Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies.
Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies.
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DOI：
10.1126/scitranslmed.3005365
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发表时间：
2013-05-08
影响因子：
17.1
通讯作者：
Portnow J
中科院分区：
文献类型：
--
作者：
Aboody KS;Najbauer J;Metz MZ;D'Apuzzo M;Gutova M;Annala AJ;Synold TW;Couture LA;Blanchard S;Moats RA;Garcia E;Aramburo S;Valenzuela VV;Frank RT;Barish ME;Brown CE;Kim SU;Badie B;Portnow J
高级别神经胶质瘤非常难以治疗，因为它们是侵入性的，因此不能通过手术切除治愈;目前化疗和放疗的毒性限制了可以使用的剂量。神经干细胞（NSC）具有固有的肿瘤嗜性特性，这使得它们能够用作可以选择性地将酶/前药疗法靶向肿瘤的递送载体。我们已经使用了胞嘧啶脱氨酶（CD）表达克隆人NSC系，HB1.F3.CD，在小鼠神经胶质瘤和局部转化肿瘤定位的前药5-氟胞嘧啶活性化疗5-氟尿嘧啶。体外研究证实，神经干细胞具有正常的核型、肿瘤嗜性和CD表达，表明这些细胞在遗传和功能上是稳定的。体内生物分布研究表明，即使在用放射或地塞米松预处理以模拟临床相关辅助治疗的小鼠中，这些NSC也保留了肿瘤向性。我们评估了在非肿瘤小鼠、原位胶质瘤小鼠、免疫活性小鼠和免疫缺陷小鼠中脑内给予神经干细胞后的安全性和毒性。我们没有发现与5-氟胞嘧啶转化为5-氟尿嘧啶相关的毒性差异，脑外没有神经干细胞，也没有神经干细胞引起的病理学或肿瘤发生的组织学证据。接受HB1.F3.CD NSC和5-氟胞嘧啶的小鼠的平均肿瘤体积约为对照小鼠平均体积的三分之一。基于这些结果，我们得出结论，HB1.F3.CD神经干细胞和5-氟胞嘧啶的联合治疗在小鼠中是安全、无毒和有效的。这些数据已经导致批准了第一个异基因神经干细胞介导的酶/前药靶向癌症治疗复发性高级别胶质瘤患者的非人研究。
High-grade gliomas are extremely difficult to treat because they are invasive and therefore are not curable by surgical resection; the toxicity of currently chemo- and radiation therapies limits the doses that can be used. Neural stem cells (NSCs) have inherent tumor-tropic properties that enable their use as delivery vehicles that can target enzyme/prodrug therapy selectively to tumors. We have used a cytosine deaminase (CD)-expressing clonal human NSC line, HB1.F3.CD, to home to gliomas in mice and locally convert the tumor-localized prodrug 5-fluorocytosine to the active chemotherapeutic 5-fluorouracil. In vitro studies confirmed that the NSCs have normal karyotype, tumor tropism, and CD expression, indicating that these cells are genetically and functionally stable. In vivo biodistribution studies demonstrated that these NSCs retained tumor tropism, even in mice pre-treated with radiation or dexamethasone to mimic clinically relevant adjuvant therapies. We evaluated safety and toxicity after intracerebral administration of the NSCs in non-tumor bearing, and in orthotopic glioma-bearing, immunocompetent and immunodeficient mice. We detected no difference in toxicity associated with conversion of 5-fluorocytosine to 5-fluorouracil, no NSCs outside the brain, and no histological evidence of pathology or tumorigenesis attributable to the NSCs. The average tumor volume in mice that received HB1.F3.CD NSCs and 5-fluorocytosine was approximately one-third that of the average volume in control mice. On the basis of these results, we conclude that combination therapy with HB1.F3.CD NSCs and 5-fluorocytosine is safe, non-toxic and effective in mice. These data have led to approval of a first-inhuman study of an allogeneic NSC-mediated enzyme/prodrug targeted cancer therapy in patients with recurrent high-grade glioma.
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DOI：
10.1016/j.bbrc.2004.11.106
发表时间：
2005-01-28
影响因子：
3.1
作者：
Lee, EM;Kim, JY;Ahn, C
通讯作者：
Ahn, C
DOI：
10.1158/1078-0432.ccr-11-1669
发表时间：
2012-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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作者：
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Jensen MC
影响因子：
15.9
作者：
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通讯作者：
Perides, G
DOI：
10.1073/pnas.97.23.12846
发表时间：
2000-11-07
影响因子：
11.1
作者：
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通讯作者：
Snyder, EY
影响因子：
8.3
作者：
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