SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice

Neesse, A., Frese, K. K., Chan, D. S., Bapiro, T. E., Howat, W. J., Richards, F. M., Ellenrieder, V., Jodrell, D. I., Tuveson, D. A. (2013) SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice. Gut, 63 (6). pp. 974-983. ISSN 00175749 (ISSN)

URL: http://www.ncbi.nlm.nih.gov/pubmed/24067278
DOI: 10.1136/gutjnl-2013-305559

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, KrasG12D;p53flox/-;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. © 2013 BMJ Publishing Group Ltd & British Society of Gastroenterology.

Item Type: Paper
Subjects: diseases & disorders > cancer
diseases & disorders
therapies
therapies > cancer drugs - see diseases-cancer-drugs and therapies
diseases & disorders > cancer > drugs and therapies
organism description > model organism
organism description > animal > mammal > rodent > mouse
diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > Tuveson lab
Depositing User: Matt Covey
Date Deposited: 15 Oct 2013 20:11
Last Modified: 30 May 2014 19:26
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28648

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