دورية أكاديمية
Anti-angiogenic properties of metronomic topotecan in ovarian carcinoma.
العنوان: | Anti-angiogenic properties of metronomic topotecan in ovarian carcinoma. |
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المؤلفون: | Merritt WM; Department of Gynecologic Oncology, U.T.M.D. Anderson Cancer Center, Houston, TX 77230-1439, USA., Danes CG, Shahzad MM, Lin YG, Kamat AA, Han LY, Spannuth WA, Nick AM, Mangala LS, Stone RL, Kim HS, Gershenson DM, Jaffe RB, Coleman RL, Chandra J, Sood AK |
المصدر: | Cancer biology & therapy [Cancer Biol Ther] 2009 Aug; Vol. 8 (16), pp. 1596-603. Date of Electronic Publication: 2009 Aug 13. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Taylor & Francis Country of Publication: United States NLM ID: 101137842 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1555-8576 (Electronic) Linking ISSN: 15384047 NLM ISO Abbreviation: Cancer Biol Ther Subsets: MEDLINE |
أسماء مطبوعة: | Publication: 2015- : Philadelphia, PA : Taylor & Francis Original Publication: Georgetown, TX : Landes Bioscience, c2002- |
مواضيع طبية MeSH: | Angiogenesis Inhibitors/*administration & dosage , Ovarian Neoplasms/*blood supply , Ovarian Neoplasms/*drug therapy , Topotecan/*administration & dosage, Animals ; Apoptosis/drug effects ; Cell Survival/drug effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Endothelial Cells/drug effects ; Female ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Immunohistochemistry ; In Situ Nick-End Labeling ; Mice ; Mice, Nude ; Neovascularization, Pathologic/drug therapy ; Neovascularization, Pathologic/metabolism ; Neovascularization, Pathologic/pathology ; Ovarian Neoplasms/pathology ; Reverse Transcriptase Polymerase Chain Reaction ; Vascular Endothelial Growth Factor A/metabolism |
مستخلص: | 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-1alpha 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. |
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معلومات مُعتمدة: | HD050128 United States HD NICHD NIH HHS; R01 CA109298 United States CA NCI NIH HHS; R01 CA110793 United States CA NCI NIH HHS; CA110793 United States CA NCI NIH HHS; P50 CA083639 United States CA NCI NIH HHS; K12 HD050128 United States HD NICHD NIH HHS; T32 CA101642 United States CA NCI NIH HHS; CA109298 United States CA NCI NIH HHS |
المشرفين على المادة: | 0 (Angiogenesis Inhibitors) 0 (Hypoxia-Inducible Factor 1, alpha Subunit) 0 (Vascular Endothelial Growth Factor A) 7M7YKX2N15 (Topotecan) |
تواريخ الأحداث: | Date Created: 20090910 Date Completed: 20100212 Latest Revision: 20211020 |
رمز التحديث: | 20240628 |
مُعرف محوري في PubMed: | PMC3916970 |
DOI: | 10.4161/cbt.8.16.9004 |
PMID: | 19738426 |
قاعدة البيانات: | MEDLINE |
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