Chlorodeoxyadenosine and arabinosylcytosine in patients with acute myelogenous leukemia: Pharmacokinetic, pharmacodynamic, and molecular interactions
Chlorodeoxyadenosine and arabinosylcytosine in patients with acute myelogenous leukemia: Pharmacokinetic, pharmacodynamic, and molecular interactions
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DOI：
10.1182/blood.v87.1.256.bloodjournal871256
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发表时间：
1996-01-01
期刊：
影响因子：
20.3
通讯作者：
Plunkett, W
中科院分区：
文献类型：
--
作者：
Gandhi, V;Estey, E;Plunkett, W
阿拉伯糖胞嘧啶（ara-C）治疗急性髓性白血病（AML）的有效性取决于其活性代谢物ara-C的三磷酸（ara-CTP）的形成。利用生化调节策略增加白血病原细胞中ara-CTP的积累，设计了一种结合2-氯脱氧腺苷（CdA）（一种核糖核苷酸还原酶抑制剂）和ara-C的成人AML临床方案。方案规定在第1天连续2小时输注1 g/m(2) ara-C， 24小时后开始连续输注CdA (12 mg/m(2)/d)，持续5天。在第3、4、5和6天给予相同剂量的ara-C。研究了CdA和ara-C在治疗过程中的药代动力学和药效学相互作用。为了补充这些研究，我们在体外模型系统中进行了ara-C和CdA的三磷酸对人DMA聚合酶α扩展DMA的分子作用。在9名研究患者中的7名循环白血病细胞中，ara-CTP的药代动力学显示，在CdA输注24小时后，ara-CTP的积累率中位数增加了40%。CdA对AML原细胞中ara-CTP积累的体外作用与治疗期间相似，只是增强程度较弱。与单独给药相比，CdA和ara-C联合给药更大程度地抑制了循环母细胞的DMA合成能力，并且DNA合成水平降低一直维持到下一次输注ara-C，内源性脱氧核苷酸水平在输注ara-C后24小时升高。CdA总体上降低了所有dNTPs的浓度。DNA pol α在DNA引物中以高亲和力结合CdATP和ara-CTP，延伸到定义序列的寡核苷酸模板上。人DNA聚合酶α通过加入ara-C单磷酸（ara-CMP）延长了以CdA单磷酸（CdAMP）终止的DNA引物的3'端。CdAMP和ara-CMP的串联掺入几乎完全抑制了DNA引物的延伸。两种类似物的序列插入、核糖核苷酸还原酶的抑制以及CdA输注对ara-CTP的代谢增强，可能是这种联合治疗方案持续抑制循环白血病母细胞DNA合成的原因。(C) 1996年由美国血液病学会出版。
The effectiveness of arabinosylcytosine (ara-C) for the treatment of acute myelogenous leukemia (AML) depends on the formation of its active metabolite, the triphosphate of ara-C (ara-CTP). Using biochemical modulation strategies to increase the accumulation of ara-CTP in leukemia blasts, a clinical protocol was designed combining 2-chlorodeoxyadenosine (CdA), an inhibitor of ribonucleotide reductase, and ara-C for adults with AML. The protocol stipulated an infusion of 1 g/m(2) of ara-C over 2 hours on day 1, a continuous infusion of CdA (12 mg/m(2)/d) begun 24 hours later and continued for 5 days. Identical doses of ara-C were administered on days 3, 4, 5, and 6. Pharmacokinetic and pharmacodynamic interactions between CdA and ara-C during therapy were investigated. To complement these studies, molecular actions of the triphosphate of ara-C and CdA on DMA extension by human DMA polymerase alpha in an in vitro model system was conducted, In the circulating leukemia blasts of 7 of the 9 patients studied, ara-CTP pharmacokinetics showed a median 40% increase in the rate of ara-CTP accumulation after 24 hours of CdA infusion, The ex vivo effect of CdA on accumulation of ara-CTP in AML blasts was similar to that during therapy except that the enhancement was less. The DMA synthetic capacity of the circulating blasts was inhibited to a greater extent by administration of CdA and ara-C in combination than by either one alone, Additionally the lowered level of DNA synthesis was maintained until the next infusion of ara-C, Endogenous levels of deoxynucleotides increased 24 hours after ara-C infusion. Administration of CdA in general lowered the concentrations of all dNTPs. DNA pol alpha incorporated CdATP and ara-CTP with high affinity in a DNA primer extending over an oligonucleotide template of defined sequence. Human DNA polymerase alpha extended DNA primers terminated by CdA monophosphate (CdAMP) at its 3'-end by incorporating ara-C monophosphate (ara-CMP). The tandem incorporation of CdAMP and ara-CMP resulted in nearly complete inhibition of DNA primer extension. The insertion of two analogs in sequence, inhibition of ribonucleotide reductase, and the metabolic potentiation of ara-CTP by CdA infusion may be responsible for sustained inhibition of DNA synthesis in the circulating leukemia blasts during therapy with this combination regimen. (C) 1996 by The American Society of Hematology.