Factors affecting bryostatin 1-enhanced 2-CdA cytotoxicity in resistant B-cell chronic lymphocytic leukemia.

Abstract

Pre-treatment with bryostatin 1 (bryo) has been shown to potentiate the efficacy of (2-chloro-2-deoxyadenosine, cladribine, 2-CdA) in B-cell chronic lymphocytic leukemia (B-CLL) by increasing the ratio of deoxycytidine kinase (dCK) to 5'-nucleotidase (5'-NT) activity. The bryo-induced increase in dCK/5'-NT activity alone has not been a conclusive indication of final clinical outcome. Therefore, we used an ex vivo assay to investigate factors which may affect the bryo-induced enhancement of 2-CdA efficacy in B-CLL patient-derived samples. Bryo-induced increase in dCK/5'-NT was inversely associated with Rai stage CLL (r=-0.86). Increased dCK/5'-NT activity was not correlated with increased efficacy (cell death) or percentage of cellular [8-3H]-2-CdA converted to [8-3H]-2-CdATP ex vivo. Bryo pre-treatment increased the cellular uptake of [8-3H]-2-CdA and incorporation of [8-3H]-2-CdA metabolites into the DNA fraction. Cell death from 2-CdA was inversely correlated with bryo-induced activity of the DNA repair enzyme, DNA-PKcs, (r=-0.77). Thus, the ability of B-CLL to repair damaged DNA may be a more important predictor of the response to bryo/2-CdA and eventual clinical outcome than dCK/5'-NT activity. Additional CLL patients under bryo-2-CdA therapy are needed to verify these important observations.

• Authors: Frances W J Beck, Davi S Eilender, Mahmoud H Dandashi, Fauzia Siddiq, Diane C Snell, Michele A Godmere, Ayad M Al-Katib, Ramzi M Mohammad
• Journal: International journal of molecular medicine (Int J Mol Med) Vol. 14 Issue 1 Pg. 113-9 (Jul 2004) ISSN: 1107-3756 [Print] Greece
• PMID: 15202025 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antimetabolites, Antineoplastic
• Bryostatins
• DNA-Binding Proteins
• Deoxyadenosines
• Lactones
• Macrolides
• Nuclear Proteins
• 2-Chloroadenosine
• bryostatin 1
• Deoxycytidine Kinase
• DNA-Activated Protein Kinase
• PRKDC protein, human
• Protein Serine-Threonine Kinases
• 5'-Nucleotidase
• ras Proteins
• 2-chloro-3'-deoxyadenosine

Topics

• 2-Chloroadenosine (analogs & derivatives, pharmacokinetics, toxicity)
• 5'-Nucleotidase (metabolism)
• Antimetabolites, Antineoplastic (toxicity)
• Bryostatins
• Cell Death
• DNA-Activated Protein Kinase
• DNA-Binding Proteins (metabolism)
• Deoxyadenosines (pharmacokinetics, toxicity)
• Deoxycytidine Kinase (metabolism)
• Drug Resistance, Neoplasm
• Drug Synergism
• Humans
• Lactones (pharmacology)
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, metabolism)
• Macrolides
• Nuclear Proteins
• Protein Serine-Threonine Kinases (metabolism)
• Tumor Cells, Cultured
• ras Proteins (genetics, metabolism)