CN117881404A - 用于抑制癌的浸润的药物组合物及抑制癌的浸润的方法 - Google Patents
用于抑制癌的浸润的药物组合物及抑制癌的浸润的方法 Download PDFInfo
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Abstract
本发明提供包含抑制CHST15基因表达的siRNA的用于抑制癌的浸润的药物组合物、及抑制癌的浸润的方法。
Description
技术领域
本发明涉及以CHST15 siRNA为有效成分的、用于抑制实体癌和血液癌的进展的药物组合物。仅通过原发病灶的增殖无法说明癌所致的死亡，认为大多数癌死亡的主要原因在于浸润、转移，进而由其引起的复发。浸润是癌的恶性度的最主要特征，并且成为对癌治疗效果的有效性的极大障碍(文献1～8)。如果能够使癌停留在原发病灶中，则免疫检查点抑制剂带来的抗肿瘤淋巴细胞的效果也变得容易发挥，此外，在实体癌中也能够通过外科切除而使其得到根治。但是，实际上抑制癌的浸润、使癌停留在原发病灶这样的治疗尚未得到临床应用。
背景技术
癌药物疗法中的抗癌剂作用于DNA的复制、合成、蛋白合成、或者代谢路径等，通过抑制细胞的增殖、分裂而发挥杀细胞效果的治疗药是一直以来的主流。即，由于对活跃地进行增殖、分裂的正常细胞也显示细胞毒性，因此副作用几乎是必然发生的。由于分子靶向药的出现，可以更选择性地作用于癌细胞，虽然带来了治疗效果的提高，但很难说包括副作用在内都得到了充分的成果，大部分患者对一次化疗的反应减弱，发展到二次或三次化疗(文献1～8)。在期待与以往的细胞增殖-分裂抑制不同作用机制的抗癌剂的过程中，出现了通过患者自身所具有的抗肿瘤淋巴细胞的效果而具有杀伤癌细胞的作用的免疫检查点抑制剂，确认了治疗效果的进一步提高。但是，其效果仍然是有限的，需要进一步利用抗癌剂进行集合各学科的/综合性的治疗。
仅通过原发病灶的增殖无法说明癌所致的死亡，认为大多数癌死亡的主要原因在于浸润、转移，进而由其引起的复发。浸润是癌的恶性度的最主要特征，并且成为对癌治疗效果的有效性的极大障碍(文献1-8)。如果能够使癌停留在原发病灶中，则免疫检查点抑制剂带来的抗肿瘤淋巴细胞的效果也变得容易发挥，此外，在实体癌中也能够通过外科切除而使其得到根治。但是，实际上抑制癌的浸润、使癌停留在原发病灶这样的治疗尚未得到临床应用。
属于糖硫酸转移酶的CHST15(Carbohydrate sulfotransferase 15，磺基转移酶15)是将硫酸基转移到硫酸软骨素A(CS-A)的GalNAc(4SO4)残基的6位，合成高度硫酸化的硫酸软骨素E(CS-E)的II型的跨膜型高尔基蛋白(文献9、10)。已知在正常的人组织中几乎不表达，但在炎症、纤维化、癌中其表达增强。利用CHST15 siRNA抑制mRNA的表达时，CS-E的合成受到抑制，纤维化受到抑制，这在心纤维化疾病、肺纤维化疾病、以及消化道的纤维化疾病中有所报告(文献11～16)。就癌而言，报告了其在体外抑制人胰腺癌细胞株Panc-1的细胞增殖，并且在Panc-1皮下移植小鼠模型中也抑制肿瘤尺寸的增大，已知由癌细胞增殖抑制带来的抗肿瘤效果(文献17)。
现有技术文献
非专利文献
非专利文献1：Siegel RL,Miller KD,Fuchs HE,Jemal A.Cancer Statistics,2021.CA Cancer J Clin 71:7-33,2021.
非专利文献2：Falzone L,Salomone S,Libra M.Evolution of CancerPharmacological Treatments at the Turn of the Third Millennium.FrontPharmacol 9:1300,2018.
非专利文献3：Murciano-Goroff YR,Warner AB,Wolchok JD.The future ofcancer immunotherapy:microenvironment-targeting combinations.Cell Res 6:507-519,2020.
非专利文献4：Hegde PS,Chen DS.Top 10Challenges in CancerImmunotherapy.Immunity 52:17-35,2020.
