title: MRI tumor characterization using Gd-GlyMe-DOTA-perfluorooctyl-mannose-conjugate (Gadofluorine M), a protein-avid contrast agent.
abstract: The rationale and objectives were to define the MRI tumor-characterizing potential of a new protein-avid contrast agent, Gd-GlyMe-DOTA-perfluorooctyl-mannose-conjugate (Gadofluorine M; Schering AG, Berlin, Germany) in a chemically induced tumor model of varying malignancy. Because of the tendency for this agent to form large micelles in water and to bind strongly to hydrophobic sites on proteins, it was hypothesized that patterns of dynamic tumor enhancement could be used to differentiate benign from malignant lesions, to grade the severity of malignancies and to define areas of tumor necrosis. Gadofluorine M, 0.05 mmol Gd kg(-1), was administered intravenously to 28 anesthetized rats that had developed over 10 months mammary tumors of varying degrees of malignancy as a consequence of intraperitoneal administration of N-ethyl-N-nitrosourea (ENU), 45-250 mg kg(-1). These tumors ranged histologically from benign fibroadenomas to highly undifferentiated adenocarcinomas. Dynamic enhancement data were analyzed kinetically using a two-compartment tumor model to generate estimates of fractional plasma volume (fPV), apparent fractional extracellular volume (fEV*) and an endothelial transfer coefficient (K(PS)) for this contrast agent. Tumors were examined microscopically for tumor type, degree of malignancy (Scarff-Bloom-Richardson score) and location of necrosis. Eighteen tumor-bearing rats were successfully imaged. MRI data showed an immediate strong and gradually increasing tumor enhancement. K(PS) and fEV*, but not fPV obtained from tumors correlated significantly (p < 0.05) with the SBR tumor grade, r = 0.65 and 0.56, respectively. Estimates for K(PS) and fEV* but not fPV were significantly lower in a group consisting of benign and low-grade malignant tumors compared with the group of less-differentiated high-grade tumors (1.61 +/- 0.64 vs 3.37 +/- 1.49, p < 0.01; 0.45 +/- 0.17 vs 0.78 +/- 0.24, p < 0.01; and 0.076 +/- 0.048 vs 0.121 +/- 0.088, p = 0.24, respectively). It is concluded that the protein-avid MRI contrast agent Gadofluorine M enhances tumors of varying malignancy depending on the tumor grade, higher contrast agent accumulation for more malignant lesions. The results show potential utility for differentiating benign and low-grade malignant lesions from high-grade cancers.
authors.affiliation: Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Raatschen
authors.forename: Rebecca
authors.initials: R
authors.lastname: Swain
authors.forename: David M
authors.initials: DM
authors.lastname: Shames
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Fu
authors.forename: Zachary
authors.initials: Z
authors.lastname: Boyd
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Zierhut
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wendland
authors.forename: Bernd
authors.initials: B
authors.lastname: Misselwitz
authors.forename: Hanns-Joachim
authors.initials: HJ
authors.lastname: Weinmann
authors.forename: Karl-Jürgen
authors.initials: KJ
authors.lastname: Wolf
authors.forename: Robert C
authors.initials: RC
authors.lastname: Brasch
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000473:pathology; D000818:Animals; D003287:Contrast Media / Q000032:analysis; D005038:Ethylnitrosourea; D005260:Female; D018226:Fibroadenoma / Q000175:diagnosis* / Q000473:pathology; D005466:Fluorocarbons; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000175:diagnosis* / Q000473:pathology; D009367:Neoplasm Staging / Q000379:methods; D009942:Organometallic Compounds; D011856:Radiographic Image Enhancement / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D003287:Contrast Media; D005466:Fluorocarbons; D009942:Organometallic Compounds; C477144:gadofluorine; C517961:gadofluorine M; D005038:Ethylnitrosourea