title: Dynamic contrast-enhanced magnetic resonance imaging of the metastatic potential of melanoma xenografts.
abstract: OBJECTIVE
  Gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been suggested as a useful noninvasive method for characterizing the physiologic microenvironment of tumors. In the present study, we investigated whether Gd-DTPA-based DCE-MRI has the potential to provide biomarkers for hypoxia-associated metastatic dissemination.
  
  
  METHODS
  C-10 and D-12 melanoma xenografts were used as experimental tumor models. Pimonidazole was used as a hypoxia marker. A total of 60 tumors were imaged, and parametric images of K(trans) (volume transfer constant of Gd-DTPA) and v(e) (fractional distribution volume of Gd-DTPA) were produced by pharmacokinetic analysis of the DCE-MRI series. The host mice were killed immediately after DCE-MRI, and the primary tumor and the lungs were resected and prepared for histologic assessment of the fraction of pimonidazole-positive hypoxic tissue and the presence of lung metastases, respectively.
  
  
  RESULTS
  Metastases were found in 11 of 26 mice with C-10 tumors and 14 of 34 mice with D-12 tumors. The primary tumors of the metastatic-positive mice had a greater fraction of hypoxic tissue (p = 0.00031, C-10; p < 0.00001, D-12), a lower median K(trans) (p = 0.0011, C-10; p < 0.00001, D-12), and a lower median v(e) (p = 0.014, C-10; p = 0.016, D-12) than the primary tumors of the metastatic-negative mice.
  
  
  CONCLUSIONS
  These findings support the clinical attempts to establish DCE-MRI as a method for providing biomarkers for tumor aggressiveness and suggests that primary tumors characterized by low K(trans) and low v(e) values could have a high probability of hypoxia-associated metastatic spread.
authors.affiliation: Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Kirsti Marie
authors.initials: KM
authors.lastname: Ovrebø
authors.forename: Christine
authors.initials: C
authors.lastname: Ellingsen
authors.forename: Kanthi
authors.initials: K
authors.lastname: Galappathi
authors.forename: Einar K
authors.initials: EK
authors.lastname: Rofstad
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis / Q000493:pharmacokinetics; D015687:Cell Hypoxia / Q000502:physiology*; D003287:Contrast Media / Q000493:pharmacokinetics; D005260:Female; D019786:Gadolinium DTPA / Q000493:pharmacokinetics; D006801:Humans; D008168:Lung; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008546:Melanoma, Experimental / Q000378:metabolism / Q000503:physiopathology / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009593:Nitroimidazoles / Q000032:analysis / Q000493:pharmacokinetics; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: D014408:Biomarkers, Tumor; D003287:Contrast Media; D009593:Nitroimidazoles; C033815:pimonidazole; D019786:Gadolinium DTPA