CN109045042A - Atm抑制剂在制备抑制急性淋巴细胞性白血病复发的药物中的应用 - Google Patents

Atm抑制剂在制备抑制急性淋巴细胞性白血病复发的药物中的应用 Download PDF

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CN109045042A
CN109045042A CN201811112613.9A CN201811112613A CN109045042A CN 109045042 A CN109045042 A CN 109045042A CN 201811112613 A CN201811112613 A CN 201811112613A CN 109045042 A CN109045042 A CN 109045042A
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lymphatic leukemia
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acute lymphatic
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段才闻
陈亚莉
张梦怡
唐超
周斌兵
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Shanghai Childrens Medical Center Affiliated to Shanghai Jiaotong University School of Medicine
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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Abstract

ATM抑制剂在制备抑制急性淋巴细胞性白血病复发的药物中的应用，它涉及一种分子调控剂在制备抑制急性淋巴细胞性白血病复发的药物中的应用。本发明以ATM抑制剂作为制备抑制急性淋巴细胞性白血病复发药物中的活性成分。本发明根据急性淋巴细胞性白血病治疗后耐药复发的分子机制，建立了全新体系的治疗药物，可实现靶向给药，对降低儿童急性淋巴细胞性白血病化疗后患儿的复发率具有重大意义。

Description

ATM抑制剂在制备抑制急性淋巴细胞性白血病复发的药物中 的应用
技术领域
本发明涉及一种分子调控剂在制备抑制急性淋巴细胞性白血病复发的药物中的应用。
背景技术
急性淋巴细胞性白血病(ALL)是严重危害人类身体健康的重大疾病，是儿童及青少年最常发生的肿瘤。儿童ALL的治疗和愈后健康状况已有显著改善，但仍有15％～20％的患儿会复发，复发后的治愈率不足40％。
发明内容
本发明针对儿童ALL化疗后患儿复发率高、复发患儿治愈率低的问题，提供了一种ATM抑制剂在制备抑制急性淋巴细胞性白血病复发的药物中的应用。
本发明以ATM抑制剂作为制备抑制急性淋巴细胞性白血病复发药物中的活性成分。
ALL细胞移植后浸润并破坏正常的骨髓微环境结构，目前临床上治疗ALL的化疗药物多为抗代谢类药物，包括阿糖胞苷(Ara-C)和嘌呤(如6-MP和6-TG)，其作用机制主要是抑制DNA合成中所需的叶酸、嘌呤、嘧啶及嘧啶核苷的合成途径，从而抑制肿瘤细胞的生存和复制所必需的代谢途径，进而导致肿瘤细胞的死亡。这些抗代谢类化疗药抑制DNA的合成，诱使细胞发生DNA损伤反应(DDR)并分泌细胞因子。化疗后ALL细胞分泌的细胞因子(CCL3、CCL4和GDF15)招募正常的骨髓细胞来重建动态演化微环境(NSM-niche)，借此保护残留的ALL细胞，从而导致儿童ALL化疗后仍有15％～20％的患儿复发，并产生耐药性。
本发明经过实验验证化疗诱导白血病细胞分泌细胞因子是通过ATM介导的DDR信号途径来调节的，并且阻断DDR途径可有效地提高急淋细胞对化疗的敏感性。本发明采用不同于现有抗代谢类药物的ATM抑制剂作为制备抑制急性淋巴细胞性白血病复发药物中的活性成分，根据急性淋巴细胞性白血病治疗后耐药复发的分子机制，建立了全新体系的治疗药物，可实现靶向给药，对降低儿童急性淋巴细胞性白血病化疗后患儿的复发率具有重大意义。
