Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer

Cancer Res. 2007 Jan 1;67(1):281-8. doi: 10.1158/0008-5472.CAN-06-3282.

Abstract

Metronomic chemotherapy is the frequent administration of low doses of chemotherapeutic agents targeting tumor-associated endothelial cells. We examined the efficacy of metronomic taxanes alone and in combination with AEE788-a dual epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) inhibitor-in an orthotopic mouse model of ovarian cancer. Growth-modulating effects of metronomic and maximum tolerated dose (MTD) regimens on overall survival were tested in vivo using both chemotherapy-sensitive (HeyA8 and SKOV3ip1) and chemotherapy-resistant (HeyA8-MDR) models. Treated tumors were stained for microvessel density (CD31), proliferation index (proliferating cell nuclear antigen), and apoptosis (terminal deoxyribonucleotide transferase-mediated nick-end labeling). The cytotoxic effects of MTD and metronomic dosing were tested with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Effects of metronomic regimens on circulating endothelial precursors (CEP) and tumor-specific cell-free DNA levels were assessed. In vivo, metronomic docetaxel resulted in significant reduction of tumor growth in the taxane-sensitive cell lines, whereas metronomic docetaxel plus AEE788 had an additive effect resulting in significant prolongation in survival. Combination therapy was effective even in the taxane-resistant model. Metronomic chemotherapy alone and combined with AEE788 resulted in a decrease in the proliferative index and microvessel density of treated tumors, whereas combination therapy increased the apoptotic index (P < 0.001). In vitro, metronomic taxanes caused endothelial cell toxicity at 10- to 100-fold lower concentrations compared with MTD dosing. Metronomic regimens inhibited mobilization of CEPs (P < 0.05) and led to a decrease in cell-free DNA levels (P < 0.05). Our results suggest that metronomic taxane chemotherapy with dual EGFR and VEGFR inhibition is highly efficacious and should be considered for future clinical trials.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / administration & dosage*
  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Apoptosis / drug effects
  • Cell Growth Processes / drug effects
  • Cell Survival / drug effects
  • DNA, Neoplasm / blood
  • Docetaxel
  • Drug Administration Schedule
  • Drug Resistance, Neoplasm
  • Endothelial Cells / drug effects
  • Endothelial Cells / pathology
  • Female
  • Humans
  • Mice
  • Neovascularization, Pathologic / blood
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / pathology
  • Ovarian Neoplasms / blood
  • Ovarian Neoplasms / blood supply*
  • Ovarian Neoplasms / drug therapy*
  • Purines / administration & dosage*
  • Taxoids / administration & dosage*

Substances

  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • DNA, Neoplasm
  • Purines
  • Taxoids
  • Docetaxel
  • AEE 788