一种治疗儿童急性淋巴细胞白血病的潜在药物

  来自澳大利亚的一个研究团队近日研究发现，一种用于安全治疗成年人白血病的药物或可有效治疗患急性淋巴细胞白血病(ALL)的儿童，相关研究刊登于Blood上。每年大约有150名澳大利亚儿童以及相同数量的成年人被诊断为ALL，其中有15%的个体会患上恶性的ALL亚型（T-ALL），而这种亚型白血病对疗法敏感性非常差，而且很容易复发。
  研究者Richard Lock指出，一种名为PR-104的药物可以帮助动物模型有效抵御恶性的T-ALL；随后研究者在儿科临床前测试程序中检测了PR-104，并且在对恶性癌症患儿的研究中追踪了药物的表现；在10年间研究人员检测了70种药物和其组合方式，最终发现PR-104是最让他们激动的一个，而且该药物完全有潜力进入儿童临床试验中。
  研究者表示，药物PR-104可以有效抵御T-ALL，大约15%的急性淋巴细胞白血病患者都会患T-ALL，同时85%的患者的疾病都会影响B细胞的功能，而PR-104并不能有效抵御B细胞白血病。研究者认为，PR-104是一种有效的药物，其适用于治疗起初可以从常规疗法获益，但最终却发生复发的T-ALL患者；为何T-ALL会对PR-104产生反应，研究者发现，仅在T细胞亚型中会表达高水平的酶类AKR1C3，该酶类可以有效激活PR-104。
  随后研究人员检测了AKR1C3的分子生物学功能，来阐明为何T-ALL细胞可以表达高水平的AKR1C3，如果研究者发现了激活T细胞中AKR1C3酶类的机制，那么或许可以寻找到激活B细胞中该酶类的机制，从而使得B细胞疾病对药物更加敏感；很明显理想情况下我们就可以将药物的功能延伸到包括治疗所有急性淋巴细胞白血病患者在内。
  同时研究者还可以利用PR-104来靶向作用表达高水平AKR1C3的恶性T-ALL患者，目前研究人员正在寻找新的思路来进行临床试验，检测PR-104对于治疗T-ALL儿童患者的作用。（转化医学网360zhyx.com）
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转化医学网推荐的原文摘要：

AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia.
Blood     
Moradi Manesh D1, El-Hoss J1, Evans K1, Richmond J1, Toscan CE1, Bracken LS1, Hedrick A2, Sutton R1, Marshall GM3, Wilson WR4, Kurmasheva RT5, Billups C6, Houghton PJ5, Smith MA7, Carol H1, Lock RB8.
PR-104, a phosphate ester of the nitrogen mustard prodrug PR-104A, has shown evidence of efficacy in adult leukemia clinical trials. Originally designed to target hypoxic cells, PR-104A is independently activated by aldo-keto-reductase 1C3 (AKR1C3). The aim of this study was to test whether AKR1C3 is a predictive biomarker of in vivo PR-104 sensitivity. In a panel of 7 patient-derived pediatric acute lymphoblastic leukemia (ALL) xenografts, PR-104 showed significantly greater efficacy against T-lineage ALL (T-ALL) than B-cell-precursor (BCP)-ALL xenografts. Single agent PR-104 was more efficacious against T-ALL xenografts compared with a combination regimen of vincristine, dexamethasone and L-asparaginase. Expression of AKR1C3 was significantly higher in T-ALL xenografts compared with BCP-ALL, and correlated with PR-104/PR-104A sensitivity in vivo and in vitro. Overexpression of AKR1C3 in a resistant BCP-ALL xenograft resulted in dramatic sensitization to PR-104 in vivo. Testing leukemic blasts from 11 patients confirmed that T-ALL cells were more sensitive than BCP-ALL to PR-104A in vitro, and that sensitivity correlated with AKR1C3 expression. Collectively, these results indicate that PR-104 shows promise as a novel therapy for relapsed/refractory T-ALL, and that AKR1C3 expression could be used as a biomarker to select patients most likely to benefit from such treatment in prospective clinical trials.