具体实施方式
本发明技术方案不局限于以下所列举具体实施方式，还包括各具体实施方式间的任意组合。
具体实施方式一：本实施方式以ATM抑制剂作为制备抑制急性淋巴细胞性白血病复发药物中的活性成分；特别是制备抑制儿童急性淋巴细胞性白血病化疗后复发药物中的活性成分。
具体实施方式二：本实施方式以ATM抑制剂作为制备抑制急性淋巴细胞性白血病复发药物中的活性成分；所述ATM抑制剂为抑制剂Ku60019、抑制剂KU-55933、抑制剂CP-466722、抑制剂AZD6738或抑制剂ETP46464。
本实施方式中ATM抑制剂Ku60019、KU-55933、CP-466722、AZD6738、ETP46464均购自MCE公司。
实施例1
1、急淋细胞化疗后上调表达细胞因子
采用不同的化疗药物(Ara-C、6MP、MTX、VCR、DNR、CTX和DXMS)处理两种急性淋巴细胞性白血病细胞系(Nalm-6和Reh)，利用RT-PCR等技术检测细胞因子(CCL3，CCL4和GDF-15)的表达水平，发现除DXMS以外，其余的药物都使细胞中CCL3，CCL4和GDF-15的mRNA水平明显上升。
2、确认细胞因子上调是通过ATM介导的DDR信号途径完成的
临床常用化疗药物阿糖胞苷(Ara-C)和嘌呤(6-MP和6-TG)作用机制主要是抑制DNA合成途径，诱使细胞发生DNA损伤反应(DDR)进而导致肿瘤细胞的死亡。本实施例采用不同浓度的Ara-C处理ALL细胞系(Nalm-6和Reh)，提取细胞总蛋白用WesternBlot检测与DDR途径相关的一些蛋白的表达情况，发现这些蛋白的磷酸化水平随着Ara-C浓度的增加而升高。本实施例还利用免疫荧光(IF)检测到在原代ALL细胞中DDR途径相关蛋白的表达也明显上升。数据表明化疗药物处理细胞可以诱导DDR信号通路激活。
采用ShRNA慢病毒包装技术，用Nalm-6和Reh分别构建ATM knockdown(ATM-KD敲除ATM基因的急性淋巴细胞性白血病细胞株)、ATR knockdown(ATR-KD敲除ATR基因的急性淋巴细胞性白血病细胞株)及对照共6种稳定的细胞株，然后用Ara-C处理，用RT-PCR技术来检测CCL3、CCL4和GDF-15的mRNA表达水平，发现在ATM-KD细胞中Ara-C处理后细胞因子的高表达水平有一定程度的逆转，而在ATR-KD细胞中却没有此现象，说明化疗药物处理细胞使DDR信号途径激活，高表达保护性细胞因子是通过ATM介导DDR途径，而不是通过ATR介导DDR途径。
ATM：ataxia telangiectasia-mutated gene(共济失调毛细血管扩张突变基因)。
ATR：ATM-and Rad3-related gene。
3、体外实验
采用ShRNA慢病毒包装技术构建Nalm6-ATM-KD、Nalm6-Ctr(转入空载的Nalm-6细胞)细胞，用的Ara-C(20ng/ml)处理细胞48h，检测细胞的凋亡情况，发现经药物处理后Nalm6-ATM-KD，Nalm6-Ctr细胞的凋亡并没有显著差异。同时采用含抑制剂Ku60019(10uM)的Ara-C(20ng/ml)处理细胞，Nalm6-ATM-KD细胞和Nalm6-Ctr细胞，细胞的凋亡也没有显著差异。表明在体外抑制细胞因子的分泌并没有提高ALL细胞对药物的敏感性。
4、体内实验
实验组A：建立了Nalm6-ATM-KD-GFP异种移植小鼠模型，且移植细胞已经渗透到颅骨的全部血管中，用化疗药物Ara-C(50mg/kg)处理；实验组B：建立Nalm6-Ctr-GFP异种移植小鼠模型，且移植细胞已经渗透到颅骨的全部血管中，用含抑制剂Ku60019(70mg/kg)的化疗药物Ara-C(50mg/kg)处理；实验组C：建立Nalm6-Ctr-GFP异种移植小鼠模型，且移植细胞已经渗透到颅骨的全部血管中，用化疗药物Ara-C(50mg/kg)处理。
治疗后检测发现，A组小鼠和B组小鼠中残留的GFP+ALL细胞比C组小鼠显著的降低；同时检测化疗后小鼠骨髓中残留的GFP+ALL细胞，发现在C组小鼠中GFP+ALL细胞大约有16.4％，而A组小鼠中只有7.2％，B组小鼠中只有5.9％。实验结果表明，阻断了ATM介导的DDR途径小鼠体内ALL细胞提高了对化疗药物Ara-C的敏感性。
GFP：绿色荧光蛋白。

