التفاصيل البيبلوغرافية
| العنوان: |
SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice. |
| المؤلفون: |
Neesse, Albrecht1,2, Frese, Kristopher K.1, Chan, Derek S.1, Bapiro, Tashinga E.1, Howat, William J.1, Richards, Frances M.1, Ellenrieder, Volker2, Jodrell, Duncan I.1, Tuveson, David A.1,3 dtuveson@cshl.edu |
| المصدر: |
Gut. Jun2014, Vol. 63 Issue 6, p974-983. 10p. 5 Graphs. |
| مصطلحات موضوعية: |
*PHARMACODYNAMICS, *DRUG delivery systems, *OSTEONECTIN, *PACLITAXEL, *ANTINEOPLASTIC agents, *PHARMACOKINETICS |
| مستخلص: |
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 highresolution 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. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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