Nab-paclitaxel efficacy in the orthotopic model of human breast cancer is significantly enhanced by concurrent anti-vascular endothelial growth factor A therapy.
Nab-paclitaxel is an albumin-bound 130-nm particle form of paclitaxel that has shown an improved efficacy in experimental tumor models and clinical studies compared with solvent-based paclitaxel. Anti-vascular endothelial growth factor A (VEGF-A) antibody bevacizumab is known to enhance antitumor activity of cytotoxic drugs. This study evaluated the effects of combined nab-paclitaxel and bevacizumab therapy on growth and metastatic spread of orthotopic breast tumors. Cytotoxic and clonogenic assays measured VEGF-A-dependent modulation of nabpaclitaxel toxicity on cultured tumor cells. Antitumor effects were assessed in mice with luciferase-tagged, well-established MDA-MB-231 tumors (250-310 mm3) treated with one, two, or three cycles of nab-paclitaxel (10 mg/kg, daily for five consecutive days), bevacizumab (2-8 mg/kg, twice a week), or with combination of both drugs. VEGF-A protected MDA-MB-231 cells against nab-paclitaxel cytotoxicity, whereas bevacizumab sensitized cells to the effect of the drug. Combined bevacizumab and nab-paclitaxel treatment synergistically inhibited tumor growth and metastasis resulting in up to 40% of complete regressions of well-established tumors. This therapy also decreased the incidence of lymphatic and pulmonary metastases by 60% and 100%, respectively. The significant increase in the cure of tumor-bearing mice in the nab-paclitaxel/bevacizumab combined group compared with mice treated with single drugs strongly advocates for implementing such strategy in clinics.
Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, 801 N Rutledge, Springfield, IL, 62794-9678, USA.
Lisa D
LD
Volk
Michael J
MJ
Flister
Christopher M
CM
Bivens
Alan
A
Stutzman
Neil
N
Desai
Vuong
V
Trieu
Sophia
S
Ran
D000418:Albumins / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000627:therapeutic use*
C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D008156:Luciferases; D017239:Paclitaxel