College of Pharmacy, Department of Experimental and Clinical Pharmacology, University of Minnesota, 308 Harvard ST SE, Minneapolis, MN, USA.
Naunyn Schmiedebergs Arch Pharmacol. 2012 May;385(5):519-25. doi: 10.1007/s00210-011-0719-6. Epub 2012 Jan 17.
Fludarabine, clofarabine, and cladribine are anticancer agents which are analogues of the purine nucleoside adenosine. These agents have been associated with cardiac and neurological toxicities. Because these agents are analogues of adenosine, they may act through adenosine receptors to elicit their toxic effects. The objective of this study was to evaluate the ability of cytotoxic nucleoside analogues to bind and activate adenosine receptor subtypes (A(1), A(2A), A(2B), and A(3)). Radioligand binding studies utilizing Chinese hamster ovary cells, stably transfected with adenosine A(1), A(2A), or A(3) receptor subtype, were used to assess the binding affinities of these compounds, whereas adenylyl cyclase activity was used to assess the binding to A(2B) receptors. Clofarabine and cladribine both bound to the A(2A) receptor with a K (i) of 17 and 15 μM, respectively. Clofarabine was the only adenosine analogue to bind to the A(3) receptor with a K (i) of 10 μM, and none of these compounds bound to the A(2B) receptor. Results show that clofarabine, cladribine, and fludarabine bind to the A(1) receptor. In addition, clofarabine, cladribine, and fludarabine were A(1) agonists (IC(50) 3.1, 30, and 30 μM, respectively). Neither pyrimidine nucleoside analogues gemcitabine nor cytarabine associated with any of the adenosine receptor subtypes (K (i) > 100μM). This is the first report of an interaction between all adenosine receptor subtypes and chemotherapeutic nucleoside analogues commonly used in the treatment of cancer. Therefore, activation of these receptors may be at least one mechanism through which fludarabine-associated toxicity occurs.
氟达拉滨、克拉屈滨和卡培他滨是几种抗癌药物，它们是腺嘌呤核苷的类似物。这些药物与心脏和神经系统毒性相关。由于这些药物是腺嘌呤的类似物，它们可能通过腺苷受体发挥作用，从而产生其毒性作用。本研究的目的是评估细胞毒性核苷类似物与腺苷受体亚型（A1、A2A、A2B 和 A3）结合和激活的能力。利用稳定转染腺苷 A1、A2A 或 A3 受体亚型的中国仓鼠卵巢细胞进行放射性配体结合研究，以评估这些化合物的结合亲和力，而腺苷酸环化酶活性则用于评估与 A2B 受体的结合。克拉屈滨和卡培他滨均与 A2A 受体的 Ki 值分别为 17 和 15μM 结合。克拉屈滨是唯一与 A3 受体结合的腺嘌呤类似物，Ki 值为 10μM，而这些化合物均不与 A2B 受体结合。结果表明，克拉屈滨、卡培他滨和氟达拉滨与 A1 受体结合。此外，克拉屈滨、卡培他滨和氟达拉滨均为 A1 受体激动剂（IC50 分别为 3.1、30 和 30μM）。嘧啶核苷类似物吉西他滨和阿糖胞苷均与任何一种腺苷受体亚型均无关联（Ki 值均>100μM）。这是首次报道所有腺苷受体亚型与癌症治疗中常用的化疗核苷类似物之间的相互作用。因此，这些受体的激活可能是氟达拉滨相关毒性发生的至少一种机制。
