title: Magnetic resonance imaging measurements of the response of murine and human tumors to the vascular-targeting agent ZD6126.
abstract: OBJECTIVE
  ZD6126 is a novel vascular targeting agent currently undergoing clinical evaluation. It acts by destabilizing the microtubulin of fragile and proliferating neoendothelial cells in tumors. The drug leads to blood vessel congestion, the selective destruction of the vasculature, and extensive necrosis in experimental tumors. The aim of the study reported here was to assess the ability of dynamic contrast enhanced magnetic resonance imaging (MRI) to measure the antivascular effects of ZD6126 in tumors.
  
  
  METHODS
  The work was carried out in mice bearing C38 colon adenocarcinoma and in patients with advanced cancers. MRI was performed before and 6 h (human tumors) or 24 h (C38 tumors) after i.v. drug administration. Contrast agent (gadolinium diethylenetriaminepentaacetate) enhancement was characterized by the initial area under the gadolinium diethylenetriaminepentaacetate uptake versus time curve (IAUC). IAUC reflects blood flow, vascular permeability, and the fraction of interstitial space.
  
  
  RESULTS
  The median IAUC was reduced in all C38 tumors after ZD6126 administration [by 6-48% at 50 mg/kg (n = 3)], 58-91% at 100 mg/kg (n = 4), and 11-93% at 200 mg/kg (n = 6). In contrast, the administration of vehicle only led to no consistent change in median IAUC (n = 4). The ZD6126-induced changes in median IAUC appeared to be dose dependent (P = 0.045). No ZD6126-induced changes were apparent in murine muscle. Similar effects were seen in preliminary data from human tumors (11 tumors studied, 9 patients). At doses of 80 mg/m(2) and higher, the median IAUC post-ZD6126 treatment was reduced in all of the tumors studied (8 tumors, 6 patients) to 36-72% from the baseline value. There was a significant trend of increasing reductions with increasing exposure (P < 0.01). No drug-induced changes in human muscle or spleen IAUC were apparent. The reproducibility of the median IAUC parameter was investigated in patients. In 19 human tumors (measured in 19 patients) inter- and intratumor coefficients of variation were 64 and 18%.
  
  
  CONCLUSIONS
  The contrast enhanced-MRI measured median IAUC is a useful end point for quantifying ZD6126 antivascular effects in human tumors.
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Harper Hospital MR Center, Detroit, Michigan 48201, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Evelhoch
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.forename: Zhanquan
authors.initials: Z
authors.lastname: He
authors.forename: Zachary
authors.initials: Z
authors.lastname: DelProposto
authors.forename: Lisa
authors.initials: L
authors.lastname: Polin
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Corbett
authors.forename: Peter
authors.initials: P
authors.lastname: Langmuir
authors.forename: Catherine
authors.initials: C
authors.lastname: Wheeler
authors.forename: Andrew
authors.initials: A
authors.lastname: Stone
authors.forename: Joanna
authors.initials: J
authors.lastname: Leadbetter
authors.forename: Anderson J
authors.initials: AJ
authors.lastname: Ryan
authors.forename: David C
authors.initials: DC
authors.lastname: Blakey
authors.forename: John C
authors.initials: JC
authors.lastname: Waterton
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D019540:Area Under Curve; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003287:Contrast Media / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D019786:Gadolinium DTPA / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D009336:Necrosis; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D003287:Contrast Media; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; D019786:Gadolinium DTPA