非专利文献5：Waldman AD,Fritz JM,Lenardo MJ.A guide to cancerimmunotherapy:from T cell basic science to clinical practice.Nat Rev Immunol11:651-668,2020.
非专利文献6：Murciano-Goroff YR,Taylor BS,Hyman DM,Schram AM.Toward aMore Precise Future for Oncology.Cancer Cell 37:431-442,2020.
非专利文献7：Fisher G,Rittie L.Restoration of the basement membraneafter wounding:a hallmark of young human skin alters with aging.J Cell CommunSignal 12:401-411,2018.
非专利文献8：Martinez M,Moon EK.CAR T Cells for Solid Tumors:NewStrategies for Finding,Infiltrating,and Surviving in the TumorMicroenvironment.Front Immunol 10:128,2019.
非专利文献9：Ohtake S,Kondo S,Morisaki T,et al.Expression ofsulfotransferase involved in the biosynthesis of chondroitin sulfate E in thebone marrow derived mast cells.Biochemical Biophysica Acta 1780:687-95,2008.
非专利文献10：Habuchi O,Moroi R,Ohtake S,et al.Enzymatic synthesis ofchondroitin sulfate E by N-acetylgalactosamine 4-sulfate 6-O-sulfotransferasepurified from squid cartilage.Anal Biochem 310:129-36,2002.
非专利文献11：Kai Y,Tomoda K,Yoneyama H et al.Silencing ofcarbohydrate sulfotransferase 15hinders murine pulmonary fibrosisdevelopment.Mol Ther Nucleic Acid 6:163-172,2017.
非专利文献12：Sato H,Sagara S,Nakajima S,et al.Prevention ofesophageal stricture after endoscopic submucosal dissection,using siRNA-basedsilencing of carbohydrate sulfotransferase 15in pig.Endoscopy 49:491-497,2017.
非专利文献13：Suzuki K,Yokoyama J,Kawauchi Y,et al.Phase 1clinicalstudy of siRNA targeting carbohydrate sulfotransferase 15in Crohn’s diseasepatients with active mucosal lesions.J Crohns Colitis 11:221-228,2017.
非专利文献14：Suzuki K,Arumugam S,Yokoyama J,et al.Pivotal role ofcarbohydrate sulfotransferase 15in fibrosis and mucosal healing in mousecolitis.PLoS One 11:e0158977,2016.
