Comparative benefits of Nab-paclitaxel over gemcitabine or polysorbate-based docetaxel in experimental pancreatic cancer.

Abstract

Gemcitabine has limited clinical benefits in pancreatic ductal adenocarcinoma. The solvent-based traditional taxanes docetaxel and paclitaxel have not shown clinical results superior to gemcitabine. Nab-paclitaxel, 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 pancreatic ductal adenocarcinoma cells AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1, gemcitabine IC50 ranged from 494nM to 23.9 μM; docetaxel IC50 range was from 5 to 34nM; nab-paclitaxel IC50 range was from 243nM 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-smooth muscle actin, S100A4 and collagen 1 expression. Animal survival was prolonged after nab-paclitaxel treatment (41 days, P < 0.002) compared with gemcitabine (32 days, P = 0.005), docetaxel (32 days, P = 0.005) and controls (20 days). Survival in nab-paclitaxel/gemcitabine and docetaxel/gemcitabine sequential treatment groups was not superior to nab-paclitaxel alone. Low-dose combination of gemcitabine with nab-paclitaxel or docetaxel was more effective compared with controls or gemcitabine alone but not superior to regular dose nab-paclitaxel alone. Combination treatment of gemcitabine+nab-paclitaxel or gemcitabine+docetaxel 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 pancreatic ductal adenocarcinoma.

• Authors: Niranjan Awasthi, Changhua Zhang, Anna M Schwarz, Stefan Hinz, Changguang Wang, Noelle S Williams, Margaret A Schwarz, Roderich E Schwarz
• Journal: Carcinogenesis (Carcinogenesis) Vol. 34 Issue 10 Pg. 2361-9 (Oct 2013) ISSN: 1460-2180 [Electronic] England
• PMID: 23803690 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Albumin-Bound Paclitaxel
• Albumins
• Antineoplastic Agents
• Stathmin
• Taxoids
• Tubulin
• Deoxycytidine
• Docetaxel
• Paclitaxel
• Gemcitabine

Topics

• Albumin-Bound Paclitaxel
• Albumins (administration & dosage, pharmacology)
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Deoxycytidine (administration & dosage, analogs & derivatives, pharmacology)
• Disease Models, Animal
• Docetaxel
• Female
• Humans
• Inhibitory Concentration 50
• Neoplasms, Experimental (drug therapy, mortality, pathology)
• Paclitaxel (administration & dosage, pharmacology)
• Pancreatic Neoplasms (drug therapy, mortality, pathology)
• Stathmin (metabolism)
• Stromal Cells (drug effects)
• Taxoids (administration & dosage, pharmacology)
• Tubulin (metabolism)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays
• Gemcitabine