CN106890322A - 一种预防或治疗放射性和化学性损伤的方法 - Google Patents
一种预防或治疗放射性和化学性损伤的方法 Download PDFInfo
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Abstract
本发明涉及纤维蛋白溶酶原在预防、治疗、改善和/或消除受试者放射和化学损伤及其相关病症中的用途,进而为治疗不同类型的放射和化学损伤提供全新的治疗策略。
Description
技术领域:
本发明涉及纤维蛋白溶酶原或纤维蛋白溶酶在预防和/或治疗、改善和/或消除受试者放射和化学损伤及其相关病症中的用途,进而为预防和/或治疗不同类型的放射和化学损伤提供全新的预防和/或治疗策略。
背景技术
放射损伤是由放射线照射引起的机体组织损害。一般来说,放射线是由天然或人工能源产生的高能电磁波或高能粒子。大剂量射线瞬间照射或低剂量射线长时间照射都可能引起组织损伤。化学损伤是化学物接触人体后产生的局部损害或全身损害。其损害程度与化学物的性质、剂量、浓度、接触时间及面积、处理是否及时及有效等因素有关。临床上,普遍使用放射治疗或化疗或两者的结合用于治疗或改善肿瘤和癌症患者。其中,放疗通常使用X射线、γ射线、中子和其它来源射线杀死癌细胞或破坏细胞内的遗传物质。而化疗通过单独或组合使用细胞毒性药物破坏癌细胞复制或增殖。几乎所有的癌症患者在经历一次或多次放疗、化疗或放化疗后都表现出严重的副作用,包括粘膜溃疡、免疫功能下降、骨髓抑制、消化障碍、炎症、心脏毒性、肾脏毒性、肺纤维化、静脉炎、神经***毒性、肝脏毒性等。因此,化疗和放射疗法副作用的预防和保护对癌症患者来说至关重要。
纤溶酶是纤溶酶原激活***(PA***)的关键组分。它是一种广谱的蛋白酶,能够水解细胞外基质(ECM)的几个组分,包括纤维蛋白、明胶、纤连蛋白、层粘连蛋白和蛋白聚糖[1]。此外,纤溶酶能将一些金属蛋白酶前体(pro-MMP)激活形成具有活性的金属蛋白酶(MMP)。因此纤溶酶被认为是胞外蛋白水解作用的一个重要的上游调节物[2,3]。纤溶酶是由纤溶酶原通过两种生理性的PA:组织型纤溶酶原激活剂(tPA)或尿激酶型纤溶酶原激活剂(uPA)蛋白水解形成的。由于纤溶酶原在血浆和其他体液中相对水平较高,传统上认为PA***的调节主要通过PA的合成和活性水平实现。PA***组分的合成受不同因素严格调节,如激素、生长因子和细胞因子。此外,还存在纤溶酶和PA的特定生理抑制剂。纤溶酶的主要抑制剂是α2-抗纤溶酶(α2-antiplasmin)。某些细胞表面具有直接水解活性的uPA特异性细胞表面受体(uPAR)[4,5]。
纤溶酶原(plasminogen,plg)是一个单链糖蛋白,由791个氨基酸组成,分子量约为92kDa[6,7]。纤溶酶原主要在肝脏合成,大量存在于胞外液中。血浆中纤溶酶原含量约为2μM。因此纤溶酶原是组织和体液中蛋白质水解活性的一个巨大的潜在来源[8,9]。纤溶酶原存在两种分子形式:谷氨酸-纤溶酶原(Glu-plasminogen)和赖氨酸-纤溶酶原(Lys-plasminogen)。天然分泌和未裂解形式的纤溶酶原具有一个氨基末端(N-末端)谷氨酸,因此被称为谷氨酸-纤溶酶原。然而,在纤溶酶存在时,谷氨酸-纤溶酶原在Lys76-Lys77处水解成为赖氨酸-纤溶酶原。与谷氨酸-纤溶酶原相比,赖氨酸-纤溶酶原与纤维蛋白具有更高的亲和力,并可以更高的速率被PA激活。这两种形式的纤溶酶原的Arg560-Val561肽键可被uPA或tPA切割,导致二硫键连接的双链蛋白酶纤溶酶的形成[10]。纤溶酶原的氨基末端部分包含五个同源三环,即所谓的kringle,羧基末端部分包含蛋白酶结构域。一些kringle含有介导纤溶酶原与纤维蛋白及其抑制剂α2-AP特异性相互作用的赖氨酸结合位点。最新发现一个纤维蛋白溶酶原为38kDa的片段,其中包括kringle1-4,是血管生成的有效抑制剂。这个片段被命名为血管抑素,可通过几个蛋白酶水解纤溶酶原产生。
纤溶酶的主要底物是纤维蛋白,纤维蛋白的溶解是预防病理性血栓形成的关键[11]。纤溶酶还具有对ECM几个组分的底物特异性,包括层粘连蛋白、纤连蛋白、蛋白聚糖和明胶,表明纤溶酶在ECM重建中也起着重要作用[7,12,13]。间接地,纤溶酶还可以通过将某些蛋白酶前体转化为活性蛋白酶来降解ECM的其他组分,包括MMP-1、MMP-2、MMP-3和MMP-9。因此,有人提出,纤溶酶可能是细胞外蛋白水解的一个重要的上游调节器[14]。此外,纤溶酶具有激活某些潜在形式的生长因子的能力[15-17]。在体外,纤溶酶还能水解补体***的组分并释放趋化补体片段。