非专利文献15：Watanabe K,Arumugam S,Sreedhar R,et al.Small interferingRNA therapy against carbohydrate sulfotransferase 15inhibits cardiacremodeling in rats with dilated cardiomyopathy.Cell Signal 27:1517-1524,2015.
非专利文献16：Yamada S and Sugahara K.Potential therapeuticApplication of chondroitin sulfate/dermatan sulfate.Current Drug DiscoveryTechnologies 5:289-301,2008.
非专利文献17：Takakura K,Shibazaki Y,Yoneyama H,et al.Inhibition ofCell Proliferation and Growth of Pancreatic Cancer by Silencing ofCarbohydrate Sulfotransferase 15In Vitro and in a Xenograft Model.PLoS One10:e0142981,2015.
发明内容
发明所要解决的课题
本发明的课题在于提供一种药物组合物(以下也称为癌的浸润抑制剂)，其用于在实体癌和血液癌中抑制癌细胞的浸润，使其不进展而停留。
用于解决课题的手段
本发明者们使用各种人癌细胞株研究了抑制CHST15基因表达的siRNA的效果，结果发现，其具有与根据现有技术预测的癌细胞的增殖抑制效果完全不同性质的、抑制癌细胞的进展并使其停留在局部的效果。另外，还发现其效果不仅对实体癌细胞而且对血液癌细胞也具有。通过以与增殖对照不同的机制使癌细胞停留在局部，期待应用于能够减轻以往的基于增殖-分裂抑制机制的抗癌剂、分子靶向药物的副作用的并用疗法、与基于抗肿瘤免疫机制的免疫检查点抑制剂的并用疗法、以及提高基于浸润-转移的抑制的外科手术、放射线疗法的效果等集合各学科的癌的治疗、复发预防。
更具体而言，本发明提供以下的[1]～[8]。
[1]一种用于抑制癌的浸润的药物组合物，其包含抑制CHST15基因表达的siRNA。
[2]根据[1]所述的药物组合物，其用于抑制癌的转移。
[3]根据[1]或[2]所述的药物组合物，其中，癌为实体癌或血液癌。
[4]根据[1]～[3]中任一项所述的药物组合物，其特征在于，通过使癌停留来抑制进展。
[5]一种抑制癌的浸润的方法，其包含给药抑制CHST15基因表达的siRNA的工序。
[6]一种抑制CHST15基因表达的siRNA，其是在抑制癌的浸润的方法中使用的。
[7]抑制CHST15基因表达的siRNA在制造癌的浸润抑制剂中的用途。
[8]一种癌的浸润抑制剂的制造方法，其包含使用抑制CHST15基因表达的siRNA的工序。
发明效果
癌细胞的进展有原发病灶中的增殖、浸润、转移、转移病灶中的血管新生这样的过程，通过各种不同的机制受到控制。现有的抗癌剂、分子靶向药物大多以增殖抑制为主体，但存在因对正常细胞也产生影响而导致的副作用的问题。另外，由于细胞的增殖-迁移的Dichotomy(增殖或迁移二选一)，增殖受到抑制时，迁移反而可活跃化，这特别是对于迁移能力高的癌细胞而言，成为抗抗癌剂、放射线治疗的一个因素。因此，对于CHST15 siRNA而言，根据以往报告的增殖抑制作用考虑，反而会担心可能会使迁移活跃化。
因此，使用与已报告的Panc-1细胞同样为胰腺癌但为其它细胞株的BxPC-3细胞实施体外试验，结果通过加入CHST15 siRNA来抑制CHST15的表达，几乎未见增殖抑制效果，但获得了浸润受到抑制这样的预料不到的结果。更令人惊讶的是，首次清楚了不仅对实体癌，而且对血液癌也具有该浸润抑制效果。
根据本发明，能够应用于能够减轻以往的基于增殖/分裂抑制机制的抗癌剂、分子靶向药物的副作用的并用疗法、与基于抗肿瘤免疫机制的免疫检查点抑制剂的并用疗法、以及提高基于浸润/转移的抑制的外科手术、放射线疗法的效果等集合各学科的癌的治疗、复发预防。
附图说明
图1表示人胰腺癌细胞株BxPC-3中的由CHST15 siRNA带来的敲减效果(A)、增殖抑制效果(B)及浸润抑制效果(C)。
图2表示各种人癌细胞株中的由CHST15 siRNA带来的浸润抑制效果。除了人甲状腺未分化癌细胞株ASH-3、人肺癌细胞株A549、人乳腺癌细胞株BT-549、人胃癌细胞株NUGC-3、人卵巢癌细胞株OVCAR-3等实体癌以外，在人多发性骨髓瘤的癌细胞株RPMI8226中也显示出浸润抑制。
