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Blood：NUDT15基因型指导MP剂量个体化可在不影响治疗效果的前体下降低其相关毒副作用

2018-03-26 MedSci MedSci原创

巯基嘌呤急性淋巴细胞白血病NUDT15DNA-GT
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巯基嘌呤类药物是高效的抗白血病药物，但也存在剂量限制性毒性。近期Rina Nishii等人研究证实遗传性NUDT15缺陷是一种新型的巯基嘌呤毒性的遗传因素，并提供强有力的理论支持以NUDT15-指导的剂量个体化来预防该药物的副作用。研究人员利用CRISPR-Case9基因编辑技术，建立Nudt15-/-小鼠模型，来评估该策略用于活体时的有效性。与野生型小鼠相比，交叉MP剂量时，Nudt15-/-小

巯基嘌呤类药物是高效的抗白血病药物，但也存在剂量限制性毒性。近期Rina Nishii等人研究证实遗传性NUDT15缺陷是一种新型的巯基嘌呤毒性的遗传因素，并提供强有力的理论支持以NUDT15-指导的剂量个体化来预防该药物的副作用。

研究人员利用CRISPR-Case9基因编辑技术，建立Nudt15-/-小鼠模型，来评估该策略用于活体时的有效性。与野生型小鼠相比，交叉MP剂量时，Nudt15-/-小鼠发生重度白细胞减少、体重迅速下降、早期毒性死亡和骨髓细胞减少更明显。在MP剂量依赖性模式中，Nudt15-/-小鼠的巯基嘌呤活性代谢产物过度积累（如DNA-TG），似是毒性增加的原因。MP剂量减少，可有效减少Nudt15-/-小鼠产生的DNA-TG量，大幅度的减轻Nudt15缺乏介导的毒性。

在95位急性淋巴细胞白血病患儿中，校正MP剂量也可直接改变DNA-TG水平，其效应与NUDT15缺乏的程度成正比。此外，研究人员利用携带整合性Nudt15基因型的白血病小鼠发现，与暴露在标准剂量下的野生型小鼠相比，MP剂量减少时，对于Nudt15-/-小鼠，仍具有治疗效果。

综上所述，本研究证实NUDT15基因型指导MP剂量个体化可在不影响治疗效果的前体下，预先减少毒性。

原始出处：

Rina Nishii，et al.Preclinical evaluation of NUDT15-guided thiopurine therapy and its effects on toxicity and anti-leukemic efficacy.Blood  2018  ：blood-2017-11-815506；  doi： https：//doi.org/10.1182/blood-2017-11-815506

