دورية أكاديمية
أعرض في EDS

Anti-angiogenic properties of metronomic topotecan in ovarian carcinoma.

التفاصيل البيبلوغرافية
العنوان: Anti-angiogenic properties of metronomic topotecan in ovarian carcinoma.
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
الوصف
تدمد:1555-8576
DOI:10.4161/cbt.8.16.9004