Claims (3)

1.ATM抑制剂在制备抑制急性淋巴细胞性白血病复发的药物中的应用，其特征在于以ATM抑制剂作为制备抑制急性淋巴细胞性白血病复发药物中的活性成分。
2.根据权利要求1所述的应用，其特征在于所述急性淋巴细胞性白血病为儿童急性淋巴细胞性白血病。
3.根据权利要求1所述的应用，其特征在于所述ATM抑制剂为抑制剂Ku60019、抑制剂KU-55933、抑制剂CP-466722、抑制剂AZD6738或抑制剂ETP46464。
CN201811112613.9A 2018-09-21 2018-09-21 Atm抑制剂在制备抑制急性淋巴细胞性白血病复发的药物中的应用 Pending CN109045042A (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110151775A (zh) * 2019-07-01 2019-08-23 中国医科大学附属盛京医院 Hsp90抑制剂17-DMAG在制备抑制儿童急性淋巴细胞白血病药物中的应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1867566A (zh) * 2003-08-13 2006-11-22 库多斯药物有限公司 氨基吡喃酮和它们作为atm抑制剂的用途
WO2017117182A1 (en) * 2015-12-29 2017-07-06 Board Of Regents, The University Of Texas System Inhibition of p38 mapk for the treatment of cancer
CN107889488A (zh) * 2015-04-02 2018-04-06 默克专利股份公司 咪唑酮基喹啉和其作为atm激酶抑制剂的用途
CN108834414A (zh) * 2016-04-07 2018-11-16 阿斯利康(瑞典)有限公司 N，n-二甲基-3-[[5-(3-甲基-2-氧代-1-四氢吡喃-4-基-咪唑并[4，5-c]喹啉-8-基)-2-吡啶基]氧基]丙烷-1-胺氧化物作为atm(共济失调毛细血管扩张症突变的)激酶调节剂用于治疗癌症

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1867566A (zh) * 2003-08-13 2006-11-22 库多斯药物有限公司 氨基吡喃酮和它们作为atm抑制剂的用途
CN107889488A (zh) * 2015-04-02 2018-04-06 默克专利股份公司 咪唑酮基喹啉和其作为atm激酶抑制剂的用途
WO2017117182A1 (en) * 2015-12-29 2017-07-06 Board Of Regents, The University Of Texas System Inhibition of p38 mapk for the treatment of cancer
CN108834414A (zh) * 2016-04-07 2018-11-16 阿斯利康(瑞典)有限公司 N，n-二甲基-3-[[5-(3-甲基-2-氧代-1-四氢吡喃-4-基-咪唑并[4，5-c]喹啉-8-基)-2-吡啶基]氧基]丙烷-1-胺氧化物作为atm(共济失调毛细血管扩张症突变的)激酶调节剂用于治疗癌症

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
A THOMAS ET AL.: "The dual-acting chemotherapeutic agent Alchemix induces", 《ONCOGENE》 *
ANIKA MARIA WEBER ET AL.: "ATM and ATR as therapeutic targets in cancer", 《PHARMACOLOGY & THERAPEUTICS》 *
M MEIER ET AL.: "Relation between genetic variants of the ataxia telangiectasia-mutated (ATM) gene, drug resistance, clinical outcome and predisposition to childhood T-lineage acute lymphoblastic leukaemia", 《LEUKEMIA》 *
MEI HUA JIN ET AL.: "ATM in DNA repair in cancer", 《PHARMACOLOGY & THERAPEUTICS》 *
YA-LI CHEN ET AL.: "Blocking ATM-dependent NF-κB pathway overcomes niche protection and improves chemotherapy response in acute lymphoblastic leukemia", 《LEUKEMIA》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110151775A (zh) * 2019-07-01 2019-08-23 中国医科大学附属盛京医院 Hsp90抑制剂17-DMAG在制备抑制儿童急性淋巴细胞白血病药物中的应用
CN110151775B (zh) * 2019-07-01 2022-06-03 中国医科大学附属盛京医院 17-dmag在制备抑制儿童急性淋巴细胞白血病药物中的应用

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