title: Patupilone induced vascular disruption in orthotopic rodent tumor models detected by magnetic resonance imaging and interstitial fluid pressure.
abstract: OBJECTIVE
  Evaluation of vascular disruptive activity in orthotopic models as potential surrogate biomarkers of tumor response to the microtubule-stabilizing agent patupilone.
  
  
  METHODS
  Mice bearing metastatic B16/BL6 melanoma and rats bearing mammary BN472 tumors received vehicle or efficacious patupilone doses (4 and 0.8-1.5 mg/kg i.v., respectively). Tumor vascularity assessment by dynamic contrast-enhanced or dynamic susceptibility contrast magnetic resonance imaging and interstitial fluid pressure (IFP) occurred at baseline, 2 days (mice and rats), and 6 days (rats) after treatment and were compared with histologic measurements and correlated with tumor response.
  
  
  RESULTS
  In B16/BL6 metastases, patupilone (4 mg/kg) induced a 21 +/- 5% decrease (P < 0.001) in tumor blood volume and a 32 +/- 15% decrease (P = 0.02) in IFP after 2 days and reduced tumor growth and vessel density (>42%) after 2 weeks (P < or = 0.014). Patupilone dose-dependently inhibited BN472 tumor growth (day 6) and reduced IFP on days 2 and 6 (-21% to -70%), and the percentage change in IFP correlated (P < 0.01) with the change in tumor volume. In both models, histology and vascular casts confirmed decreases in tumor blood volume. One patupilone (0.8 mg/kg) administration decreased (P < 0.01) tumor IFP (54 +/- 4%), tumor blood volume (50 +/- 6%), and vessel diameter (40 +/- 11%) by day 6 but not the apparent diffusion coefficient, whereas histology showed that apoptosis was increased 2.4-fold and necrosis was unchanged. Apoptosis correlated negatively (P < 0.001) with IFP, tumor blood volume, and tumor volume, whereas tumor blood volume and IFP were correlated positively (P = 0.0005).
  
  
  CONCLUSIONS
  Vascular disruptive effects of patupilone were detected in situ using dynamic contrast-enhanced or dynamic susceptibility contrast magnetic resonance imaging and IFP. Changes in IFP preceded and correlated with tumor response, suggesting that IFP may be a surrogate biomarker for patupilone efficacy.
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Stephane
authors.initials: S
authors.lastname: Ferretti
authors.forename: Peter R
authors.initials: PR
authors.lastname: Allegrini
authors.forename: Terence
authors.initials: T
authors.lastname: O'Reilly
authors.forename: Christian
authors.initials: C
authors.lastname: Schnell
authors.forename: Michael
authors.initials: M
authors.lastname: Stumm
authors.forename: Markus
authors.initials: M
authors.lastname: Wartmann
authors.forename: Jeanette
authors.initials: J
authors.lastname: Wood
authors.forename: Paul M J
authors.initials: PM
authors.lastname: McSheehy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001808:Blood Vessels / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003287:Contrast Media / Q000494:pharmacology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology; D034261:Epothilones / Q000494:pharmacology*; D005260:Female; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008279:Magnetic Resonance Imaging / Q000379:methods; D008545:Melanoma / Q000473:pathology; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D011312:Pressure; D051381:Rats; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D003287:Contrast Media; D034261:Epothilones; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C093788:epothilone B