Metronomic Chemotherapy Enhances the Efficacy of Antivascular Therapy in Ovarian Cancer

Abstract

Metronomic chemotherapy is the frequent administration of low doses of chemotherapeutic agents targeting tumorassociated 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. Growthmodulating 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.

Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma—Mechanistics, review of phase III randomized clinical trials, and regulatory implications

“…This pronounced effect on OS in the bevacizumab + weekly paclitaxel arm is consistent with pre-clinical data in orthotopic models of advanced EOC, where metronomic therapy resulted in suppression of tumor vascularity and reduction in micro-vessel density and enhanced the efficacy of alternate anti-vascular drugs [67]. Three additional studies have explored weekly dose dense chemotherapy with bevacizumab.…”

Chemotherapy Dosing Schedule Influences Drug Resistance Development in Ovarian Cancer

“…Therefore, a focus on the development of drug resistance upon more frequent chemotherapy is warranted not only in endothelial cells, but especially in tumor cells, which are highly heterogeneous and mutagenic (2). The present study addressed this issue by examining the development of drug resistance upon an intermittent, 1Â/wk docetaxel administration schedule, a more frequent, 3Â/wk schedule as used in preclinical metronomic chemotherapy studies (41), and a continuous schedule with no treatment-free intervals.…”

MicroRNA-30c-2* Expressed in Ovarian Cancer Cells Suppresses Growth Factor–Induced Cellular Proliferation and Downregulates the Oncogene BCL9

“…OVCAR-3, SKOV-3, and A549 cells were acquired from American Type Culture Collection and maintained in Cellgro RPMI (Mediatech, Inc.) supplemented with 10% FBS (Sigma). The HeyA8-MDR cell line, a taxane-resistant line generated by the long-term exposure to paclitaxel, was a kind gift from Dr. Isaiah J. Fidler (Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX) and is verified and presented elsewhere (19). HeyA8-MDR cells are maintained in RPMI 1640 medium with 300 ng/mL paclitaxel with 15% FBS.…”