具体实施方式
以下，对本发明详细地进行说明。
本发明人发现，通过抑制CHST15(Carbohydrate sulfotransferase15，糖硫酸转移酶15)基因表达，不仅对实体癌，而且对血液癌也发挥浸润抑制效果。更详细而言，本发明人发现，通过利用RNAi(RNA interferance；RNA干扰)效果来抑制CHST15基因的表达，不仅对实体癌，而且对血液癌也具有浸润抑制效果。
本发明的CHST15基因没有特别限制，通常为动物来源，更优选为哺乳动物来源，最优选为人来源。需要说明的是，本发明的CHST15也被称为GalNAc4S-6ST(N-acetylgalactosamine 4-sulfate 6-0sulfotransfe-rase，N-乙酰半乳糖胺4硫酸盐6-O-磺基转移酶)。
本发明的CHST15(GalNAc4S-6ST)的序列例如可以基于登录号NM_015892获得。作为一例，将本发明的CHST15基因的碱基序列记载于序列号3，将由该基因编码的氨基酸序列记载于序列号4。即使是由除上述以外的氨基酸序列构成的蛋白，例如与序列号4所记载的序列具有高同源性(通常为70％以上，优选为80％以上，更优选为90％以上，最优选为95％以上)，且具有上述蛋白所具有的功能的蛋白也包括在本发明的CHST15蛋白中。上述蛋白是指例如由在序列号4所记载的氨基酸序列中添加、缺失、替换、插入有1个以上氨基酸的氨基酸序列构成的蛋白，通常变化的氨基酸数为30个氨基酸以内，优选为10个氨基酸以内，更优选为5个氨基酸以内，最优选为3个氨基酸以内。
本发明中的上述基因中例如包括与由序列号3所记载的碱基序列构成的DNA对应的其他生物中的内源性基因(人的上述基因的同源物等)。另外，与由序列号3所记载的碱基序列构成的DNA对应的其他生物的内源性DNA通常分别与序列号3所记载的DNA具有高同源性(相同性)。高同源性是指优选70％以上、进一步优选80％以上、更优选90％以上(例如95％以上、进而96％、97％、98％或99％以上)的相同性。该相同性可以通过mBLAST算法(Altschul et al.(1990)Proc.Natl.Acad.Sci.USA 87:2264-8；Karlin and Altschul(1993)Proc.Natl.Acad.Sci.USA 90:5873-7)来确定。另外，认为该DNA从生物体内分离时，分别在严格的条件下与序列号3中记载的DNA杂交。在此，作为“严格的条件”，例如可举出“2×SSC、0.1％SDS、50℃”、“2×SSC、0.1％SDS、42℃”、“1×SSC、0.1％SDS、37℃”，作为更严格的条件，可举出“2×SSC、0.1％SDS、65℃”、“0.5×SSC、0.1％SDS、42℃”及“0.2×SSC、0.1％SDS、65℃”的条件。
本说明书中，“抑制CHST15基因表达的siRNA”也可以表述为“CHST15 siRNA”，优选为在一条链的3’端和另一条链的3’端具有悬垂的碱基的结构的siRNA，更优选为序列号1和2中记载的RNA杂交而成的结构的siRNA。
本发明中的siRNA可以不必是全部核苷酸为核糖核苷酸(RNA)。即，在本发明中，构成siRNA的1个或多个核糖核苷酸只要作为分子本身具有抑制CHST15基因表达的功能，则也可以是对应的脱氧核糖核苷酸。该“对应的”是指糖部分的结构不同，但为同一碱基种类(腺嘌呤、鸟嘌呤、胞嘧啶、胸腺嘧啶(尿嘧啶))。例如，与具有腺嘌呤的核糖核苷酸对应的脱氧核糖核苷酸是指具有腺嘌呤的脱氧核糖核苷酸。另外，上述“多个”没有特别限制，优选是指2～5个左右的少数。
本发明的siRNA对于本领域技术人员而言可以使用市售的核酸合成机来适当制作。另外，关于所期望的RNA的合成，可以利用一般的合成委托服务。
本发明的CHST15 siRNA具有以单剂抑制癌的浸润或使癌停留的效果，因此本发明提供含有CHST15 siRNA作为有效成分的癌的浸润抑制剂、即抑制癌的浸润的用于治疗或预防的药物组合物。或者，本发明提供包含给药抑制CHST15基因表达的siRNA的工序的抑制癌的浸润的方法，用于在抑制癌的浸润的方法中使用的抑制CHST15基因表达的siRNA、抑制CHST15基因表达的siRN A在复剂的制造中的用途、以及包含使用抑制CHST15表达的siRNA(制成制剂和/或与药学上或生理学上可接受的载体混合)的工序的癌的浸润抑制剂的制造方法。