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    2018-04-27 liuyong2980

    #毒副作用#

    0

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    2018-10-22 showtest

    #副作用#

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    2018-05-08 jxrzshh

    #治疗效果#

    0

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    2018-10-30 kzlchina

    #基因型#

    0

  5. [GetPortalCommentsPageByObjectIdResponse(id=2078791, encodeId=ef1d20e87919f, content=<a href='/topic/show?id=6dbc635680d' target=_blank style='color:#2F92EE;'>#毒副作用#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=93, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=63568, encryptionId=6dbc635680d, topicName=毒副作用)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=de89102, createdName=liuyong2980, createdTime=Fri Apr 27 11:24:00 CST 2018, time=2018-04-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1824281, encodeId=1039182428183, content=<a href='/topic/show?id=56a932e7800' target=_blank style='color:#2F92EE;'>#副作用#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=32778, encryptionId=56a932e7800, topicName=副作用)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=8f0715, createdName=showtest, createdTime=Mon Oct 22 22:24:00 CST 2018, time=2018-10-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1894045, encodeId=157c18940458b, content=<a href='/topic/show?id=5e456463eee' target=_blank style='color:#2F92EE;'>#治疗效果#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=88, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=64637, encryptionId=5e456463eee, topicName=治疗效果)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=373a131, createdName=jxrzshh, createdTime=Tue May 08 23:24:00 CST 2018, time=2018-05-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1890844, encodeId=edb51890844ed, content=<a href='/topic/show?id=742341e1782' target=_blank style='color:#2F92EE;'>#基因型#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=41717, encryptionId=742341e1782, topicName=基因型)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f984116, createdName=kzlchina, createdTime=Tue Oct 30 14:24:00 CST 2018, time=2018-10-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1435374, encodeId=df2314353e42f, content=<a href='/topic/show?id=9a5c212e88f' target=_blank style='color:#2F92EE;'>#个体化#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=63, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=21278, encryptionId=9a5c212e88f, topicName=个体化)], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyheQLjPSX3OUs5GmkyBlcCOwTPIeq3why9NGibxxUqYo6hcx8qZLHZFgNPnBK1yzWeOFpyg2OnWOt0/0, createdBy=fa4716, createdName=zhouqu_8, createdTime=Wed Mar 28 12:24:00 CST 2018, time=2018-03-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1031704, encodeId=47961031e04f1, content=谢谢梅斯提供这么好的信息，学到很多, beContent=null, objectType=article, channel=null, level=null, likeNumber=93, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=内科新手, createdTime=Tue Mar 27 00:24:00 CST 2018, time=2018-03-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=299967, encodeId=39ce29996e8d, content=学习了.谢谢分享., beContent=null, objectType=article, channel=null, level=null, likeNumber=92, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/xkvRjYnJzzRJ2R0y7VhicibvkjPWHjIMmu4ZpKnE9cWAu4lVicS3uDUCfF4M4JWvrkrYfpb2KehPV0Ee29tPqyPEebBUibiaKhnvD/0, createdBy=f8412001184, createdName=惠映实验室, createdTime=Mon Mar 26 21:29:41 CST 2018, time=2018-03-26, status=1, ipAttribution=)]
    2018-03-28 zhouqu_8

    #个体化#

    0

  6. [GetPortalCommentsPageByObjectIdResponse(id=2078791, encodeId=ef1d20e87919f, content=<a href='/topic/show?id=6dbc635680d' target=_blank style='color:#2F92EE;'>#毒副作用#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=93, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=63568, encryptionId=6dbc635680d, topicName=毒副作用)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=de89102, createdName=liuyong2980, createdTime=Fri Apr 27 11:24:00 CST 2018, time=2018-04-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1824281, encodeId=1039182428183, content=<a href='/topic/show?id=56a932e7800' target=_blank style='color:#2F92EE;'>#副作用#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=32778, encryptionId=56a932e7800, topicName=副作用)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=8f0715, createdName=showtest, createdTime=Mon Oct 22 22:24:00 CST 2018, time=2018-10-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1894045, encodeId=157c18940458b, content=<a href='/topic/show?id=5e456463eee' target=_blank style='color:#2F92EE;'>#治疗效果#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=88, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=64637, encryptionId=5e456463eee, topicName=治疗效果)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=373a131, createdName=jxrzshh, createdTime=Tue May 08 23:24:00 CST 2018, time=2018-05-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1890844, encodeId=edb51890844ed, content=<a href='/topic/show?id=742341e1782' target=_blank style='color:#2F92EE;'>#基因型#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=41717, encryptionId=742341e1782, topicName=基因型)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f984116, createdName=kzlchina, createdTime=Tue Oct 30 14:24:00 CST 2018, time=2018-10-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1435374, encodeId=df2314353e42f, content=<a href='/topic/show?id=9a5c212e88f' target=_blank style='color:#2F92EE;'>#个体化#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=63, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=21278, encryptionId=9a5c212e88f, topicName=个体化)], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyheQLjPSX3OUs5GmkyBlcCOwTPIeq3why9NGibxxUqYo6hcx8qZLHZFgNPnBK1yzWeOFpyg2OnWOt0/0, createdBy=fa4716, createdName=zhouqu_8, createdTime=Wed Mar 28 12:24:00 CST 2018, time=2018-03-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1031704, encodeId=47961031e04f1, content=谢谢梅斯提供这么好的信息，学到很多, beContent=null, objectType=article, channel=null, level=null, likeNumber=93, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=内科新手, createdTime=Tue Mar 27 00:24:00 CST 2018, time=2018-03-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=299967, encodeId=39ce29996e8d, content=学习了.谢谢分享., beContent=null, objectType=article, channel=null, level=null, likeNumber=92, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/xkvRjYnJzzRJ2R0y7VhicibvkjPWHjIMmu4ZpKnE9cWAu4lVicS3uDUCfF4M4JWvrkrYfpb2KehPV0Ee29tPqyPEebBUibiaKhnvD/0, createdBy=f8412001184, createdName=惠映实验室, createdTime=Mon Mar 26 21:29:41 CST 2018, time=2018-03-26, status=1, ipAttribution=)]
    2018-03-27 内科新手