我们在研究中惊奇发现纤维蛋白溶酶原或纤维蛋白溶酶对机体的放射和化学损伤有明显的治疗作用,且安全性高。因此,使用纤维蛋白溶酶原或纤维蛋白溶酶是一种新的用于治疗不同类型的放射和化学损伤其相关病症的治疗策略。
发明简述
一方面,本发明涉及纤维蛋白溶酶原或纤维蛋白溶酶在制备治疗和/或消除受试者辐射损伤和化学损伤及其相关病症的药物中的用途。同时,本发明涉及纤维蛋白溶酶原或纤维蛋白溶酶在制备治疗和/或消除受试者放射治疗、化疗或放化疗引起的机体器官和组织损伤及其相关病症的药物中的用途。在一个实施方案中,所述损伤包括对骨髓造血***、皮肤、粘膜、免疫***和生殖***的损伤。在一个实施方案中,所述损伤包括对肝脏、脾脏、肾脏、肺脏、胃肠道、胸腺、骨髓、睾丸、附睾的损伤。在一个实施方案中,所述损伤是放射治疗、化疗或放化疗导致的一般健康状况的下降,全身副作用和局部副作用,包括急性副作用、长期副作用和累积副作用。在一个实施方案中,所述损伤相关病症包括:粘膜溃疡、免疫功能下降、骨髓抑制、消化功能障碍、心、肝、脾、肺、肾、卵巢、睾丸中毒性功能障碍、神经***中毒性功能障碍。在一个实施方案中,所述纤维蛋白溶酶原与序列2、6、8、10或12具有至少80%、85%、90%、95%、96%、97%、98%或99%的序列同一性,并且仍然具有纤维蛋白溶酶原活性。在一个实施方案中,所述纤维蛋白溶酶原是包含纤溶酶原活性片段、并且仍然具有纤维蛋白溶酶原活性的蛋白质。在一个实施方案中,所述纤维蛋白溶酶原或纤维蛋白溶酶可与一种或多种其它药物或疗法联合施用,包括:抗癌药物、抗感染药物、免疫增强剂、止痛药、营养剂和解毒剂。
在一个实施方案中,所述受试者为哺乳动物,优选为人。
在一个实施方案中,所述受试者缺乏纤维蛋白溶酶或者纤维蛋白溶酶原。具体地,所述缺乏是先天的、继发的和/或局部的。
在一个实施方案中,纤维蛋白溶酶原与序列2、6、8、10或12具有至少80%、85%、90%、95%、96%、97%、98%或99%的序列同一性,并且仍然具有纤维蛋白溶酶原活性。在一个实施方案中,纤维蛋白溶酶原是在序列2、6、8、10或12的基础上,添加、删除和/或取代1-100、1-90、1-80、1-70、1-60、1-50、1-45、1-40、1-35、1-30、1-25、1-20、1-15、1-10、1-5、1-4、1-3、1-2、1个氨基酸,并且仍然具有纤维蛋白溶酶原活性的蛋白质。在一个实施方案中,纤溶酶原是包含纤溶酶原活性片段、并且仍然具有纤维蛋白溶酶原活性的蛋白质。在一个实施方案中,纤溶酶原选自Glu-纤维蛋白溶酶原、Lys-纤维蛋白溶酶原、小纤维蛋白溶酶原、微纤维蛋白溶酶原、δ-纤溶酶原或其任意组合。在一个实施方案中,纤溶酶原是选自如下的保守取代变体:Glu-纤维蛋白溶酶原、Lys-纤维蛋白溶酶原、小纤维蛋白溶酶原、δ-纤溶酶原或微纤维蛋白溶酶原。在一个实施方案中,纤维蛋白溶酶原为人天然纤维蛋白溶酶原,例如序列2所示的纤溶酶原的直向同系物,例如,来自灵长类动物或啮齿类动物的纤维蛋白溶酶原直向同系物,例如来自大猩猩、恒河猴、鼠、牛、马、狗的纤维蛋白溶酶原直向同系物。最优选,本发明的纤维蛋白溶酶原的氨基酸序列如序列2、6、8、10或12所示。
在一个实施方案中,所述纤维蛋白溶酶原或纤维蛋白溶酶通过外用,口服,全身或局部给药。在一个实施方案中,通过以下途径施用:表面、静脉内、肌内、皮下、吸入、椎管内、局部注射、关节内注射或通过直肠。在一个实施方案中,所述的施用方式是外用。在一个实施方案中,所述局部给药通过在受损区域直接给予纤维蛋白溶酶原或纤维蛋白溶酶来进行预防和/或治疗。
在一个实施方案中,所述纤溶酶原与适当的多肽载体或稳定剂组合施用。在一个实施方案中,所述纤溶酶原以每天0.0001-2000mg/kg、0.001-800mg/kg、0.01-600mg/kg、0.1-400mg/kg、1-200mg/kg、1-100mg/kg、10-100mg/kg(以每公斤体重计算)或0.0001-2000mg/cm2、0.001-800mg/cm2、0.01-600mg/cm2、0.1-400mg/cm2、1-200mg/cm2、1-100mg/cm2、10-100mg/cm2(以每平方厘米体表面积计算)的剂量施用,优选至少重复一次,优选至少每天施用。在局部施用的情况下,上述剂量还可以根据情况进一步调整。
