Related Experiment Video

Updated: May 3, 2026

HPLC-based Assay to Monitor Extracellular Nucleotide/Nucleoside Metabolism in Human Chronic Lymphocytic Leukemia Cells
11:29

HPLC-based Assay to Monitor Extracellular Nucleotide/Nucleoside Metabolism in Human Chronic Lymphocytic Leukemia Cells

Published on: July 20, 2016

10.3K

Poly(ADP-ribose) polymerase inhibitor CEP-8983 synergizes with bendamustine in chronic lymphocytic leukemia cells in

Robert L Dilley1, Weijie Poh1, Douglas E Gladstone1

  • 1Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.

Leukemia Research
|January 21, 2014
PubMed

Insights

Chronic lymphocytic leukemia (CLL) shows DNA repair issues. A PARP inhibitor combined with bendamustine demonstrated synergistic cytotoxicity in most CLL samples, suggesting a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Chronic lymphocytic leukemia (CLL) is characterized by DNA repair aberrations and chromosomal instability.
  • The relationship between DNA repair deficiencies and epigenetic modifications, specifically promoter methylation, in CLL requires further investigation.

Purpose of the Study:

  • To investigate the methylation status of nine DNA repair protein promoter regions in CLL.
  • To assess BRCA1 mRNA expression in CLL samples.
  • To evaluate the sensitivity of CLL cells to a novel PARP inhibitor, CEP-8983, alone and in combination with bendamustine, in relation to DNA repair protein alterations.

Main Methods:

  • Bisulfite sequencing was employed to examine the methylation of nine DNA repair protein promoter regions in 26 primary CLL samples.
  • Quantitative PCR was performed on a subset of samples to determine BRCA1 mRNA expression levels.
  • Cytotoxicity assays were conducted to assess the efficacy of CEP-8983 and its combination with bendamustine against CLL cells.

Main Results:

  • No significant promoter hypermethylation was observed for most DNA repair genes, with only minor BRCA1 hypermethylation in two cases.
  • CLL samples consistently exhibited reduced BRCA1 mRNA expression compared to non-malignant lymphocytes, independent of promoter methylation status.
  • CEP-8983 showed single-agent cytotoxicity, and its combination with bendamustine exhibited synergistic cytotoxicity across most CLL samples, including those with 17p deletion and previously treated patients.

Conclusions:

  • Reduced BRCA1 mRNA expression in CLL is a uniform finding, not directly linked to promoter hypermethylation.
  • The combination of a PARP inhibitor and bendamustine demonstrates significant synergistic cytotoxicity in CLL, supporting its potential as a novel therapeutic strategy.
  • This combination therapy warrants further clinical exploration for treating chronic lymphocytic leukemia, including high-risk subgroups.
Keywords:
BendamustineCEP-8983Chronic lymphocytic leukemia (CLL)Poly(ADP-ribose) polymerase (PARP)

More Related Videos

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs10:44

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

12.9K
Potentiation of Anticancer Antibody Efficacy by Antineoplastic Drugs: Detection of Antibody-drug Synergism Using the Combination Index Equation15:04

Potentiation of Anticancer Antibody Efficacy by Antineoplastic Drugs: Detection of Antibody-drug Synergism Using the Combination Index Equation

Published on: January 19, 2019

11.8K

Related Concept Videos

Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
4.9K
Combined Effects of Drugs: Synergism01:27

Combined Effects of Drugs: Synergism

Synergism is a useful mechanism where combining two or more drugs is more effective than each constituent used alone. Such combinations are also called supra-additive interactions. The drugs collectively enhance the final therapeutic effect by acting on different targets. Another advantage is that the low dose of each constituent drug is sufficient to achieve the desired effect. This helps reduce the duration of therapy and lower the adverse effects of these drugs.
Such synergistic combinations...
6.2K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
7.0K
Inhibitors of Bacterial DNA Synthesis01:28

Inhibitors of Bacterial DNA Synthesis

Bacterial pathogens depend on precise and efficient DNA replication to sustain infection. Two type II topoisomerases—DNA gyrase and topoisomerase IV—are critical to this process, as they resolve DNA supercoiling and unlink chromosomes during replication. Fluoroquinolones, synthetic derivatives of quinolones, exploit this mechanism by stabilizing the transient DNA–enzyme cleavage complex, preventing strand religation, and causing lethal double-strand breaks. These...
130
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
81
Inhibitors of Bacterial Protein Synthesis01:25

Inhibitors of Bacterial Protein Synthesis

Aminoglycosides constitute a highly potent class of bactericidal antibiotics that exert their antimicrobial effects by targeting the bacterial ribosome, specifically disrupting protein synthesis. These polycationic molecules consist of amino-modified sugars linked via glycosidic bonds to an aminocyclitol core such as 2-deoxystreptamine or streptamine. Their strong positive charges facilitate tight binding to the negatively charged phosphate backbone of ribosomal RNA (rRNA), primarily at the 16S...
106