Preclinical and Clinical Evaluation of Forodesine in Pediatric and Adult B-Cell Acute Lymphoblastic Leukemia
Preclinical and Clinical Evaluation of Forodesine in Pediatric and Adult B-Cell Acute Lymphoblastic Leukemia
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DOI：
10.1016/j.clml.2013.04.009
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发表时间：
2013-08-01
影响因子：
2.7
通讯作者：
Gandhi, Varsha
中科院分区：
文献类型：
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作者：
Balakrishnan, Kumudha;Ravandi, Farhad;Gandhi, Varsha
福洛地辛最初是为T细胞白血病开发的，对T细胞急性淋巴细胞白血病(T-ALL)有效。目前的研究是为了测试其在B细胞ALL(B-ALL)中的实用性。我们的临床前研究(来自B-ALL儿童患者的淋巴母细胞[n=12])显示了体外活性。临床上活性最低的药物建议该药应与其他已有的或新的ALL药物联合使用。背景：嘌呤核苷磷酸化酶(PNP)缺乏导致T细胞淋巴细胞减少的发现是引入PNP抑制剂治疗T细胞白血病的基础。Forodesine是一种口服生物利用的PNP抑制剂，具有皮摩尔效力。由于T淋巴母细胞和惰性慢性淋巴细胞性白血病(CLL)B细胞固有地具有积累脱氧鸟苷三磷酸(DGTP)的良好药代动力学，福洛地辛在T细胞急性淋巴细胞白血病(1-ALL)和B细胞CLL(B-CLL)患者的临床前和临床环境中显示出良好的活性。然而，福洛地辛在B细胞急性淋巴细胞白血病(B-ALL)中的应用尚不清楚。患者和方法：将10例初发B-ALL患儿的白血病细胞与福尔地辛和脱氧鸟苷(DGuo)共同孵育，检测细胞凋亡、细胞内dGTP积聚、RNA和DNA合成抑制的生物学终点。另外，成人B-ALL患者(n=2)每日静脉滴注80 Rng/m(2)/d，连续5天。分析治疗后的临床反应、毒性、实验室生物标志物包括PNP酶抑制、血浆福洛地辛、dGuo和细胞内dGTP水平。结果：我们的体外研究表明，福地辛处理抑制了新生B-ALL淋巴母细胞的增殖，并诱导了适度的凋亡。DGTP呈时间依赖性积累，RNA和DNA合成受到抑制。在治疗期间，两名患者都没有达到完全缓解(CR)，但两名患者的病情都稳定了几周。两组患者红细胞内PNP酶活性均明显受到抑制，血浆中Forodesine和dGuo积聚，细胞内dGTP积聚。结论：我们的临床前和临床研究表明，福洛地辛对B-ALL有活性。然而，它需要注入dGuo或基于机理原理与现有的化疗药物联合使用。(C)2013 Elsevier Inc.保留所有权利。
Forodesine was originally developed for T-cell leukemias and was effective in T-cell acute lymphoblastic leukemia (T-ALL). The current study was done to test its utility in B-cell ALL (B-ALL). Our preclinical investigations (lymphoblasts from pediatric patients with B-ALL [n = 12]) demonstrate activity in vitro. Minimal activity in the clinic suggests that this agent should be used in combination with other established or novel ALL agents.Background: The discovery that purine nucleoside phosphorylase (PNP) deficiency leads to T-cell lymphopenia was the basis for introducing PNP inhibitors for T-cell leukemias. Forodesine is an orally bioavailable PNP inhibitor with picomolar potency. Because T lymphoblasts and indolent chronic lymphocytic leukemia (CLL) B cells inherently elicit favorable pharmacokinetics to accumulate deoxyguanosine triphosphate (dGTP), forodesine demonstrated promising activity in preclinical and clinical settings for patients with T-cell acute lymphoblastic leukemia (1-ALL) and B-cell CLL (B-CLL). However, the use of forodesine in B-cell ALL (B-ALL) is unknown. Patients and Methods: Leukemic blasts obtained from pediatric patients with de novo B-ALL (n = 10) were incubated with forodesine and deoxyguanosine (dGuo), and the biological end points of apoptosis, intracellular dGTP accumulation, and inhibition of RNA and DNA synthesis were measured. Additionally, adult patients with B-ALL (n = 2) were intravenously infused with 80 rng/m(2)/d daily for 5 days. After therapy, clinical response, toxicity, laboratory biomarkers including PNP enzyme inhibition, and plasma forodesine, dGuo, and intracellular dGTP levels were analyzed. Results: Our in vitro investigations demonstrated that forodesine treatment inhibited proliferation and induced modest apoptosis in de novo B-ALL lymphoblasts. There was time-dependent accumulation of dGTP and inhibition of RNA and DNA synthesis. During therapy, neither patient achieved a complete response (CR), but there was disease stabilization for several weeks in both patients. There was significant maintained inhibition of PNP enzyme in red blood cells, accumulation of forodesine and, dGuo in plasma, and intracellular dGTP accumulation in both patients. Conclusion: Our preclinical and clinical investigations suggest that forodesine has activity in B-ALL. However, it needs to be either infused with dGuo or combined with established chemotherapeutic agents based on mechanistic rationale. (C) 2013 Elsevier Inc. All rights reserved.