Biochemical Modulation of Arabinosylcytosine for Therapy of Leukemias
作者:
GandhiVarsha,
EsteyElihu,
KeatingMichael J.,
PlunkettWilliam,
期刊:
Leukemia&Lymphoma
(Taylor Available online 1993)
卷期:
Volume 10,
issue sup1
页码: 109-114
ISSN:1042-8194
年代: 1993
DOI:10.3109/10428199309149122
出版商: Taylor&Francis
关键词: Acute myelogeneous leukemia;arabinosylcytosine;biochemical modulation;chronic lymphocytic leuekmia;fludarabine
数据来源: Taylor
摘要:
Analysis of different ribonucleotide reductase inhibitors to modulate arabinosylcytosine (ara-C) metabolism suggested that pretreatment with arabinosyl-2-fluoroadenine (F-ara-A) significantly potentiated the rate of ara-CTP (5′-triphosphate of ara-C) accumulation in both quiescent lymphocytes (p = 0.046) and in cycling blasts (p = 0.017). In vitro incubations of freshly isolated leukemia cells from patients with chronic (n = 7) or acute (n = 5) leukemias with F-ara-A, increased the rate of ara-CTP accumulation by a median of 1.5 or 1.7-fold, respectively, when subsequently incubated with ara-C.The objective of the present investigation was to test the hypothesis that ara-C can be biochemically modulated during therapy of leukemias. To test the biochemical modulation of ara-C in the clinical setting, we designed two protocols to administer fludarabine (clinical formulation of F-ara-A) and ara-C in a pharmacologically directed sequence for patients with chronic lymphocytic leukemia (CLL) refractory to conventional fludarabine therapy or for patients with acute myelogenous leukemia (AML) in relapse. Comparison of ara-CTP pharmacokinetics demonstrated a significant increase in the area under concentration curve (AUC) of ara-CTP both in CLL (median 1.5-fold) and AML cells (median 1.8-fold) after fludarabine infusion. Analyses of different processes involved in the metabolism of ara-CTP indicated that the increase in AUC was due to potentiation of the rate of ara-CTP accumulation. These studies demonstrate that protocols designed on biochemical and pharmacological rationales modulate ara-C metabolism during therapies.
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