title: Cilengitide-induced temporal variations in transvascular transfer parameters of tumor vasculature in a rat glioma model: identifying potential MRI biomarkers of acute effects.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Tavarekere N
authors.initials: TN
authors.lastname: Nagaraja
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, United States of America ; Department of Physics, Oakland University, Rochester, Michigan, United States of America.
authors.forename: Madhava P
authors.initials: MP
authors.lastname: Aryal
authors.affiliation: Department of Radiation Oncology, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Brown
authors.affiliation: Department of Diagnostic Radiology, Henry Ford Hospital, Detroit, Michigan, United States of America ; Department of Physics, Oakland University, Rochester, Michigan, United States of America.
authors.forename: Hassan
authors.initials: H
authors.lastname: Bagher-Ebadian
authors.affiliation: Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.affiliation: Public Health Sciences, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: James J
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Swayamprava
authors.initials: S
authors.lastname: Panda
authors.affiliation: Department of Anesthesiology, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Keenan
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Glauber
authors.initials: G
authors.lastname: Cabral
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, United States of America ; Department of Physics, Oakland University, Rochester, Michigan, United States of America ; Department of Neurology, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: James R
authors.initials: JR
authors.lastname: Ewing
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000503:physiopathology*; D002199:Capillary Permeability / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D005910:Glioma / Q000098:blood supply* / Q000188:drug therapy* / Q000532:radiotherapy; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D051381:Rats; D011923:Rats, Nude; D012910:Snake Venoms / Q000494:pharmacology*; D013997:Time Factors; D014841:von Willebrand Factor
chemical_list: D012910:Snake Venoms; D014841:von Willebrand Factor; C422910:Cilengitide