Comparative Benefits of Nab-paclitaxel over Gemcitabine or Polysorbate-based Docetaxel in Experimental Pancreatic Cancer

Gemcitabine (Gem) has limited clinical benefits in pancreatic ductal adenocarcinoma (PDAC). The solvent-based traditional taxanes docetaxel (DT) and paclitaxel have not shown clinical results superior to gemcitabine. Nab-paclitaxel (NPT), a water-soluble albumin-bound paclitaxel, may carry superior distribution properties into the tumor microenvironment and has shown efficacy in multiple tumor types. We evaluated nab-paclitaxel effects compared with gemcitabine or docetaxel. For PDAC cells AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1, Gem IC50 ranged from 494 nM to 23.9 μM; DT IC50 range was 5 nM to 34 nM; and NPT IC50 range was 243 nM to 4.9 μM. Addition of IC25 dose of docetaxel or nab-paclitaxel decreased gemcitabine IC50. Net tumor growth inhibition after gemcitabine, docetaxel or nab-paclitaxel was 67%, 31% and 72%, which corresponded with intratumoral proliferative and apoptotic indices. Tumor stromal density was decreased by nab-paclitaxel and to a lesser extent by docetaxel as measured through reduction in α-SMA, S100A4 and collagen-1 expression. Animal survival was prolonged after nab-paclitaxel treatment (41 days, p<0.002) compared to gemcitabine (32 days, p=0.005), docetaxel (32 days, p=0.005) and controls (20 days). Survival in NPT/Gem and DT/Gem sequential treatment groups was not superior to nab-paclitaxel alone. Low dose combination of gemcitabine with nab-paclitaxel or docetaxel were more effective compared with controls or gemcitabine alone but not superior to regular dose nab-paclitaxel alone. Combination treatment of Gem+NPT or Gem+DT increased gemcitabine concentration in plasma and tumor. The superior antitumor activity of nab-paclitaxel provides a strong rationale for considering nab-paclitaxel as first-line monotherapy in PDAC.

http://carcin.oxfordjournals.org/content/early/2013/06/26/carcin.bgt227.abstract

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