SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice. Issue 6 (25th September 2013)

• Record Type: Journal Article
• Authors: Neesse, Albrecht; Frese, Kristopher K; Chan, Derek S; Bapiro, Tashinga E; Howat, William J; Richards, Frances M; Ellenrieder, Volker; Jodrell, Duncan I; Tuveson, David A
• Is Part Of: Gut. Volume 63:Issue 6(2014)
• Page Start: 974
• Page End: 983
• Publication Date: 2013-09-25
• Subjects: Pancreatic Cancer; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2013-305559
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Design: Pharmacokinetic and pharmacodynamic parameters of cremophor-paclitaxel, nab -paclitaxel (human-albumin-bound paclitaxel, Abraxane) and a novel mouse-albumin-bound paclitaxel ( m-nab -paclitaxel) were evaluated in genetically engineered mouse models (GEMMs) by liquid chromatography-tandem mass spectrometry (LC-MS/MS), histological and biochemical analysis. Preclinical evaluation of m-nab -paclitaxel included assessment by three-dimensional high-resolution ultrasound and molecular analysis in a novel secreted protein acidic and rich in cysteine (SPARC)-deficient GEMM of pancreatic ductal adenocarcinoma (PDA). Results: nab -Paclitaxel exerted its antitumoural effects in a dose-dependent manner and was associated with less toxicity compared with cremophor-paclitaxel. SPARC nullizygosity in a GEMM of PDA, Kras G12D ;p53 flox/− ;p48Cre (KPfC), resulted in desmoplastic ductal pancreas tumours with impaired collagen maturation. Paclitaxel concentrations were significantly decreased in SPARC null plasma samples and tissues when administered as low-dose m-nab -paclitaxel. At the maximally tolerated dose, SPARC deficiency did not affect the intratumoural paclitaxel concentration, stromal deposition and the immediate therapeutic response. Conclusions: nab -Paclitaxel accumulates and acts in a dose-dependent manner. The interaction of plasma SPARC and albumin-bound drugs is observed at low doses of nab -paclitaxel but is saturated at therapeutic doses in murine tumours. Thus, this study provides important information for future preclinical and clinical trials in PDA using nab -paclitaxel in combination with novel experimental and targeted agents.