title: 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 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.affiliation: Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Aparna A
authors.initials: AA
authors.lastname: Kamat
authors.forename: Tae Jin
authors.initials: TJ
authors.lastname: Kim
authors.forename: Charles N
authors.initials: CN
authors.lastname: Landen
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.forename: Liz Y
authors.initials: LY
authors.lastname: Han
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: Lin
authors.forename: William M
authors.initials: WM
authors.lastname: Merritt
authors.forename: Premal H
authors.initials: PH
authors.lastname: Thaker
authors.forename: David M
authors.initials: DM
authors.lastname: Gershenson
authors.forename: Farideh Z
authors.initials: FZ
authors.lastname: Bischoff
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jaffe
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000097:blood; D000077143:Docetaxel; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D010051:Ovarian Neoplasms / Q000097:blood / Q000098:blood supply* / Q000188:drug therapy*; D011687:Purines / Q000008:administration & dosage*; D043823:Taxoids / Q000008:administration & dosage*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D011687:Purines; D043823:Taxoids; D000077143:Docetaxel; C489254:AEE 788