KRN5500: A novel therapeutic agent with in vitro activity against human B-cell chronic lymphocytic leukemia cells mediates cytotoxicity via the intrinsic pathway of apoptosis

John G. Byrd, David M. Lucas, Andrew P. Mone, Joshua B. Kitner, Joseph Drabick, Michael R. Grever

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Therapy of B-cell chronic lymphocytic leukemia (CLL) is currently palliative, emphasizing the need for identification of new therapies for this disease. KRN5500 is a novel agent that has a unique sensitivity pattern in the National Cancer Institute cell line screening panel, suggesting a unique mechanism of action. To assess its in vitro activity in CLL, we exposed peripheral mononuclear cells from CLL patients (n = 11) to varying concentrations of this agent. Viability of the CLL cells was reduced by 50% (LC50) at 4 hours, 24 hours, and 4 days at KRN5500 concentrations of 2.50 μM, 0.276 μM, and 0.139 μM, respectively. KRN5500 induced cellular injury via caspase-dependent apoptosis involving the intrinsic mitochondrial (caspase-9) initiating caspase and caspase-3 effector caspase; however, expression of the antiapoptotic mitochondrial membrane protein Bcl-2 was unaffected. These data demonstrate KRN5500 has significant in vitro activity against human CLL cells, thus providing support for introduction of this agent into clinical trials for patients with CLL.

Original languageEnglish (US)
Pages (from-to)4547-4550
Number of pages4
JournalBlood
Volume101
Issue number11
DOIs
StatePublished - Jun 1 2003

Fingerprint

B-Cell Chronic Lymphocytic Leukemia
Cytotoxicity
Human Activities
Cells
Apoptosis
Caspases
Effector Caspases
Caspase 9
Therapeutics
Caspase 3
Screening
Membrane Proteins
National Cancer Institute (U.S.)
Mitochondrial Proteins
Mitochondrial Membranes
In Vitro Techniques
KRN 5500
Clinical Trials
Cell Line
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

Byrd, John G. ; Lucas, David M. ; Mone, Andrew P. ; Kitner, Joshua B. ; Drabick, Joseph ; Grever, Michael R. / KRN5500 : A novel therapeutic agent with in vitro activity against human B-cell chronic lymphocytic leukemia cells mediates cytotoxicity via the intrinsic pathway of apoptosis. In: Blood. 2003 ; Vol. 101, No. 11. pp. 4547-4550.
@article{7fafec2a0be7439ebe688d24475b07c4,
title = "KRN5500: A novel therapeutic agent with in vitro activity against human B-cell chronic lymphocytic leukemia cells mediates cytotoxicity via the intrinsic pathway of apoptosis",
abstract = "Therapy of B-cell chronic lymphocytic leukemia (CLL) is currently palliative, emphasizing the need for identification of new therapies for this disease. KRN5500 is a novel agent that has a unique sensitivity pattern in the National Cancer Institute cell line screening panel, suggesting a unique mechanism of action. To assess its in vitro activity in CLL, we exposed peripheral mononuclear cells from CLL patients (n = 11) to varying concentrations of this agent. Viability of the CLL cells was reduced by 50{\%} (LC50) at 4 hours, 24 hours, and 4 days at KRN5500 concentrations of 2.50 μM, 0.276 μM, and 0.139 μM, respectively. KRN5500 induced cellular injury via caspase-dependent apoptosis involving the intrinsic mitochondrial (caspase-9) initiating caspase and caspase-3 effector caspase; however, expression of the antiapoptotic mitochondrial membrane protein Bcl-2 was unaffected. These data demonstrate KRN5500 has significant in vitro activity against human CLL cells, thus providing support for introduction of this agent into clinical trials for patients with CLL.",
author = "Byrd, {John G.} and Lucas, {David M.} and Mone, {Andrew P.} and Kitner, {Joshua B.} and Joseph Drabick and Grever, {Michael R.}",
year = "2003",
month = "6",
day = "1",
doi = "10.1182/blood-2002-08-2623",
language = "English (US)",
volume = "101",
pages = "4547--4550",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "11",

}

KRN5500 : A novel therapeutic agent with in vitro activity against human B-cell chronic lymphocytic leukemia cells mediates cytotoxicity via the intrinsic pathway of apoptosis. / Byrd, John G.; Lucas, David M.; Mone, Andrew P.; Kitner, Joshua B.; Drabick, Joseph; Grever, Michael R.

In: Blood, Vol. 101, No. 11, 01.06.2003, p. 4547-4550.

Research output: Contribution to journalArticle

TY - JOUR

T1 - KRN5500

T2 - A novel therapeutic agent with in vitro activity against human B-cell chronic lymphocytic leukemia cells mediates cytotoxicity via the intrinsic pathway of apoptosis

AU - Byrd, John G.

AU - Lucas, David M.

AU - Mone, Andrew P.

AU - Kitner, Joshua B.

AU - Drabick, Joseph

AU - Grever, Michael R.

PY - 2003/6/1

Y1 - 2003/6/1

N2 - Therapy of B-cell chronic lymphocytic leukemia (CLL) is currently palliative, emphasizing the need for identification of new therapies for this disease. KRN5500 is a novel agent that has a unique sensitivity pattern in the National Cancer Institute cell line screening panel, suggesting a unique mechanism of action. To assess its in vitro activity in CLL, we exposed peripheral mononuclear cells from CLL patients (n = 11) to varying concentrations of this agent. Viability of the CLL cells was reduced by 50% (LC50) at 4 hours, 24 hours, and 4 days at KRN5500 concentrations of 2.50 μM, 0.276 μM, and 0.139 μM, respectively. KRN5500 induced cellular injury via caspase-dependent apoptosis involving the intrinsic mitochondrial (caspase-9) initiating caspase and caspase-3 effector caspase; however, expression of the antiapoptotic mitochondrial membrane protein Bcl-2 was unaffected. These data demonstrate KRN5500 has significant in vitro activity against human CLL cells, thus providing support for introduction of this agent into clinical trials for patients with CLL.

AB - Therapy of B-cell chronic lymphocytic leukemia (CLL) is currently palliative, emphasizing the need for identification of new therapies for this disease. KRN5500 is a novel agent that has a unique sensitivity pattern in the National Cancer Institute cell line screening panel, suggesting a unique mechanism of action. To assess its in vitro activity in CLL, we exposed peripheral mononuclear cells from CLL patients (n = 11) to varying concentrations of this agent. Viability of the CLL cells was reduced by 50% (LC50) at 4 hours, 24 hours, and 4 days at KRN5500 concentrations of 2.50 μM, 0.276 μM, and 0.139 μM, respectively. KRN5500 induced cellular injury via caspase-dependent apoptosis involving the intrinsic mitochondrial (caspase-9) initiating caspase and caspase-3 effector caspase; however, expression of the antiapoptotic mitochondrial membrane protein Bcl-2 was unaffected. These data demonstrate KRN5500 has significant in vitro activity against human CLL cells, thus providing support for introduction of this agent into clinical trials for patients with CLL.

UR - http://www.scopus.com/inward/record.url?scp=0037804761&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037804761&partnerID=8YFLogxK

U2 - 10.1182/blood-2002-08-2623

DO - 10.1182/blood-2002-08-2623

M3 - Article

C2 - 12595316

AN - SCOPUS:0037804761

VL - 101

SP - 4547

EP - 4550

JO - Blood

JF - Blood

SN - 0006-4971

IS - 11

ER -