另一方面,本发明涉及用于预防和/或治疗和/或消除受试者辐射损伤和化学损伤及其相关病症的纤维蛋白溶酶原或纤维蛋白溶酶,以及预防和/或治疗和/或消除受试者辐射损伤和化学损伤及其相关病症的、包含纤维蛋白溶酶原或纤维蛋白溶酶的药物组合物。同时,本发明涉及用于预防和/或治疗和/或消除受试者放射治疗、化疗或放化疗引起的机体器官和组织损伤及其相关病症的纤维蛋白溶酶原或纤维蛋白溶酶,以及用于治疗和/或消除受试者放射治疗、化疗或放化疗引起的机体器官和组织损伤及其相关病症的、包含纤维蛋白溶酶原或纤维蛋白溶酶的药物组合物。在一个实施方案中,所述损伤包括对骨髓造血***、皮肤、粘膜、免疫***和生殖***的损伤。在一个实施方案中,所述损伤包括对肝脏、脾脏、肾脏、肺脏、胃肠道、胸腺、骨髓、睾丸、附睾的损伤。在一个实施方案中,所述损伤是放射治疗、化疗或放化疗导致的一般健康状况的下降,全身副作用和局部副作用,包括急性副作用、长期副作用和累积副作用。在一个实施方案中,所述损伤相关病症包括:粘膜溃疡、免疫功能下降、骨髓抑制、消化功能障碍、心、肝、脾、肺、肾、卵巢、睾丸中毒性功能障碍、神经***中毒性功能障碍。在一个实施方案中,所述纤维蛋白溶酶原与序列2、6、8、10或12具有至少80%、85%、90%、95%、96%、97%、98%或99%的序列同一性,并且仍然具有纤维蛋白溶酶原活性。在一个实施方案中,所述纤维蛋白溶酶原是包含纤溶酶原活性片段、并且仍然具有纤维蛋白溶酶原活性的蛋白质。在一个实施方案中,所述纤维蛋白溶酶原或纤维蛋白溶酶可与一种或多种其它药物或疗法联合施用,包括:抗癌药物、抗感染药物、免疫增强剂、止痛药、营养剂和解毒剂。
在一个实施方案中,所述受试者为哺乳动物,优选为人。
在一个实施方案中,所述受试者缺乏纤维蛋白溶酶或者纤维蛋白溶酶原。具体地,所述缺乏是先天的、继发的和/或局部的。
在一个实施方案中,纤维蛋白溶酶原与序列2、6、8、10或12具有至少80%、85%、90%、95%、96%、97%、98%或99%的序列同一性,并且仍然具有纤维蛋白溶酶原活性。在一个实施方案中,纤维蛋白溶酶原是在序列2、6、8、10或12的基础上,添加、删除和/或取代1-100、1-90、1-80、1-70、1-60、1-50、1-45、1-40、1-35、1-30、1-25、1-20、1-15、1-10、1-5、1-4、1-3、1-2、1个氨基酸,并且仍然具有纤维蛋白溶酶原活性的蛋白质。在一个实施方案中,纤溶酶原是包含纤溶酶原活性片段、并且仍然具有纤维蛋白溶酶原活性的蛋白质。在一个实施方案中,纤溶酶原选自Glu-纤维蛋白溶酶原、Lys-纤维蛋白溶酶原、小纤维蛋白溶酶原、δ-纤溶酶原微纤维蛋白溶酶原、或其任意组合。在一个实施方案中,纤溶酶原是选自如下的保守取代变体:Glu-纤维蛋白溶酶原、Lys-纤维蛋白溶酶原、小纤维蛋白溶酶原、δ-纤溶酶原或微纤维蛋白溶酶原。在一个实施方案中,纤维蛋白溶酶原为人天然纤维蛋白溶酶原,例如序列2所示的纤溶酶原的直向同系物,例如,来自灵长类动物或啮齿类动物的纤维蛋白溶酶原直向同系物,例如来自大猩猩,恒河猴、鼠、牛、马,狗的纤维蛋白溶酶原直向同系物。最优选,本发明的纤维蛋白溶酶原的氨基酸序列如序列2、6、8、10或12所示。
在一个实施方案中,所述纤维蛋白溶酶原或纤维蛋白溶酶通过外用,口服,全身或局部给药。在一个实施方案中,通过以下途径施用:表面、静脉内、肌内、皮下、吸入、椎管内、局部注射、关节内注射或通过直肠。在一个实施方案中,所述的施用方式是外用。在一个实施方案中,所述局部给药通过在受损区域直接给予纤维蛋白溶酶原或纤维蛋白溶酶来进行预防和/或治疗。
在一个实施方案中,所述纤溶酶原与适当的多肽载体或稳定剂组合施用。在一个实施方案中,所述纤溶酶原以每天0.0001-2000mg/kg、0.001-800mg/kg、0.01-600mg/kg、0.1-400mg/kg、1-200mg/kg、1-100mg/kg、10-100mg/kg(以每公斤体重计算)或0.0001-2000mg/cm2、0.001-800mg/cm2、0.01-600mg/cm2、0.1-400mg/cm2、1-200mg/cm2、1-100mg/cm2、10-100mg/cm2(以每平方厘米体表面积计算)的剂量施用,优选至少重复一次,优选至少每天施用。在局部施用的情况下,上述剂量还可以根据情况进一步调整。