成为本发明中的治疗或预防的对象的癌只要是本发明的抑制CHST15基因表达的siRNA可发挥治疗效果的实体癌和血液癌就没有特别限定，包括乳腺、心脏、肺、小肠、大肠、脾脏、肾脏、膀胱、头部、颈部、卵巢、前列腺、脑、胰脏、皮肤、骨、骨髓、血液、胸腺、子宫、睾丸和肝脏的癌或肿瘤。在特定的实施方式中，作为本发明的治疗或预防对象的癌还包括肿瘤，为腺瘤、腺癌、血管肉瘤、星形细胞瘤、上皮癌、生殖细胞肿瘤、胶质母细胞瘤、神经胶质瘤、血管内皮瘤、血管肉瘤、血肿、肝母细胞瘤、白血病、淋巴瘤、髓母细胞瘤、黑色素瘤、神经母细胞瘤、骨肉瘤、视网膜母细胞瘤、横纹肌肉瘤、肉瘤、畸胎瘤、肢端雀斑样黑色素瘤、日光性角化病、腺癌、腺样囊性癌、腺瘤、腺肉瘤、腺鳞状细胞癌、星形细胞瘤、外阴前庭大腺癌、基底细胞癌、支气管腺癌、毛细血管类癌、细胞癌、癌肉瘤、胆管细胞癌、软骨肉瘤、囊腺瘤、卵黄囊瘤、子宫内膜增殖症、子宫内膜间质肉瘤、类内膜腺癌、室管膜瘤、尤因氏肉瘤、局灶性结节增生、产胃泌素瘤、生殖系列肿瘤、神经胶质瘤、胰高血糖素瘤、血管母细胞瘤、血管内皮细胞瘤、血管瘤、肝腺瘤、肝腺瘤症、肝细胞癌、胰岛素瘤、上皮内肿瘤、上皮内扁平细胞肿瘤、浸润性扁平细胞癌、大细胞癌、脂肪肉瘤、肺癌、淋巴母细胞性白血病、淋巴细胞性白血病、平滑肌肉瘤、黑色素瘤、恶性黑色素瘤、恶性间皮瘤、神经鞘瘤、髓母细胞瘤、髓上皮瘤、间皮瘤、黏液表皮样癌、骨髓性白血病、神经母细胞瘤、神经上皮腺癌、结节性黑色素瘤、骨肉瘤、卵巢癌、浆液性乳头状腺癌、垂体肿瘤、浆细胞瘤、假性肉瘤、前列腺癌、肺母细胞瘤、肾细胞癌、视网膜母细胞瘤、横纹肌肉瘤、肉瘤、浆液性癌、扁平细胞癌、小细胞癌、软组织癌、生长抑素瘤、扁平上皮癌、扁平上皮细胞癌、未分化癌、葡萄膜黑色素瘤、疣状癌、阴道/外阴部癌、VIP(血管致动性肠肽)产生肿瘤及肾母细胞瘤、脑癌、头颈部癌、结直肠癌、急性髓性白血病、前体B细胞急性淋巴母细胞白血病、膀胱癌、星形细胞瘤、优选II、III或IV级的星形细胞瘤、胶质母细胞瘤、多形性胶质母细胞瘤、小细胞癌、及非小细胞癌、优选非小细胞肺癌、肺腺癌、转移性黑色素瘤、雄激素非依赖性转移性前列腺癌、雄激素依赖性转移性前列腺癌、前列腺癌、乳腺癌、乳管癌，特别优选为胶质母细胞瘤、胰腺癌、乳腺癌、膀胱癌、肾癌、头颈部癌、卵巢癌、大肠癌、宫颈癌、前列腺癌、肺癌、胃癌、甲状腺癌、或骨髓瘤。
在本发明中，“抑制癌的浸润”是指使癌细胞停留在原发病灶中，预防癌的发展、转移和/或提高癌治疗效果。另外，本发明中的“治疗”并不一定限定于具有完全的治疗效果的情况，也可以是具有部分效果的情况。
本发明的用于抑制癌的浸润的药物组合物可以与药学上或生理学上可接受的载体、赋形剂或稀释剂等混合，经口或非经口地给药。作为口服剂，可以制成颗粒剂、散剂、片剂、胶囊剂、溶剂、乳剂或悬浮剂等剂型。作为非口服剂，可以选择注射剂、点滴剂、外用药剂、吸入剂(雾化器)或栓剂等剂型。注射剂可以表示皮下注射剂、肌肉注射剂、腹腔内注射剂、颅内给药注射剂或鼻内给药注射剂等。外用药剂可以表示经鼻给药剂或软膏剂等。以包含作为主成分的本发明的药物组合物的方式制成上述剂型的制剂技术是公知的。
例如，经口给药用的片剂可以通过在本发明的用于恢复组织完整性的药物组合物中加入赋形剂、崩解剂、粘合剂和润滑剂等并混合，进行压缩整形来制造。赋形剂通常使用乳糖、淀粉或甘露醇等。作为崩解剂，通常使用碳酸钙、羧甲基纤维素钙等。粘合剂使用阿拉伯胶、羧甲基纤维素或聚乙烯吡咯烷酮。作为润滑剂，公知有滑石、硬脂酸镁等。
包含本发明的用于抑制癌的浸润的药物组合物的片剂为了制成掩蔽、肠溶性制剂，可以实施公知的包衣。包衣剂可以使用乙基纤维素、聚氧乙二醇等。
另外，注射剂可以通过将作为主成分的本发明的用于抑制癌的浸润的药物组合物与适当的分散剂一起溶解、溶解或分散于分散介质而得到。通过选择分散介质，可以制成水性溶剂和油性溶剂中的任一种剂型。制成水性溶剂时，将蒸馏水、生理盐水或林格氏液等作为分散介质。油性溶剂中，将各种植物油、丙二醇等用于分散介质。此时，也可以根据需要添加对羟基苯甲酸酯等防腐剂。另外，可以在注射剂中加入氯化钠、葡萄糖等公知的等渗剂。此外，还可以添加苯扎氯铵、盐酸普鲁卡因这样的无痛化剂。
