CN102918392A - 尿路表皮癌的检测方法 - Google Patents
尿路表皮癌的检测方法 Download PDFInfo
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Abstract
本发明提供一种尿路表皮癌的检测方法，可以简易且高精度地进行尿路表皮癌的检测。对被检体给药5-氨基乙酰丙酸（ALA）或其衍生物或者它们的盐之后从该被检体中采集尿液，检测所采集的尿液中的细胞内的荧光的存在或者荧光量。
Description
技术领域
本发明涉及尿路表皮癌的检测方法，具体地说是涉及使用了5-氨基乙酰丙酸（ALA）或其衍生物或者它们的盐（以下，有时称为“ALA类”）的尿路表皮癌的检测方法。
背景技术
尿路表皮癌的检测，通常是对脱落在尿液中的细胞进行巴氏染色后在显微镜下观察来进行的，诊断要求熟练，还存在细胞漏看多的问题。检测困难会关系到癌症发现的延误，并且也会关系到病症复发的错过。
另一方面，已知在膀胱癌患者的内视镜手术中，将ALA类注入膀胱内，观察膀胱内的癌细胞发出的荧光来决定切除部位（例如，参照非专利文献1），还知道通过口服给药或者静脉注射ALA类也可以观察膀胱内的荧光（参照专利文献1）。
此外，还提出有一种含有ALA类的肿瘤诊断剂，其目的在于，将该肿瘤诊断剂按照一次每1kg体重给药0.001mg~10g后，通过测量血液、体液、组织、尿、粪便、唾液、汗、髓液、精液或者眼泪等从体内或体外采集到的试料中的原卟啉IX、尿卟啉I、粪卟啉I等来判断所诊断的脑、鼻道、鼻腔、气管、支气管、口腔、咽、食道、胃、乳房、结肠直肠、肺、卵巢、中枢神经系统、肝脏、膀胱、尿道、尿管、胰腺、颈管、腹腔、肛门管或者子宫颈等组织中有无肿瘤（例如，参照专利文献2）。
此外，现已报告有PDD细胞学（PDDcytology）法，该法以荧光尿中的剥离细胞为对象，进行用于检测ALA诱导荧光阳性细胞的荧光细胞学诊断以及流式细胞术，该荧光尿中的剥离细胞通过将从膀胱癌患者回收的尿液残渣溶解于ALA浓度被调整到200μg/mL的无血清培养液中，在37℃下在暗室中保温2个小时后再用于检测的体外培养（In vitro incubation）法或者从膀胱癌患者的膀胱内保持了2个小时后的ALA溶液（1.5gALA/50mL缓冲液）中回收的尿液残渣用于检测的体内培养（in vivo incubation法）法进行了处理（例如，参照非专利文献2）。
现有技术文献
专利文献
专利文献1：WO2009/130893号公报
专利文献2：日本特开2006-124372号公报
非专利文献
非专利文献1：5-アミノレブリン酸(5-ALA)膀胱内注入による蛍光膀胱鏡を用いた膀胱癌の光力学的診断、井上啓史、辛島尚、鎌田雅行、執印太郎、倉林睦、大朏祐治、日本泌尿器科學會雜誌、Vol.97、pp.719-729
非专利文献2:膀胱癌の光力学的診断-蛍光尿細胞診の有用性-、藤本清秀、三宅牧人、中井清、松村善昭、穴井智、平尾佳彦、日本泌尿器科学界雑誌Vol．101、No．2、総会特集号February、2010
如上所述，由于以往的尿路表皮癌的检测要求熟练，而且存在细胞漏看多的问题，所以期待有高精度且简易的新手法。例如，在上述的体外培养（In vitro incubation）法中，需要在暗黑的环境中进行培养的培养装置，而且，在采尿后至结果出来之前，患者需要等待几个小时。在上述体内培养（in vivo incubation）法中，存在着在膀胱内注入ALA溶液时给患者造成了负担，且只能发现膀胱癌的问题。
发明内容
本发明的目的在于提供一种不需要特殊的培养装置，在采尿后立刻就能进行判断等，可以简单且高精度地检测出尿路表皮癌的尿路表皮癌检测方法。
本发明的发明者们，在使用上述ALA类的技术是否也可以应用到尿路表皮癌的细胞诊断的构思下，经过反复努力研究的结果，发现通过检测给药ALA类的被检体的排出到体外的尿液中游离的癌细胞中的荧光，可以查出尿路表皮癌，而且，也发现该ALA类的给药量，为过去的用于决定切除部位的用量的一半以下这样的极少量就足够，并据此完成了本发明。
