Back to Browse Journals » OncoTargets and Therapy » Volume 4

Systematic in-vitro evaluation of the NCI/NIH Developmental Therapeutics Program Approved Oncology Drug Set for the identification of a candidate drug repertoire for MLL-rearranged leukemia

Authors Hoeksema KA, Jayanthan A, Cooper T, Gore L, Trippett T, Boklan J, Arceci RJ, Narendran A

Published Date September 2011 Volume 2011:4 Pages 149—168

DOI http://dx.doi.org/10.2147/OTT.S21553

Published 5 September 2011

Kimberley A Hoeksema1, Aarthi Jayanthan1, Todd Cooper2, Lia Gore3, Tanya Trippett4, Jessica Boklan6, Robert J Arceci5, Aru Narendran1
1
Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, AB, Canada; 2Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, Emory University, Atlanta, GA, USA; 3Center for Cancer and Blood Disorders, Children's Hospital, University of Colorado Denver, Aurora, CO, USA; 4Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 5Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA; 6Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, USA

Abstract: Despite significant progress made in the overall cure rate, the prognosis for relapsed and refractory malignancies in children remains extremely poor. Hence, there is an urgent need for studies that enable the timely selection of appropriate agents for Phase I clinical studies. The Pediatric Oncology Experimental Therapeutics Investigators' Consortium (POETIC) is systematically evaluating libraries of known and novel compounds for activity against subsets of high-risk pediatric malignancies with defined molecular aberrations for future clinical development. In this report, we describe the in-vitro activity of a diverse panel of approved oncology drugs against MLL-rearranged pediatric leukemia cell lines. Agents in the Approved Oncology Drug Set II (National Cancer Institute/National Institutes of Health Developmental Therapeutics Program) were evaluated by in-vitro cytotoxicity assays in pediatric acute lymphoblastic leukemia and acute myeloid leukemia cell lines with MLL gene rearrangements. Validation studies were carried out with patient leukemia cells in culture. Comparative analysis for toxicity against nonmalignant cells was evaluated in normal bone marrow stromal cells and normal human lymphocytes. Results from this study show that 42 of the 89 agents tested have measurable cytotoxicity against leukemia cells, and among these, 12 were effective against all five MLL-rearranged cell lines (IC50 [half maximal inhibitory concentration] < 1 µM). These 12 agents include cladribine, dactinomycin, daunorubicin, docetaxel, etoposide, gemcitabine, mitomycin C, mitoxantrone, teniposide, topotecan, triethylenemelamine, and vinblastine. We show that the Approved Oncology Drug Set II contains a number of agents with potent antileukemic activity in the tested cell lines. As approved drugs, these agents have been used in clinical settings for many years for other malignancies, thus their toxicity profile, pharmacokinetics, and other properties are readily available. Further evaluation of their use in future clinical trials for pediatric leukemia with MLL abnormalities should be considered.

Keywords: drug screening, therapeutic repertoire

Download Article [PDF] View Full Text [HTML] 

Creative Commons License This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution - Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php

Readers of this article also read:

Consequences of the 118A>G polymorphism in the OPRM1 gene: translation from bench to bedside?

Mura E, Govoni S, Racchi M, Carossa V, Ranzani GN, Allegri M, van Schaik RHN

Journal of Pain Research 2013, 6:331-353

Published Date: 1 May 2013

Changes in cervical cancer screening behavior for women attending Pap Test Week clinics

Poliquin V, Decker K, Altman AD, Lotocki R

International Journal of Women's Health 2013, 5:141-148

Published Date: 8 April 2013

Bioreducible and acid-labile poly(amido amine)s for efficient gene delivery

Yu ZQ, Yan JJ, You YZ, Zhou QH

International Journal of Nanomedicine 2012, 7:5819-5832

Published Date: 23 November 2012

Increased brain radioactivity by intranasal 32P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels

Perez AP, Mundiña-Weilenmann C, Romero EL, Morilla MJ

International Journal of Nanomedicine 2012, 7:1373-1385

Published Date: 12 March 2012

Nanoparticles isolated from blood: a reflection of vesiculability of blood cells during the isolation process

Šuštar V, Bedina-Zavec A, Štukelj R, Frank M, Bobojević G, Janša R, Ogorevc E, Kruljc P, Mam K, Šimunič B, Manček-Keber M, Jerala R, Rozman B, Veranič P, Hägerstrand H, Kralj-Iglič V

International Journal of Nanomedicine 2011, 6:2737-2748

Published Date: 8 November 2011

Critical evaluation of ivabradine for the management of chronic stable angina

Khan W, Borer JS

Research Reports in Clinical Cardiology 2011, 2:87-98

Published Date: 5 September 2011

Role of aliskiren in cardio-renal protection and use in hypertensives with multiple risk factors

Eduardo Pimenta, Suzanne Oparil

Vascular Health and Risk Management 2009, 5:453-463

Published Date: 19 May 2009