Intracellular pharmacokinetics of 2-chlorodeoxyadenosine in leukemia cells from patients with chronic lymphocytic leukemia.
2-Chlorodeoxyadenosine (2-CdA) is an important agent in the treatment of hairy cell leukemia and chronic lymphocytic leukemia (CLL). Others have reported that levels of 2-CdA phosphates present in human leukemia cells decline rapidly when the cells are in 2-CdA-free medium (Santana et al. J Clin Oncol 1991; 9: 416-422). In the present study, time-courses of 2-CdA loss from CLL cells were biexponential: the mean half-life of the initial phase was 0.30 +/- 0.18 h; the presence of 0.5 microM nitrobenzylthioinosine (NBMPR, a classical inhibitor of nucleoside transport) in the suspending medium, significantly decreased the initial rate of 2-CdA efflux (mean half-life, 0.43 +/- 0.22 h). As a consequence, AUCs (areas under time-course plots) were significantly higher in the NBMPR-treated cells (4.56 +/- 2.01 pmol.h/10(6) cells, n = 19) than in untreated control cells (3.83 +/- 1.74 pmol.h/10(6) cells; n = 19). 2-CdA was the principal efflux product released into the medium from 2-CdA-loaded CLL cells. We conclude that nucleoside transport processes contribute to the efflux of 2-CdA from CLL cells and that NBMPR may be useful as a retentive agent.
Alessi-Severini
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Department of Pharmacology, University of Alberta, Edmonton, Canada.
Gati
W P
WP
Belch
A R
AR
Paterson
A R
AR
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000187:drug effects; D017338:Cladribine / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology
D000970:Antineoplastic Agents; D013868:Thioinosine; D017338:Cladribine; C001789:4-nitrobenzylthioinosine