"目录号: HY-13768
Cell Cycle/DNA DamageAutophagy-
Topotecan (SKF104864)是拓扑异构酶I抑制剂。
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生物活性
Description
Topotecan is aTopoisomerase Iinhibitor. TheIC50values of Topotecan at 24 h are 2.73±0.25 μM of U251 cells, 2.95±0.23 μM of U87 cells, 5.46±0.41 μM of GSCs-U251 and 5.95±0.24 μM of GSCs-U87.
IC50& Target
Topoisomerase I[1]
In Vitro
Topotecan obviously inhibits proliferation of not only human glioma cells but also glioma stem cells (GSCs) in a dose- and time-dependent manner. According to the IC50values at 24 h, 3 μM of Topotecan is selected as the optimal administration concentration. In addition, Topotecan induces cell cycle arrest in G0/G1 and S phases and promoted apoptosis. Results show that the cell viability is inhibited by Topotecan in a dose-dependent manner. 2, 20 and 40 μM of Topotecan obviously inhibits the cell viability compared with the control groups. The IC50values of Topotecan at 24 h are 2.73±0.25 μM of U251 cells, 2.95±0.23 μM of U87 cells, 5.46±0.41 μM of GSCs-U251 and 5.95±0.24 μM of GSCs-U87. Thus 3 μM of Topotecan is selected as the optimal administration concentration in the subsequent experiments[1].
In Vivo
NUB-7 metastatic model, the animals belonging to all the 4 groups are sacrificed after 14 days treatment. Compared with the control, Low dose metronomic (LDM) Topotecan (TP) and TP+Pazopanib (PZ) liver weights are significantly lower in TP+PZ-treated animals, compared with PZ. Microscopic tumors are visible in the livers of mice belonging to all the groups except TP+PZ confirming the ability of TP+PZ to control liver metastasis. In a previous dose-response study, the daily dose of oral metronomic Topotecan (0.5, 1.0, and 1.5 mg/kg) causes greater reduction in microvascular density compared with weekly maximum-tolerated dose regimen (7.5 and 15 mg/kg) in an ovarian cancer model, but the mice treated with 1.5 mg/kg daily, oral Topotecan show decreased food intake, and a lesser antitumor effect[2].
Clinical Trial
GlaxoSmithKline
Lung Cancer, Small Cell
October 2010
The Hospital for Sick Children-C17 Council
Solid Tumors-Central Nervous System Tumors
March 2015
Phase 1-Phase 2
Michael Vogelbaum, MD, PhD-Infuseon Therapeutics, Inc.-Case Comprehensive Cancer Center
Malignant Glioma-WHO Grade III or IV Recurrent Glioma
December 9, 2014
Early Phase 1
New York University School of Medicine-OSI Pharmaceuticals
Ovarian Cancer
August 2009
Phase 2
Accelerated Community Oncology Research Network-GlaxoSmithKline-Genentech, Inc.
Metastatic Solid Tumor
June 2006
Phase 1
Accelerated Community Oncology Research Network-GlaxoSmithKline
Tumors
November 2006
Phase 1-Phase 2
SCRI Development Innovations, LLC-GlaxoSmithKline
Small Cell Lung Cancer-Carcinoma, Small Cell
February 2006
Phase 2
JSehouli-GlaxoSmithKline-Charite University, Berlin, Germany
Ovarian Cancer
May 2012
Phase 1-Phase 2
GlaxoSmithKline
Lung Cancer, Small Cell
June 2007
Phase 1
Assistance Publique - Hôpitaux de Paris
Ovarian Cancer-Relapses
April 2009
Phase 1
Katy Peters-GlaxoSmithKline-Schering-Plough-Duke University
Glioblastoma-Gliosarcoma-Anaplastic Astrocytoma
April 2004
Phase 1
MEI Pharma, Inc.-SCRI Development Innovations, LLC
Solid Tumors
April 2014
Phase 1-Phase 2
Alliance Foundation Trials, LLC.-Merck Sharp & Dohme Corp.