另一方面,本发明涉及用于预防和/或治疗和/或消除受试者辐射损伤和化学损伤及其相关病症的、包含纤维蛋白溶酶原或纤维蛋白溶酶的制品或药盒,以及用于预防和/或治疗和/或消除受试者放射治疗、化疗或放化疗引起的机体器官和组织损伤及其相关病症的、包含纤维蛋白溶酶原或纤维蛋白溶酶的制品或药盒。在一个实施方案中,所述损伤包括对骨髓造血***、皮肤、粘膜、免疫***和生殖***的损伤。在一个实施方案中,所述损伤包括对肝脏、脾脏、肾脏、肺脏、胃肠道、胸腺、骨髓、睾丸、附睾的损伤。在一个实施方案中,所述损伤是放射治疗、化疗或放化疗导致的一般健康状况的下降,全身副作用和局部副作用,包括急性副作用、长期副作用和累积副作用。在一个实施方案中,所述损伤相关病症包括:粘膜溃疡、免疫功能下降、骨髓抑制、消化功能障碍、心、肝、脾、肺、肾、卵巢、睾丸中毒性功能障碍、神经***中毒性功能障碍。在一个实施方案中,所述纤维蛋白溶酶原与序列2、6、8、10或12具有至少80%、85%、90%、95%、96%、97%、98%或99%的序列同一性,并且仍然具有纤维蛋白溶酶原活性。在一个实施方案中,所述纤维蛋白溶酶原是包含纤溶酶原活性片段、并且仍然具有纤维蛋白溶酶原活性的蛋白质。在一个实施方案中,所述纤维蛋白溶酶原或纤维蛋白溶酶可与一种或多种其它药物或疗法联合施用,包括:抗癌药物、抗感染药物、免疫增强剂、止痛药、营养剂和解毒剂。
在一个实施方案中,所述制品或药盒进一步包含含有一种或多种其它的药物的容器。该药盒还可包含使用说明书,说明所述纤维蛋白溶酶原或纤维蛋白溶酶可以用于预防和/或治疗所述损伤及其相关病症,并且可以进一步说明,所述纤维蛋白溶酶原或纤维蛋白溶酶可以在其它药物或疗法施用之前,同时,和/或之后施用。
在一个实施方案中,所述受试者为哺乳动物,优选为人。
在一个实施方案中,所述受试者缺乏纤维蛋白溶酶或者纤维蛋白溶酶原。具体地,所述缺乏是先天的、继发的和/或局部的。
在一个实施方案中,纤维蛋白溶酶原与序列2、6、8、10或12具有至少80%、85%、90%、95%、96%、97%、98%或99%的序列同一性,并且仍然具有纤维蛋白溶酶原活性。在一个实施方案中,纤维蛋白溶酶原是在序列2、6、8、10或12的基础上,添加、删除和/或取代1-100、1-90、1-80、1-70、1-60、1-50、1-45、1-40、1-35、1-30、1-25、1-20、1-15、1-10、1-5、1-4、1-3、1-2、1个氨基酸,并且仍然具有纤维蛋白溶酶原活性的蛋白质。在一个实施方案中,纤溶酶原是包含纤溶酶原活性片段、并且仍然具有纤维蛋白溶酶原活性的蛋白质。在一个实施方案中,纤溶酶原选自Glu-纤维蛋白溶酶原、Lys-纤维蛋白溶酶原、小纤维蛋白溶酶原、δ-纤溶酶原微纤维蛋白溶酶原、或其任意组合。在一个实施方案中,纤溶酶原是选自如下的保守取代变体:Glu-纤维蛋白溶酶原、Lys-纤维蛋白溶酶原、小纤维蛋白溶酶原、δ-纤溶酶原或微纤维蛋白溶酶原。在一个实施方案中,纤维蛋白溶酶原为人天然纤维蛋白溶酶原,例如序列2所示的纤溶酶原的直向同系物,例如,来自灵长类动物或啮齿类动物的纤维蛋白溶酶原直向同系物,例如来自大猩猩,恒河猴、鼠、牛、马,狗的纤维蛋白溶酶原直向同系物。最优选,本发明的纤维蛋白溶酶原的氨基酸序列如序列2、6、8、10或12所示。
在一个实施方案中,所述纤维蛋白溶酶原或纤维蛋白溶酶通过外用,口服,全身或局部给药。在一个实施方案中,通过以下途径施用:表面、静脉内、肌内、皮下、吸入、椎管内、局部注射、关节内注射或通过直肠。在一个实施方案中,所述的施用方式是外用。在一个实施方案中,所述局部给药通过在受损区域直接给予纤维蛋白溶酶原或纤维蛋白溶酶来进行预防和/或治疗。
在一个实施方案中,所述纤溶酶原与适当的多肽载体或稳定剂组合施用。在一个实施方案中,所述纤溶酶原以每天0.0001-2000mg/kg、0.001-800mg/kg、0.01-600mg/kg、0.1-400mg/kg、1-200mg/kg、1-100mg/kg、10-100mg/kg(以每公斤体重计算)或0.0001-2000mg/cm2、0.001-800mg/cm2、0.01-600mg/cm2、0.1-400mg/cm2、1-200mg/cm2、1-100mg/cm2、10-100mg/cm2(以每平方厘米体表面积计算)的剂量施用,优选至少重复一次,优选至少每天施用。在局部施用的情况下,上述剂量还可以根据情况进一步调整。
