title: Anti-angiogenic properties of metronomic topotecan in ovarian carcinoma.
abstract: OBJECTIVE
  Metronomic chemotherapy regimens have shown anti-tumor activity by anti-angiogenic mechanisms, however, the efficacy of metronomic topotecan in ovarian cancer is not known and the focus of the current study.
  
  
  METHODS
  In vivo dose-finding and therapy experiments with oral metronomic topotecan were performed in an orthotopic model of advanced ovarian cancer. Tumor vascularity (MVD: CD31), proliferation (PCNA) and apoptosis (TUNEL) were examined among treatment arms. In vitro experiments including MTT and western blot analysis were performed to identify specific anti-angiogenic mechanisms of topotecan.
  
  
  RESULTS
  Compared to controls, metronomic (0.5, 1.0 and 1.5 mg/kg; daily) and maximum tolerated therapy (MTD; 7.5 and 15 mg/kg; weekly) dosing regimens reduced tumor growth in dose-finding experiments, but significant morbidity and mortality was observed with higher doses. Metronomic and MTD topotecan therapy significantly reduced tumor growth in both HeyA8 and SKOV3ip1 models: 41-74% (metronomic), and 64-86% (MTD dosing) (p < 0.05 for both regiments compared to controls). Compared to controls, the greatest reduction in tumor MVD was noted with metronomic dosing (32-33%; p < 0.01). Tumor cell proliferation was reduced (p < 0.001 vs. controls) and apoptosis increased in all treatment arms (p < 0.01 vs. controls) for both dosing regimens. Endothelial cells demonstrated a significantly higher sensitivity to topotecan using metronomic dosing versus MTD in vitro. Pro-angiogenic regulators Hif-1alpha and VEGF levels were reduced in vitro (HeyA8 and SKOV3ip1) with topotecan independent of proteasome degradation and topoisomerase I.
  
  
  CONCLUSIONS
  Metronomic topotecan may be a novel therapeutic strategy for ovarian carcinoma with significant anti-tumor activity and target modulation of key pro-angiogenic mediators.
authors.affiliation: Department of Gynecologic Oncology, U.T.M.D. Anderson Cancer Center, Houston, TX 77230-1439, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Merritt
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Danes
authors.forename: Mian M K
authors.initials: MM
authors.lastname: Shahzad
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: Lin
authors.forename: Aparna A
authors.initials: AA
authors.lastname: Kamat
authors.forename: Liz Y
authors.initials: LY
authors.lastname: Han
authors.forename: Whitney A
authors.initials: WA
authors.lastname: Spannuth
authors.forename: Alpa M
authors.initials: AM
authors.lastname: Nick
authors.forename: Lingegowda S
authors.initials: LS
authors.lastname: Mangala
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Stone
authors.forename: Hye Sun
authors.initials: HS
authors.lastname: Kim
authors.forename: David M
authors.initials: DM
authors.lastname: Gershenson
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jaffe
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.forename: Joya
authors.initials: J
authors.lastname: Chandra
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019772:Topotecan / Q000008:administration & dosage*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D019772:Topotecan