Patupilone induced vascular disruption in orthotopic rodent tumor models detected by magnetic resonance imaging and interstitial fluid pressure.
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.
Ferretti
Stephane
S
Oncology Research, Novartis Institutes for BioMedical Research, Basel, Switzerland.
Allegrini
Peter R
PR
O'Reilly
Terence
T
Schnell
Christian
C
Stumm
Michael
M
Wartmann
Markus
M
Wood
Jeanette
J
McSheehy
Paul M J
PM
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
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