本发明明确涵盖了属于本发明实施方案之间的技术特征的所有组合,并且这些组合后的技术方案在本申请中已经明确公开,就像上述技术方案已经单独且明确公开一样。另外,本发明还明确涵盖各个实施方案及其要素的所有亚组合,并且在本文中公开,就像每一个此类亚组合单独且明确在本文中公开一样。
发明详述
“放射损伤”也称“辐射损伤”是由放射线照射引起的机体全身或局部器官、组织损害(损伤)。一般来说,放射线是由天然或人工能源产生的高能电磁波或高能粒子。大剂量射线瞬间照射或低剂量射线长时间照射都可能引起器官、组织损伤。“化学损伤”是化学物接触人体后产生的局部损害(损伤)或全身损害(损伤)。其损害程度与化学物的性质、剂量、浓度、接触时间及面积、处理是否及时及有效等因素有关。
辐射损伤和化学损伤可表现为机体器官、组织结构和功能的损伤,例如,骨髓造血***生理结构和功能的损伤、皮肤、粘膜的生理结构和功能损伤、免疫***的生理结构和功能损伤和生殖***的生理结构和功能损伤。在一个实施方案中,所述损伤包括对肝脏、脾脏、肾脏、肺脏、胃肠道、胸腺、骨髓、睾丸、附睾的生理结构和功能的损伤。所述损伤相关病症表现为损伤器官和组织的功能障碍,例如粘膜溃疡、免疫功能下降、骨髓抑制、消化功能障碍、心、肝、脾、肺、肾、卵巢、睾丸中毒性功能障碍、神经***中毒性功能障碍。
“放射治疗”与“放疗”可以互换使用。化学药物的治疗通常简称为“化疗”。“放化疗”指放疗或化疗二者的结合。临床上,普遍使用放射治疗或化疗或两者的结合用于治疗或改善肿瘤和癌症患者。其中,放疗通常使用X射线、γ射线、中子和其它来源射线杀死癌细胞或破坏细胞内的遗传物质。而化疗通过单独或组合使用细胞毒性药物破坏癌细胞复制或增殖,而正常细胞在放疗中也受损并无法自身修复。放疗期可出现副作用,包括皮肤刺激、治疗区域脱发,也可损伤骨髓。
“化疗”是指单独或联合使用细胞毒性药物,以杀死癌细胞。如放疗一样,癌细胞可被损伤并最终死亡,但是健康细胞在化疗后的自我修复过程中受到影响。细胞毒性药物通过干扰生长细胞的分化和增殖能力而起作用。因此,除癌细胞之外,其他正常快速分化和生长的细胞也会受到影响。例如,它们可影响骨髓的造血功能,引起骨髓抑制。此外,它们还可影响消化道、口腔内壁和生殖***的细胞、影响毛囊,造成腹泻、口腔疼痛和脱发。
“放化疗的副作用”是指与放化疗有关,通常在不同阶段出现的副作用,如出现在治疗期间(急性副作用),治疗后数月或数年(长期副作用),或重复治疗后(累积副作用)。其性质、严重性和副作用时间长短取决于接受治疗的器官、治疗本身(放射类型、剂量、分级、合并化学疗法)和患者。
大多数副作用是可以预测和预期的。放疗的副作用通常仅限于患者接受治疗的局部区域。现代放疗方法的目标旨在将副作用降至最小,并帮助患者了解和处理那些无法避免的副作用。
骨髓抑制是诸多放疗和化疗副作用之一。其结果是减少血细胞生成,包括红细胞、白细胞和血小板。结果,患者由于贫血而疲劳,由于白血球减少症而变得容易感染;由于血小板减少,当有伤口时候,更容易出现瘀伤和出血更多。
“一般健康状况”是一种健康标准,是指身体、相关组织和器官在没有活动性疾病、不适和不安的基础上,个体能够饮食、说话和参加社交,而有助于满足基本康乐。一般健康的主要标志包括生理健康和心理健康。
“纤溶酶”是存在于血液中的一种非常重要的酶,能将纤维蛋白凝块水解为纤维蛋白降解产物和D-二聚体。
“纤溶酶原”是纤溶酶的酶原形式,根据swiss prot中的序列,按含有信号肽的天然人源纤溶酶原氨基酸序列(序列4)计算由810个氨基酸组成,分子量约为92kD,主要在肝脏中合成并能够在血液中循环的糖蛋白,编码该氨基酸序列的cDNA序列如序列3所示。全长的纤溶酶原包含七个结构域:位于C末端的丝氨酸蛋白酶结构域、N末端的Pan Apple(PAp)结构域以及5个Kringle结构域(Kringle1-5)。参照swiss prot中的序列,其信号肽包括残基Met1-Gly19,PAp包括残基Glu20-Val98,Kringle1包括残基Cys103-Cys181,Kringle2包括残基Glu184-Cys262,Kringle3包括残基Cys275-Cys352,Kringle4包括残基Cys377-Cys454,Kringle5包括残基Cys481-Cys560。根据NCBI数据,丝氨酸蛋白酶域包括残基Val581-Arg804。