也就是说，本发明涉及（1）一种尿路表皮癌的检测方法，其特征在于，对被检体给药5-氨基乙酰丙酸（ALA）或其衍生物或者它们的盐之后，从该被检体中采集尿液，检测所采集的尿液中的细胞内的荧光的存在或者荧光量，（2）一种尿路表皮癌的检测方法，其特征在于，对从给药了5-氨基乙酰丙酸（ALA）或其衍生物或者它们的盐后的被检体中采集的尿液进行细胞分离，检测该细胞的荧光的存在或者荧光量，（3）如上述（1）或者（2）所述的尿路表皮癌的检测方法，其特征在于，将5-氨基乙酰丙酸（ALA）或其衍生物或者它们的盐，用ALA盐酸盐换算，按每1kg被检体给药0.05~20mg，（4）如上述（1）或者（2）所述的尿路表皮癌的检测方法，其特征在于，口服给药5-氨基乙酰丙酸（ALA）或其衍生物或者它们的盐，（5）如上述（1）或者（2）所述的尿路表皮癌的检测方法，其特征在于，被检体是尿路表皮癌的疑似患者，（6）一种尿路表皮癌检测剂，用于上述（1）或者（2）所述的方法，其特征在于，含有5-氨基乙酰丙酸（ALA）或其衍生物或者它们的盐。
技术效果
根据本发明，不需要特殊的培养装置，可以在采尿后立刻进行判断，而且还可以在检测到尿液中的细胞内的荧光的时候，判定为存在异常，可以立刻转移到用内视镜诊断或者实施尿道摘除措施。例如，在进行用于确认病症有无复发的内视镜检测之前，进行该尿液中细胞的荧光检测，没有可疑点的话则不必进行内视镜检测。这种方法，不仅很大程度上减轻了患者的负担，而且还减少了国民医疗费。像这样，本发明的方法，不仅是膀胱癌，所有的尿路表皮癌的检测都可以迅速且简易高精度地进行，是该领域的医疗中划时代的方法。而且，即使少量的ALA类的给药量也可以检测出来，有利于减少成本，并且还收到了不会实质性地引起光损伤这样安全方面的效果。
附图说明
图1是给药ALA盐酸盐1g时从尿液中分离出的细胞的荧光显微镜照片。
图2是给药ALA盐酸盐500毫克时从尿液中分离的细胞的荧光显微镜照片。
具体实施方式
作为本发明的尿路表皮癌的检测方法，只要是对被检体给药5-氨基乙酰丙酸或其衍生物或者它们的盐（ALA类）之后，从该被检体中采集尿液，检测所采集到的尿液中的细胞内的荧光（例如，检测荧光的存在或者荧光量）的方法；和对从给药了5-氨基乙酰丙酸或其衍生物或者它们的盐（ALA类）后的被检体中采集的尿液进行细胞分离，检测分离后的细胞中的荧光的方法，则没有特别的限制，对于本发明的尿路表皮癌的检测方法，还包括收集用于检测的数据的方法。此外，作为本发明的尿路表皮癌检测剂只要是在上述本发明的方法中使用的、含有ALA类的尿路表皮癌检测剂，就没有特别的限制。此外，所谓的本发明的检测对象的尿路表皮癌，就是覆盖尿路（肾脏、肾盂、尿管、膀胱、尿道）内腔的转移上皮所发生的恶性肿瘤。此外，本发明的被检体，可以是包括人在内的哺乳动物，具体地说，例示了通过问诊等诊察疑似为尿路表皮癌的人。
ALA类中，作为ALA的衍生物，可以例举出含有ALA的酯基和酰基的衍生物，优选例举了甲酯基和甲酰基，甲酯基和乙酰基，甲酯基和正丙醇基，甲酯基和正丁酰基，乙酯基和甲酰基，乙酯基和乙酰基，乙酯基和正丙醇基，乙酯基和正丁酰基的组合。
ALA类中，作为ALA或者其衍生物的盐，可列举出例如，盐酸盐、氢溴酸盐、氢碘酸盐、磷酸盐、硝酸盐、硫酸盐、醋酸盐、丙酸盐、甲苯磺酸盐、琥珀酸盐、草酸盐、乳酸盐、酒石酸盐、乙醇酸盐、甲磺酸盐、丁酸盐、戊酸盐、柠檬酸盐、延胡索酸盐、马来酸盐、苹果酸盐等酸附加盐，以及钠盐、钾盐、钙盐等金属盐，铵盐、烷基铵盐等。并且，这些盐在使用时被作为溶液使用，其作用与ALA及其衍生物是同样的。
在这些ALA类中，优选为5-氨基乙酰丙酸、或者5-氨基乙酰丙酸的甲酯，乙酯、丙酯、丁酯、戊酯、或者它们的盐酸盐，磷酸盐，硫酸盐。以上的ALA类，既可以形成水合物或者溶剂化物，还可以是任意一种单独或者2种以上适当组合使用。
