Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer. Academic Article uri icon

Overview

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.

authors

  • Kamat, Aparna A.
  • Kim, Tae Jin
  • Landen, Charles N
  • Lu, Chunhua
  • Han, Liz Y
  • Lin, Yvonne G
  • Merritt, William M
  • Thaker, Premal H
  • Gershenson, David M
  • Bischoff, Farideh Z
  • Heymach, John V
  • Jaffe, Robert B
  • Coleman, Robert L
  • Sood, Anil K

publication date

  • January 1, 2007

Research

keywords

  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Antineoplastic Combined Chemotherapy Protocols
  • Ovarian Neoplasms
  • Purines
  • Taxoids

Identity

Scopus Document Identifier

  • 33846441659

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-06-3282

PubMed ID

  • 17210709

Additional Document Info

volume

  • 67

issue

  • 1