Glu-纤溶酶原是天然全长的纤溶酶原,由791个氨基酸组成(不含有19个氨基酸的信号肽),编码该序列的cDNA序列如序列1所示,其氨基酸序列如序列2所示。在体内,还存在一种是从Glu-纤溶酶原的第76-77位氨基酸处水解从而形成的Lys-纤溶酶原,如序列6所示,编码该氨基酸序列的cDNA序列如序列5所示。δ-纤溶酶原(δ-plasminogen)是全长纤溶酶原缺失了Kringle2-Kringle5结构的片段,仅含有Kringle1和丝氨酸蛋白酶域[18,19],有文献报道了δ-纤溶酶原的氨基酸序列(序列8)[19],编码该氨基酸序列的cDNA序列如序列7。小纤溶酶原(Mini-plasminogen)由Kringle5和丝氨酸蛋白酶域组成,有文献报道其包括残基Val443-Asn791(以不含有信号肽的Glu-纤溶酶原序列的Glu残基为起始氨基酸)[20],其氨基酸序列如序列10所示,编码该氨基酸序列的cDNA序列如序列9所示。而微纤溶酶原(Micro-plasminogen)仅含有丝氨酸蛋白酶结构域,有文献报道其氨基酸序列包括残基Ala543-Asn791(以不含有信号肽的Glu-纤溶酶原序列的Glu残基为起始氨基酸)[21],也有专利文献CN102154253A报道其序列包括残基Lys531-Asn791(以不含有信号肽的Glu-纤溶酶原序列的Glu残基为起始氨基酸),本专利序列参考专利文献CN102154253A,其氨基酸序列如序列12所示,编码该氨基酸序列的cDNA序列如序列11所示。
本发明的“纤溶酶”与“纤维蛋白溶酶”、“纤维蛋白溶解酶”可互换使用,含义相同;“纤溶酶原”与“纤维蛋白溶酶原”、“纤维蛋白溶解酶原”可互换使用,含义相同。
在循环过程中,纤溶酶原采用封闭的非活性构象,但当结合至血栓或细胞表面时,在纤溶酶原激活剂(plasminogen activator,PA)的介导下,其转变为呈开放性构象的活性纤溶酶。具有活性的纤溶酶可进一步将纤维蛋白凝块水解为纤维蛋白降解产物和D-二聚体,进而溶解血栓。其中纤溶酶原的PAp结构域包含维持纤溶酶原处于非活性封闭构象的重要决定簇,而KR结构域则能够与存在于受体和底物上的赖氨酸残基结合。已知多种能够作为纤溶酶原激活剂的酶,包括:组织纤溶酶原激活剂(tPA)、尿激酶纤溶酶原激活剂(uPA)、激肽释放酶和凝血因子XII(哈格曼因子)等。
“纤溶酶原活性片段”是指在纤溶酶原蛋白中,能够与底物中的靶序列结合并发挥蛋白水解功能的活性片段。本发明涉及纤溶酶原的技术方案涵盖了用纤溶酶原活性片段代替纤溶酶原的技术方案。本发明所述的纤溶酶原活性片段为包含纤溶酶原的丝氨酸蛋白酶域的蛋白质,优选,本发明所述的纤溶酶原活性片段包含序列14、与序列14具有至少80%、90%、95%、96%、97%、98%、99%同源性的氨基酸序列的蛋白质。因此,本发明所述的纤溶酶原包括含有该纤溶酶原活性片段、并且仍然保持该纤溶酶原活性的蛋白。
目前,对于血液中纤溶酶原及其活性测定方法包括:对组织纤溶酶原激活剂活性的检测(t-PAA)、血浆组织纤溶酶原激活剂抗原的检测(t-PAAg)、对血浆组织纤溶酶原活性的检测(纤溶酶原A)、血浆组织纤溶酶原抗原的检测(纤溶酶原Ag)、血浆组织纤溶酶原激活剂抑制物活性的检测、血浆组织纤溶酶原激活剂抑制物抗原的检测、血浆纤溶酶-抗纤溶酶复合物检测(PAP)。其中最常用的检测方法为发色底物法:向受检血浆中加链激酶(SK)和发色底物,受检血浆中的纤溶酶原在SK的作用下,转变成PLM,后者作用于发色底物,随后用分光光度计测定,吸光度增加与纤溶酶原活性成正比。此外也可采用免疫化学法、凝胶电泳、免疫比浊法、放射免疫扩散法等对血液中的纤溶酶原活性进行测定。
“直系同源物或直系同系物(ortholog)”指不同物种之间的同源物,既包括蛋白同源物也包括DNA同源物,也称为直向同源物、垂直同源物。其具体指不同物种中由同一祖先基因进化而来的蛋白或基因。本发明的纤维蛋白溶酶原或纤维蛋白溶酶包括人的天然纤维蛋白溶酶原或纤维蛋白溶酶,还包括来源于不同物种的、具有纤维蛋白溶酶原或纤维蛋白溶酶活性的纤维蛋白溶酶原或纤维蛋白溶酶直系同源物或直系同系物。