这些ALA类，可以通过化学合成、微生物生产和酶生产中的任意一种方法制造，在通过微生物或者酶生产的情况下，只有在不特别含有不合适的抑制物时，可以不提炼而直接使用。
作为这些ALA类对被检体的给药量，用ALA盐酸盐换算的话，每1kg被检体，例如优选为0.02~50mg，0.05~20mg，更优选为0.2~10mg，进一步优选为5~10mg。
作为本发明的尿路表皮癌的检测方法中的ALA类的给药方法，可例举出包括舌下给药在内的口服给药，包括点滴在内的静脉注射，使用敷剂等经皮肤给药剂、栓剂、点滴等，从减轻患者负担和增强荧光的灵敏度的观点来讲，优选为口服给药。
包括上述ALA类在内的本发明的尿路表皮癌检测剂，根据需要，也可以含有其他的药效成分如营养剂、载体等其他成分。作为能够与本发明的检测剂相配合的载体，例举了适于摄取的有机或者无机的固体或者液体的、通常为惰性的制药学上可允许的载体材料，具体地说，可以例举例如，结晶性纤维素、明胶、乳糖、淀粉、硬脂酸镁、滑石、植物性及动物性脂肪、油脂、橡胶，聚亚烷基二醇。作为口服给药剂的药剂类型，可以例举出粉末、颗粒、药片、胶囊、口服液、悬浮液等，它们可以适当地使用溶剂、分散剂、增量剂、赋形剂等依照常法制造。并且，在以水溶液调制作为本发明的检测剂时，为了防止ALA类分解，优选在调制时不要让水溶液成为碱性，若是成为碱性的情况下，可通过除氧来防止分解。
本发明的尿路表皮癌的检测方法，给药ALA类（本发明的检测剂）之后采集尿液，用荧光显微镜等检测所采集的尿液中的细胞是否有荧光或荧光量，可以由此来检测尿路表皮癌。此外，还对所采集的尿液添加ALA类，按需要放置所定的时间，通过检测荧光的有无或者荧光量，能够进一步提高其灵敏度。在本发明的尿路表皮癌的检测方法中，根据荧光的存在可以机械性地进行尿路表皮癌的检测（判定），因此即使是不具备医师等特定知识的人也可以容易地进行检测，而且，还可以使用装置进行检测。
尿液的采集，最好是在给药ALA类（本发明的检测剂）之后初次排出的尿液，优选在1个小时以后12个小时以内进行，更优选在2个小时以后12个小时以内进行。此外，尿液的摄取方法，无论是自然排尿还是通过导尿管摄取都可以。
在检测细胞中的荧光时，与通常的细胞诊断一样，从尿液中通过离心分离或者过滤来进行细胞分离。在荧光检测时，用与俗特谱带相当的紫外线照射包括紫-蓝可见光线的激发光，用荧光显微镜等检测所产生的荧光。
实施例
以下，根据实施例对本发明更具体地进行说明，本发明的技术范围并不局限于这些示例。
[实施例1]
将ALA盐酸盐1g溶解到50ml的橙汁中，让某个疑似膀胱癌患者（体重约60kg）内服。约4个小时后采尿，在遮光状态下马上进行离心（3000转/分×15分），对沉淀进行显微镜检测。其结果如图1所示。此外，显微镜是在奥林巴斯（OLYMPUS）的型号为（BX50CCD）的显微镜中安装了奥林巴斯（OLYMPUS）的DP70摄像机后的显微镜，反射镜组均为欧米伽（OMEGA OPTICAL）公司制造的，激发滤色镜（Exciter）为XF1076 400AF30；分光镜（Dichroic）为XF2007 475DCLP，发射滤色镜（Emitter）为XF3090 585ALP,均为标准的荧光显微镜系统。
如图1可知，可看见清晰的癌细胞所发出的PPIX荧光。而且，对该细胞进行通常病理诊断时正确显示出就是癌细胞。
如上所述可知，根据本发明的方法，不用像以往那样进行膀胱内观察，通过检测尿液中的细胞的荧光，就能进行尿路表皮癌检测。口服给药ALA类时，由于ALA类从血液供给到癌患部，所以不仅是癌患部，甚至在从癌患部剥离下来的癌细胞中也蓄积着来自ALA类的PPIX，这是以往所没有想到的，但是实际上，从癌患部剥离下来的尿液中的癌细胞中也蓄积着源于ALA类的PPIX，通过检测尿液中的细胞荧光，收到了可以检测到尿路表皮癌这样意想不到的效果。
[实施例2]
除了将给药量降为实施例1的一半，即500mg以外，其他均与实施例1一样来实施检测法。其结果，可得出图2的图片。另外，对该细胞进行通常的病理诊断时正确显示出就是癌细胞。
产业上利用的可能性