    谢谢梅斯提供这么好的信息，学到很多

    0

  7. [GetPortalCommentsPageByObjectIdResponse(id=2078791, encodeId=ef1d20e87919f, content=<a href='/topic/show?id=6dbc635680d' target=_blank style='color:#2F92EE;'>#毒副作用#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=93, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=63568, encryptionId=6dbc635680d, topicName=毒副作用)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=de89102, createdName=liuyong2980, createdTime=Fri Apr 27 11:24:00 CST 2018, time=2018-04-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1824281, encodeId=1039182428183, content=<a href='/topic/show?id=56a932e7800' target=_blank style='color:#2F92EE;'>#副作用#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=32778, encryptionId=56a932e7800, topicName=副作用)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=8f0715, createdName=showtest, createdTime=Mon Oct 22 22:24:00 CST 2018, time=2018-10-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1894045, encodeId=157c18940458b, content=<a href='/topic/show?id=5e456463eee' target=_blank style='color:#2F92EE;'>#治疗效果#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=88, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=64637, encryptionId=5e456463eee, topicName=治疗效果)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=373a131, createdName=jxrzshh, createdTime=Tue May 08 23:24:00 CST 2018, time=2018-05-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1890844, encodeId=edb51890844ed, content=<a href='/topic/show?id=742341e1782' target=_blank style='color:#2F92EE;'>#基因型#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=41717, encryptionId=742341e1782, topicName=基因型)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f984116, createdName=kzlchina, createdTime=Tue Oct 30 14:24:00 CST 2018, time=2018-10-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1435374, encodeId=df2314353e42f, content=<a href='/topic/show?id=9a5c212e88f' target=_blank style='color:#2F92EE;'>#个体化#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=63, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=21278, encryptionId=9a5c212e88f, topicName=个体化)], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyheQLjPSX3OUs5GmkyBlcCOwTPIeq3why9NGibxxUqYo6hcx8qZLHZFgNPnBK1yzWeOFpyg2OnWOt0/0, createdBy=fa4716, createdName=zhouqu_8, createdTime=Wed Mar 28 12:24:00 CST 2018, time=2018-03-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1031704, encodeId=47961031e04f1, content=谢谢梅斯提供这么好的信息，学到很多, beContent=null, objectType=article, channel=null, level=null, likeNumber=93, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=内科新手, createdTime=Tue Mar 27 00:24:00 CST 2018, time=2018-03-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=299967, encodeId=39ce29996e8d, content=学习了.谢谢分享., beContent=null, objectType=article, channel=null, level=null, likeNumber=92, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/xkvRjYnJzzRJ2R0y7VhicibvkjPWHjIMmu4ZpKnE9cWAu4lVicS3uDUCfF4M4JWvrkrYfpb2KehPV0Ee29tPqyPEebBUibiaKhnvD/0, createdBy=f8412001184, createdName=惠映实验室, createdTime=Mon Mar 26 21:29:41 CST 2018, time=2018-03-26, status=1, ipAttribution=)]
    2018-03-26 惠映实验室

    学习了.谢谢分享.

    0

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