“保守取代变体”是指其中一个给定的氨基酸残基改变但不改变蛋白质或酶的整体构象和功能,这包括但不限于以相似特性(如酸性,碱性,疏水性,等)的氨基酸取代亲本蛋白质中氨基酸序列中的氨基酸。具有类似性质的氨基酸是众所周知的。例如,精氨酸、组氨酸和赖氨酸是亲水性的碱性氨基酸并可以互换。同样,异亮氨酸是疏水氨基酸,则可被亮氨酸,蛋氨酸或缬氨酸替换。因此,相似功能的两个蛋白或氨基酸序列的相似性可能会不同。例如,基于MEGALIGN算法的70%至99%的相似度(同一性)。“保守取代变体”还包括通过BLAST或FASTA算法确定具有60%以上的氨基酸同一性的多肽或酶,若能达75%以上更好,最好能达85%以上,甚至达90%以上为最佳,并且与天然或亲本蛋白质或酶相比具有相同或基本相似的性质或功能。
“分离的”纤维蛋白溶酶原或纤维蛋白溶酶是指从其天然环境分离和/或回收的纤维蛋白溶酶原或纤维蛋白溶酶蛋白。在一些实施方案中,所述纤维蛋白溶酶原或纤维蛋白溶酶会纯化(1)至大于90%、大于95%、或大于98%的纯度(按重量计),如通过Lowry法所确定的,例如超过99%(按重量计),(2)至足以通过使用旋转杯序列分析仪获得N端或内部氨基酸序列的至少15个残基的程度,或(3)至同质性,该同质性是通过使用考马斯蓝或银染在还原性或非还原性条件下的十二烷基硫酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE)确定的。分离的纤维蛋白溶酶原或纤维蛋白溶酶也包括通过生物工程技术从重组细胞制备,并通过至少一个纯化步骤分离的纤维蛋白溶酶原或纤维蛋白溶酶。
术语“多肽”、“肽”和“蛋白质”在本文中可互换使用,指任何长度的氨基酸的聚合形式,其可以包括遗传编码的和非遗传编码的氨基酸,化学或生物化学修饰的或衍生化的氨基酸,和具有经修饰的肽主链的多肽。该术语包括融合蛋白,包括但不限于具有异源氨基酸序列的融合蛋白,具有异源和同源前导序列(具有或没有N端甲硫氨酸残基)的融合物;等等。
关于参照多肽序列的“氨基酸序列同一性百分数(%)”定义为在必要时引入缺口以实现最大百分比序列同一性后,且不将任何保守替代视为序列同一性的一部分时,候选序列中与参照多肽序列中的氨基酸残基相同的氨基酸残基的百分率。为测定百分比氨基酸序列同一性目的的对比可以以本领域技术范围内的多种方式实现,例如使用公众可得到的计算机软件,诸如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)软件。本领域技术人员能决定用于比对序列的适宜参数,包括对所比较序列全长实现最大对比需要的任何算法。然而,为了本发明的目的,氨基酸序列同一性百分数值是使用序列比较计算机程序ALIGN-2产生的。
在采用ALIGN-2来比较氨基酸序列的情况中,给定氨基酸序列A相对于给定氨基酸序列B的%氨基酸序列同一性(或者可表述为具有或包含相对于、与、或针对给定氨基酸序列B的某一%氨基酸序列同一性的给定氨基酸序列A)如下计算:
分数X/Y乘100
其中X是由序列比对程序ALIGN-2在该程序的A和B比对中评分为相同匹配的氨基酸残基的数目,且其中Y是B中的氨基酸残基的总数。应当领会,在氨基酸序列A的长度与氨基酸序列B的长度不相等的情况下,A相对于B的%氨基酸序列同一性会不等于B相对于A的%氨基酸序列同一性。除非另有明确说明,本文中使用的所有%氨基酸序列同一性值都是依照上一段所述,使用ALIGN-2计算机程序获得的。
如本文中使用的,术语“治疗”、“处理”和“消除”指获得期望的药理和/或生理效果。所述效果可以是完全或部分预防疾病或其症状,和/或部分或完全治愈疾病和/或其症状,并且包括:(a)预防疾病在受试者体内发生,所述受试者可以具有疾病的素因,但是尚未诊断为具有疾病;(b)抑制疾病,即阻滞其形成;和(c)减轻疾病和/或其症状,即引起疾病和/或其症状消退。
术语“个体”、“受试者”和“患者”在本文中可互换使用,指哺乳动物,包括但不限于鼠(大鼠,小鼠)、非人灵长类、人、犬、猫、有蹄动物(例如马、牛、绵羊、猪、山羊)等。
“治疗有效量”或“有效量”指在对哺乳动物或其它受试者施用以治疗疾病时足以实现对疾病的所述预防和/或治疗的纤溶酶原的量。“治疗有效量”会根据所使用的纤溶酶原、要治疗的受试者的疾病和/或其症状的严重程度以及年龄、体重等而变化。
本发明纤维蛋白溶酶原或纤维蛋白溶酶的制备