另外，通过将本发明的用于抑制癌的浸润的药物组合物伴有或不伴有赋形剂或载体而制成固态、液态或半固态的组合物，可以制成外用剂。对于固态或液态的组合物，可以通过制成与先前所述的组合物同样的组合物而制成外用剂。半固态的组合物可以根据需要在适当的溶剂中加入增稠剂来制备。溶剂可以使用水、乙醇或聚乙二醇等。增稠剂通常使用膨润土、聚乙烯醇、丙烯酸、甲基丙烯酸或聚乙烯吡咯烷酮等。该组合物中可以加入苯扎氯铵等防腐剂。另外，也可以通过组合作为载体的可可脂这样的油性基材、或纤维素衍生物这样的水性凝胶基材而制成栓剂。
在使用本发明的用于抑制癌的浸润的药物组合物作为基因治疗剂的情况下，除了通过注射直接给药本发明的癌的浸润抑制剂或药物组合物的方法以外，还可举出给药整合有核酸的载体的方法。作为上述载体，可举出腺病毒载体、腺相关病毒载体、疱疹病毒载体、痘苗病毒载体、逆转录病毒载体、慢病毒载体等，通过使用这些病毒载体，可以高效地进行给药。
另外，也可以将本发明的用于抑制癌的浸润的药物组合物导入脂质体等磷脂囊泡中并给药该囊泡。将保持有siRNA的囊泡通过脂质体转染法导入特定的细胞。然后，将得到的细胞全身给药到例如静脉内、动脉内等。
另外，本发明提供一种抑制对象中的癌的浸润的方法，其包含将本发明的用于抑制癌的浸润的药物组合物给药到个体(例如患者)或其肿瘤组织的工序。作为本发明的对象的个体只要是可患有肿瘤的生物就没有特别限制，优选为人。向对象的给药例如可以通过经口给药、肿瘤内给药、皮内给药、或皮下给药、或静脉内注射等本领域技术人员公知的方法进行。可以全身给药或向肿瘤组织的直接局部给药。另外，为了将本发明的siRNA导入目标细胞、组织或器官，也可以使用市售的基因导入试剂盒。
本发明的用于抑制癌的浸润的药物组合物在认为安全的给药量范围内对包括人在内的哺乳动物对象给药所需量(有效量)。本发明的用于抑制癌的浸润的药物组合物的给药量可以考虑剂型的种类、给药方法、对象的年龄、体重、对象的症状等，最终根据本领域技术人员(医生或兽医)的判断来适当确定。给出一个例子，虽然因年龄、性别、症状、给药途径、给药次数、剂型的不同而不同，但例如本发明的CHST15siRNA的局部给药时的给药量为1天1次、每次1pM～1mM左右，单次给药或间隔1周～间隔1个月(例如间隔1周、间隔2周或间隔1个月)给药、或者连续给药。
需要说明的是，本说明书中引用的所有现有技术文献作为参照纳入本说明书中。
实施例
以下，使用实施例更具体地说明本发明。但是，本发明的技术范围并不限定于这些实施例。
其中，本实施例中使用的“CHST15 siRNA”是序列号1和2中记载的RNA杂交而成的结构的siRNA。
以下示出本实施例中使用的GalNac 4S-6ST siRNA药的碱基序列。序列并不一定仅限定于本例。
[人GalNac 4S-6ST siRNA](Gene Bank accession number NM_015892)
(北海道System Science公司制)
5’-ggagcagagcaagaugaauacaauc-ag-3’(序列号：1)
3’-ua-ccucgucucguucuacuuauguuag-5’(序列号：2)
<实施例1>
根据通过现有文献已知有细胞增殖抑制作用的Panc-1细胞是人胰腺癌细胞株，使用同样的属于人胰腺癌细胞株的BxPC-3细胞。报告了与Panc-1细胞相比，在BxPC-3细胞株中COX-2、PGE2、VEGF的表达高，启示了有可能在血管新生能力方面存在差异，但关于增殖能力、浸润能力，尚未报告在两细胞间有大的差异(综述文献：Deer EL,et al.Phenotype andgenotype of pancreatic cancer cell lines.Pancreas.39:425-435,2010)。
在体外试验中，基于常规方法培养BxPC-3细胞。在24孔板上调整各孔至0.5×105cells的密度，转染CHST15 siRNA。转染如下进行：使用Lipofectamine RNAiMAX试剂(Thermo Fisher Science公司制)，将siRNA的浓度调整为50nM或500nM，在5％的CO2浓度、37℃、加湿条件下培养48小时。另外，作为阴性对照，使用vehicle(生理盐水)。培养48小时后，从24孔板的各孔细胞中提取总RNA，使用0.1μg的总RNA合成cDNA。将合成的cDNA用DNase/RNase-FreeWater稀释至1ng/μL(模板量为5ng/reaction)，使用qPCR法测定CHST15mRNA的表达。将结果示于图1A。50nM的CHST15 siRNA显著地抑制BxPC-3细胞的CHST15mRNA。
