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. (September 2013) SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice. Gut, 63 (6). pp. 974-983. ISSN 00175749 (ISSN)
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: | 25 September 2013 |
| Date Deposited: | 15 Oct 2013 20:11 |
| Last Modified: | 19 Jul 2021 14:32 |
| PMCID: | PMC4033275 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/28648 |
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