Anti-angiogenic properties of metronomic topotecan in ovarian carcinoma
Volume 8, Issue 16
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August 15, 2009
Pages 1596 - 1603http://dx.doi.org/10.4161/cbt.8.16.9004
Authors: William M. Merritt, Christopher G. Danes, Mian M.K. Shahzad, Yvonne G. Lin, Aparna A. Kamat, Liz Y. Han, Whitney A. Spannuth, Alpa M. Nick, Lingegowda S. Mangala, Rebecca L. Stone, Hye Sun Kim, David M. Gershenson, Robert B. Jaffe, Robert L. Coleman, Joya Chandra and Anil K. Sood View affiliations
Purpose: 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.
Experimental Design: 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-1α and VEGF levels were reduced in vitro
(HeyA8 and SKOV3ip1) with topotecan independent of proteasome degradation and topoisomerase I.
Conclusion: Metronomic topotecan may be a novel therapeutic strategy for ovarian carcinoma with significant anti-tumor activity and target modulation of key pro-angiogenic mediators.