Sensitivity of chronic lymphocytic leukemia cells to small targeted therapeutic molecules: An in vitro comparative study

Experimental Hematology
Sandra Eketorp SylvanLaszlo Szekely

Abstract

New drugs targeting important cellular signaling pathways are currently being developed for chronic lymphocytic leukemia (CLL). It is therefore of interest to analyze their in vitro killing capacity in manufacturer-independent, comparative experiments. We here report on the sensitivity of CLL cells to a panel of emerging targeted therapeutics using high-throughput screening based on an automated fluorescence digital scanning system. Fresh CLL cells from 42 patients with indolent or progressive CLL were cultured for 72 hours on microtiter plates in a unique primary cell culture medium. Antitumor effects of 31 small therapeutic molecules (and, as controls, 29 cytostatic agents) at equimolar concentration were compared in a fluorescence survival assay. In vitro sensitivity to each drug exhibited considerable interpatient variability. The highest mean direct killing was observed for one survivin inhibitor (YM-155), two bcl-2 inhibitors (ABT-199, ABT-737), and one selective CDK inhibitor (dinaciclib). Their killing capacity was, in contrast to most cytostatic agents, similarly high in refractory versus untreated CLL patients and was significantly higher on cells with the 17p deletion/TP53 mutation than on cells with other cytogeneti...Continue Reading

References

Jun 8, 2004·Bioinformatics·Alok J Saldanha
Feb 25, 2005·The New England Journal of Medicine·Nicholas ChiorazziManlio Ferrarini
Feb 20, 2007·Molecular Cancer Therapeutics·Laszlo MarkaszLaszlo Szekely
Jun 20, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Elise A OlsenMadeleine Duvic
Sep 6, 2007·Leukemia & Lymphoma·Laszlo MarkaszLaszlo Szekely
Jun 4, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Claire BonfilsZuomei Li
Dec 18, 2010·Blood·William Hallett, Bryon Johnson
Feb 15, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Sebastian BöttcherMichael Kneba
Aug 30, 2012·Nature Methods·Caroline A SchneiderKevin W Eliceiri
Oct 10, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Ranjana H AdvaniNathan H Fowler
Jun 21, 2013·The New England Journal of Medicine·John C ByrdSusan O'Brien
Oct 8, 2013·Immunology Letters·Lydia Scarfò, Paolo Ghia
Dec 3, 2013·Leukemia & Lymphoma·Pauline Y HuangRichard I Christopherson
Dec 11, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Elisa ten Hacken, Jan A Burger
Jan 7, 2014·Current Hematologic Malignancy Reports·Julie E Chang, Brad S Kahl
Jan 24, 2014·The New England Journal of Medicine·Richard R FurmanSusan M O'Brien
Feb 1, 2014·Nature Reviews. Drug Discovery·David A Fruman, Christian Rommel

❮ Previous
Next ❯

Citations

Jul 30, 2016·British Journal of Haematology·Yixiang ChenSalvador Macip
Oct 4, 2016·Therapeutic Advances in Hematology·Gilad Itchaki, Jennifer R Brown
Mar 16, 2017·British Journal of Haematology·Elisabeth HöringHeiko van der Kuip

❮ Previous
Next ❯

Related Concepts

Related Feeds

B-Cell Leukemia (Keystone)

B-cell leukemia includes various types of lymphoid leukemia that affect B cells. Here is the latest research on B-cell leukemia.

BCL-2 Family Proteins

BLC-2 family proteins are a group that share the same homologous BH domain. They play many different roles including pro-survival signals, mitochondria-mediated apoptosis and removal or damaged cells. They are often regulated by phosphorylation, affecting their catalytic activity. Here is the latest research on BCL-2 family proteins.