另一方面，回收转染结束后的细胞，评价增殖能力和浸润能力。关于细胞增殖，以1.0×104～1.0×106Cells/mL的密度、在5％的CO2浓度、37℃、加湿条件下培养24小时后，使用Cell Counting Kit-8(DOJINDO Chemical Research公司制)，使用酶标仪以OD450nM进行测定。将结果示于图1B。500nM的CHST15 siRNA对BxPC-3细胞的增殖没有影响。
关于细胞浸润，调整为0.2×105Cells/300μL的密度后，使用CytoSelect 24-wellCell Invasion Assay Kit(CELL BIOLABS公司制)，进行细胞浸润试验。培养24小时、48小时，将浸润后的细胞染色，然后使用酶标仪，以OD560nM进行测定。将结果示于图1C。50nM的CHST15 siRNA显著地抑制BxPC-3细胞的浸润。这表示具有使癌细胞停留在所添加的孔中的效果。
<实施例2>
通过与实施例1同样的方法，使用各种人癌细胞株，转染CHST15siRNA，实施细胞浸润分析(Cell Invasion Assay)。人癌细胞为A549(肺癌)、NUGC-3(胃癌)、ASH-3(未分化型甲状腺癌)、BT-549(乳腺癌)、OVCAR-3(卵巢癌)、RPMI8226(骨髓瘤)这样的不仅包括实体癌也包括血液癌进行分析。将结果示于图2。50nM的CHST15siRNA明显地抑制所实施的全部种类的人癌细胞的浸润。
考察：
CHST15 siRNA不仅抑制人实体癌细胞的浸润，而且抑制人血液癌细胞的浸润。启示了可通过使癌细胞停留来抑制癌的进展。
产业上的可利用性
本发明的CHST15 siRNA显著地抑制人癌细胞株的浸润，而且其效果不仅在实体癌，而且预料不到的是在血液癌中也得到确认。考虑通过使癌细胞停留在原发部分(对于实体癌为原发实体脏器，对于血液癌为骨髓或淋巴脏器)，能够获得新的癌治疗效果。
这些结果表明了，本发明的抑制CHST15基因表达的siRNA对于抑制癌的浸润是有用的。
Claims (8)
1.一种用于抑制癌的浸润的药物组合物，其包含抑制CHST15基因表达的siRNA。
2.根据权利要求1所述的药物组合物，其用于抑制癌的转移。
3.根据权利要求1或2所述的药物组合物，其中，癌为实体癌或血液癌。
4.根据权利要求1～3中任一项所述的药物组合物，其特征在于，通过使癌停留来抑制进展。
5.一种抑制癌的浸润的方法，其包含给药抑制CHST15基因表达的siRNA的工序。
6.一种抑制CHST15基因表达的siRNA，其是在抑制癌的浸润的方法中使用的。
7.抑制CHST15基因表达的siRNA在制造癌的浸润抑制剂中的用途。
8.一种癌的浸润抑制剂的制造方法，其包含使用抑制CHST15基因表达的siRNA的工序。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/JP2021/031710 WO2023031996A1 (ja) | 2021-08-30 | 2021-08-30 | 癌の浸潤を抑制するための医薬組成物、及び癌の浸潤を抑制する方法 |
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| CN117881404A true CN117881404A (zh) | 2024-04-12 |
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- 2021-08-30 JP JP2023544804A patent/JPWO2023031996A1/ja active Pending
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| KR20240050416A (ko) | 2024-04-18 |
| JPWO2023031996A1 (zh) | 2023-03-09 |
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