Anti-angiogenic properties of metronomic topotecan in ovarian carcinoma.
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.
Merritt
William M
WM
Department of Gynecologic Oncology, U.T.M.D. Anderson Cancer Center, Houston, TX 77230-1439, USA.
Danes
Christopher G
CG
Shahzad
Mian M K
MM
Lin
Yvonne G
YG
Kamat
Aparna A
AA
Han
Liz Y
LY
Spannuth
Whitney A
WA
Nick
Alpa M
AM
Mangala
Lingegowda S
LS
Stone
Rebecca L
RL
Kim
Hye Sun
HS
Gershenson
David M
DM
Jaffe
Robert B
RB
Coleman
Robert L
RL
Chandra
Joya
J
Sood
Anil K
AK
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
D020533:Angiogenesis Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D019772:Topotecan