normalization of vasculature has the potential to increase sensitivity to RT. Evaluating acute temporal responses of tumor vasculature to putative anti-angiogenic drugs may help in optimizing their combination with other treatment modalities.