根据本发明的尿路表皮癌的检测方法，减轻了患者的负担，又可以非常迅速且简单地进行正确的检测，此外，由于ALA类的给药量用以往的一半就足够，所以可以节省费用，还可以实质性地排除偶尔出现的呕吐、肝功能障碍、光过敏等危险性，因此可以说是对尿路表皮癌的早期发现做出贡献的划时代的方法。
Claims (6)
1.一种尿路表皮癌的检测方法，其特征在于，对被检体给药5-氨基乙酰丙酸即ALA或其衍生物或者它们的盐之后，从该被检体中采集尿液，检测所采集的尿液中的细胞内的荧光。
2.一种尿路表皮癌的检测方法，其特征在于，对从给药了5-氨基乙酰丙酸即ALA或其衍生物或者它们的盐后的被检体中采集到的尿液进行细胞分离，检测分离出的细胞内的荧光。
3.如权利要求1或2所述的尿路表皮癌的检测方法，其特征在于，将5-氨基乙酰丙酸或其衍生物或者它们的盐，用ALA盐酸盐换算，按每1kg被检体给药0.05~20mg。
4.如权利要求1或2所述的尿路表皮癌的检测方法，其特征在于，口服给药5-氨基乙酰丙酸或其衍生物或者它们的盐。
5.如权利要求1或2所述的尿路表皮癌的检测方法，其特征在于，被检体为尿路表皮癌的疑似患者。
6.一种尿路表皮癌检测剂，用于权利要求1或2所述的方法，其特征在于，含有5-氨基乙酰丙酸或其衍生物或者它们的盐。
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| CN101031324A (zh) * | 2004-09-29 | 2007-09-05 | 克斯莫石油株式会社 | 肿瘤诊断剂 |
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| WO2009130839A1 (ja) * | 2008-04-25 | 2009-10-29 | パナソニック株式会社 | 光学デバイスとこれを備えた電子機器 |
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| CN106908425A (zh) | 2010-06-21 | 2017-06-30 | 思佰益药业股份有限公司 | 尿路表皮癌的检测方法 |
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| JPH04500770A (ja) * | 1989-07-28 | 1992-02-13 | クイーンズ ユニバーシティ アット キングストン | 光化学療法による悪性および非悪性病変の検出および治療方法 |
| CN101031324A (zh) * | 2004-09-29 | 2007-09-05 | 克斯莫石油株式会社 | 肿瘤诊断剂 |
| WO2009130893A1 (ja) * | 2008-04-22 | 2009-10-29 | Ｓｂｉアラプロモ株式会社 | 膀胱がん検出方法 |
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|---|---|
| US20130095520A1 (en) | 2013-04-18 |
| CN106908425A (zh) | 2017-06-30 |
| JP5476613B2 (ja) | 2014-04-23 |
| WO2011161933A1 (ja) | 2011-12-29 |
| EP2584356B9 (en) | 2016-02-17 |
| JPWO2011161933A1 (ja) | 2013-08-19 |
| EP2584356B1 (en) | 2015-09-16 |
| EP2584356A1 (en) | 2013-04-24 |
| EP2584356A4 (en) | 2013-11-27 |
| US9772286B2 (en) | 2017-09-26 |
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