title: Tumor interstitial fluid pressure as an early-response marker for anticancer therapeutics.
abstract: Solid tumors have a raised interstitial fluid pressure (IFP) due to high vessel permeability, low lymphatic drainage, poor perfusion, and high cell density around the blood vessels. To investigate tumor IFP as an early-response biomarker, we have tested the effect of seven anticancer chemotherapeutics including cytotoxics and targeted cytostatics in 13 experimental tumor models. IFP was recorded with the wick-in-needle method. Models were either ectopic or orthotopic and included mouse and rat syngeneic as well as human xenografts in nude mice. The mean basal IFP was between 4.4 and 15.2mm Hg; IFP was lowest in human tumor xenografts and highest in rat syngeneic models. Where measured, basal IFP correlated positively with relative tumor blood volume (rTBV) determined by dynamic contrast-enhanced magnetic resonance imaging. Most chemotherapeutics sooner (2 or 3 days) or later (6 or 7 days) lowered tumor IFP significantly, and the cytotoxic patupilone caused the greatest decrease in IFP. In rat mammary orthotopic BN472 tumors, significant drug-induced decreases in IFP and rTBV correlated positively with each other for both patupilone and the cytostatic vatalanib. In the two orthotopic models studied, early decreases in IFP were significantly (P < or = .005) correlated with late changes in tumor volume. Thus, drug-induced decreases in tumor IFP are an early marker of response to therapy, which could aid clinical development.
authors.affiliation: Oncology Research, Novartis Institute of Biomedical Research, 4002 Basel, Switzerland. stephane.ferretti@novartis.com
authors.forename: Stephane
authors.initials: S
authors.lastname: Ferretti
authors.forename: Peter R
authors.initials: PR
authors.lastname: Allegrini
authors.forename: Mike M
authors.initials: MM
authors.lastname: Becquet
authors.forename: Paul Mj
authors.initials: PM
authors.lastname: McSheehy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor; D003287:Contrast Media; D045604:Extracellular Fluid / Q000187:drug effects*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D051381:Rats; D011914:Rats, Inbred BN; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D003287:Contrast Media