Factors affecting bryostatin 1-enhanced 2-CdA cytotoxicity in resistant B-cell chronic lymphocytic leukemia.
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.
Beck
Frances W J
FW
Wayne State University School of Medicine, 22324 Louis M. Ellman Building, 421 E. Canfield, Detroit, MI 48201, USA. fwbeck@med.wayne.edu
Eilender
Davi S
DS
Dandashi
Mahmoud H
MH
Siddiq
Fauzia
F
Snell
Diane C
DC
Godmere
Michele A
MA
Al-Katib
Ayad M
AM
Mohammad
Ramzi M
RM
D015762:2-Chloroadenosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*; D015720:5'-Nucleotidase / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D054713:Bryostatins; D016923:Cell Death; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000378:metabolism; D003839:Deoxyadenosines / Q000493:pharmacokinetics / Q000633:toxicity*; D003842:Deoxycytidine Kinase / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D018942:Macrolides; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D054713:Bryostatins; D004268:DNA-Binding Proteins; D003839:Deoxyadenosines; D007783:Lactones; D018942:Macrolides; D009687:Nuclear Proteins; D015762:2-Chloroadenosine; C046785:bryostatin 1; D003842:Deoxycytidine Kinase; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D015720:5'-Nucleotidase; D018631:ras Proteins; C055994:2-chloro-3'-deoxyadenosine