Small Cell Lung Cancer
December 20, 2017
Phase 2
Michael Vogelbaum, MD, PhD-Infuseon Therapeutics, Inc.-Case Comprehensive Cancer Center
Brain Tumor-High Grade Glioma
July 6, 2015
Early Phase 1
SCRI Development Innovations, LLC-Novartis Pharmaceuticals
Small Cell Lung Cancer-Ovarian Cancer
March 23, 2016
Phase 1-Phase 2
Masonic Cancer Center, University of Minnesota
Lung Cancer
September 2006
Phase 2
Vejle Hospital-Abbott
Ovarian Cancer
November 2012
Phase 1-Phase 2
The Methodist Hospital System
Central Nervous System (CNS) Metastases-Brain Metastases
March 2007
Phase 2
Centre Francois Baclesse-GlaxoSmithKline-Centre d’Etudes et de Recherche pour l’Intensification du Traitement du Diabète
Cancer-Ovarian-Relapse-Chemotherapy
March 2008
Phase 2
New Approaches to Neuroblastoma Therapy Consortium-University of California, San Francisco-Children's Hospital Los Angeles-Lucile Packard Children's Hospital-Children's Hospital Medical Center, Cincinnati-University of Michigan-Seattle Children's Hospital-Dana-Farber Cancer Institute-The Hospital for Sick Children-Children's Healthcare of Atlanta-University of Chicago-Cook Children's Health Care System-Memorial Sloan Kettering Cancer Center-Children's Hospital Colorado
Neuroblastoma
April 2015
Phase 1
Jeffrey N. Bruce-Columbia University
Brain Neoplasms, Primary Malignant
March 2004
Phase 1-Phase 2
Chong Kun Dang Pharmaceutical
Epithelial Ovarian Cancer
January 2011
Phase 2
M.D. Anderson Cancer Center-AstraZeneca-GlaxoSmithKline
Ovarian Cancer-Peritoneal Neoplasms-Fallopian Tube Cancer
September 2004
Phase 1-Phase 2
Yale University-Novartis
Endometrial Cancer
December 2008
Phase 1
Children's Hospital Medical Center, Cincinnati
Retinoblastoma
October 2011
GlaxoSmithKline
Lung Cancer, Small Cell-Solid Tumor Cancer
September 2001
Phase 1
AstraZeneca-KuDOS Pharmaceuticals Limited
Malignant Solid Tumors
July 2007
Phase 1
H. Lee Moffitt Cancer Center and Research Institute-GlaxoSmithKline
Rectal Neoplasms
November 2001
Phase 1
The Methodist Hospital System-Baylor College of Medicine
Central Nervous System Tumors-Lymphoma
March 2005
Gustave Roussy, Cancer Campus, Grand Paris-St. Anna Kinderkrebsforschung-Catholic University of the Sacred Heart-Erasmus Medical Center
Neuroblastoma-Brain Tumors-Solid Tumors
June 2009
Phase 2
GlaxoSmithKline
Malignancy-Solid Tumor Cancer-Cancer
September 2006
Phase 1
Chong Kun Dang Pharmaceutical
Small Cell Lung Cancer
September 2010
Phase 2
Armando Santoro, MD-Istituto Clinico Humanitas
Small Cell Lung Cancer
January 2009
Phase 1-Phase 2
Baylor College of Medicine-GlaxoSmithKline
Neoplastic Meningitis
October 2005
Phase 1
Celgene Corporation
Small Cell Lung Cancer
September 2007
Phase 3
H. Lee Moffitt Cancer Center and Research Institute-United States Department of Defense
Ovarian Cancer
July 2008
Gynecologic Oncology Group-National Cancer Institute (NCI)
Cervical Cancer
February 2005
Phase 2
Weill Medical College of Cornell University
Ovarian Cancer
February 2003
Phase 2
Memorial Sloan Kettering Cancer Center-Genentech, Inc.-Children's Mercy Hospital Kansas City-Penn State University-University of Colorado, Denver-Sidney Kimmel Comprehensive Cancer Center-Phoenix Children's Hospital Center for Cancer & Blood Disorders-Alberta Children's Hospital-MD Anderson Cancer Center Orlando-M.D. Anderson Cancer Center
Neuroblastoma-Sarcoma
December 2011
Phase 2
Pediatric Brain Tumor Consortium-National Cancer Institute (NCI)
Brain and Central Nervous System Tumors-Carcinoma of Unknown Primary-Leukemia-Lymphoma-Unspecified Childhood Solid Tumor, Protocol Specific
August 2005
Phase 1
Michael Vogelbaum, MD, PhD-Infuseon Therapeutics, Inc.-Case Comprehensive Cancer Center
Glioma
July 2017
Early Phase 1
SCRI Development Innovations, LLC-GlaxoSmithKline
Carcinoma, Small Cell
March 2006
Phase 2
GlaxoSmithKline
Advanced Solid Tumors
September 2008
Phase 1
M.D. Anderson Cancer Center-GlaxoSmithKline
Cervical Cancer
August 2016
