Improved effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status

• Published in: Anti-cancer drugs Vol. 19; no. 9; p. 899
• Main Authors: Desai, Neil P, Trieu, Vuong, Hwang, Larn Yuan, Wu, Rujin, Soon-Shiong, Patrick, Gradishar, William J
• Format: Journal Article
• Language: English
• Published: England 01.10.2008
• Subjects: Albumin-Bound Paclitaxel; Albumins - administration & dosage; Albumins - toxicity; Animals; Female; Humans; Male; Maximum Tolerated Dose; Mice; Mice, Nude; Nanoparticles; Osteonectin - metabolism; Paclitaxel - administration & dosage; Paclitaxel - toxicity; Polysorbates; Receptor, ErbB-2; Taxoids - administration & dosage; Taxoids - toxicity; Xenograft Model Antitumor Assays
• ISSN: 0959-4973
• DOI: 10.1097/CAD.0b013e32830f9046

Nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) is an albumin-bound 130-nm particle form of paclitaxel that demonstrated higher efficacy and was well tolerated compared with solvent-based paclitaxel (Taxol) and docetaxel (Taxotere) in clinical trials for metastatic breast cancer. Nab-paclitaxel enhances tumor targeting through gp60 and caveolae-mediated endothelial transcytosis and the association with the albumin-binding protein SPARC (secreted protein, acidic and rich in cysteine) in the tumor microenvironment. The overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer has been shown to correlate with resistance to paclitaxel. To evaluate the importance of HER2 and SPARC status in determining the relative efficacy of nab-paclitaxel compared with polysorbate-based docetaxel, nude mice bearing six different human tumor xenografts were treated with nab-paclitaxel (MX-1: 15 mg/kg, once a week for 3 weeks; LX-1, MDA-MB-231/HER2+, PC3, and HT29: 50 and 120 mg/kg, every 4 days three times ; MDA-MB-231: 120 and 180 mg/kg, every 4 days three times) and polysorbate-based docetaxel (15 mg/kg). HER2 and SPARC status were analyzed by RT-PCR and immunohistochemical staining. MDA-MB-231 and MX-1 breast and LX-1 lung cancers were HER2 negative and low in SPARC expression. Nab-paclitaxel at submaximum-tolerated dosage was significantly more effective than polysorbate-based docetaxel at its maximum-tolerated dosage in these three HER2-negative tumors. The HER2-positive tumors had variable SPARC expression, with MDA-MB-231/HER2+ <PC3 <HT29. In these HER2-positive tumors, nab-paclitaxel was equal to or better than polysorbate-based docetaxel in tumors with medium to high SPARC levels (PC3 and HT29), but not in MDA-MB-231/HER2+ tumors with low SPARC expression. These results demonstrated that the relative efficacy of nab-paclitaxel was significantly higher compared with polysorbate-based docetaxel in HER2-negative tumors (three of three) and in HER2-positive tumors with high levels of SPARC. HER2 and SPARC expression may be useful biomarkers in determining antitumor effectiveness for taxanes.