纤维蛋白溶酶原或纤维蛋白溶酶可以从自然界分离并纯化用于进一步的治疗用途,也可以通过标准的化学肽合成技术来合成。当通过化学合成多肽时,可以经液相或固相进行合成。固相多肽合成(SPPS)(其中将序列的C末端氨基酸附接于不溶性支持物,接着序贯添加序列中剩余的氨基酸)是适合纤维蛋白溶酶原或纤维蛋白溶酶化学合成的方法。各种形式的SPPS,诸如Fmoc和Boc可用于合成纤维蛋白溶酶原或纤维蛋白溶酶。用于固相合成的技术描述于Barany和Solid-Phase Peptide Synthesis;第3-284页于The Peptides:Analysis,Synthesis,Biology.第2卷:Special Methods in Peptide Synthesis,PartA.,Merrifield,等J.Am.Chem.Soc.,85:2149-2156(1963);Stewart等,Solid PhasePeptide Synthesis,2nd ed.Pierce Chem.Co.,Rockford,Ill.(1984);和GanesanA.2006Mini Rev.Med Chem.6:3-10和Camarero JA等2005Protein Pept Lett.12:723-8中。简言之,用其上构建有肽链的功能性单元处理小的不溶性多孔珠。在偶联/去保护的重复循环后,将附接的固相游离N末端胺与单个受N保护的氨基酸单元偶联。然后,将此单元去保护,露出可以与别的氨基酸附接的新的N末端胺。肽保持固定在固相上,之后将其切掉。
可以使用标准重组方法来生产本发明的纤维蛋白溶酶原。例如,将编码纤维蛋白溶酶原的核酸***表达载体中,使其与表达载体中的调控序列可操作连接。表达调控序列包括但不限于启动子(例如天然关联的或异源的启动子)、信号序列、增强子元件、和转录终止序列。表达调控可以是载体中的真核启动子***,所述载体能够转化或转染真核宿主细胞(例如COS或CHO细胞)。一旦将载体掺入合适的宿主中,在适合于核苷酸序列的高水平表达及纤维蛋白溶酶原的收集和纯化的条件下维持宿主。
合适的表达载体通常在宿主生物体中作为附加体或作为宿主染色体DNA的整合部分复制。通常,表达载体含有选择标志物(例如氨苄青霉素抗性、潮霉素抗性、四环素抗性、卡那霉素抗性或新霉素抗性)以有助于对外源用期望的DNA序列转化的那些细胞进行检测。
大肠杆菌(Escherichia coli)是可以用于克隆主题抗体编码多核苷酸的原核宿主细胞的例子。适合于使用的其它微生物宿主包括杆菌,诸如枯草芽孢杆菌(Bacillussubtilis)和其他肠杆菌科(Enterobacteriaceae),诸如沙门氏菌属(Salmonella)、沙雷氏菌属(Serratia)、和各种假单胞菌属(Pseudomonas)物种。在这些原核宿主中,也可以生成表达载体,其通常会含有与宿主细胞相容的表达控制序列(例如复制起点)。另外,会存在许多公知的启动子,诸如乳糖启动子***,色氨酸(trp)启动子***,β-内酰胺酶启动子***,或来自噬菌体λ的启动子***。启动子通常会控制表达,任选在操纵基因序列的情况中,并且具有核糖体结合位点序列等,以启动并完成转录和翻译。
其他微生物,诸如酵母也可用于表达。酵母(例如酿酒酵母(S.cerevisiae))和毕赤酵母(Pichia)是合适的酵母宿主细胞的例子,其中合适的载体根据需要具有表达控制序列(例如启动子)、复制起点、终止序列等。典型的启动子包含3-磷酸甘油酸激酶和其它糖分解酶。诱导型酵母启动于特别包括来自醇脱氢酶、异细胞色素C、和负责麦芽糖和半乳糖利用的酶的启动子。
在微生物外,哺乳动物细胞(例如在体外细胞培养物中培养的哺乳动物细胞)也可以用于表达并生成本发明的抗-Tau抗体(例如编码主题抗-Tau抗体的多核苷酸)。参见Winnacker,From Genes to Clones,VCH Publishers,N.Y.,N.Y.(1987)。合适的哺乳动物宿主细胞包括CHO细胞系、各种Cos细胞系、HeLa细胞、骨髓瘤细胞系、和经转化的B细胞或杂交瘤。用于这些细胞的表达载体可以包含表达控制序列,如复制起点,启动子和增强子(Queen等,Immunol.Rev.89:49(1986)),以及必需的加工信息位点,诸如核糖体结合位点,RNA剪接位点,多聚腺苷酸化位点,和转录终止子序列。合适的表达控制序列的例子是白免疫球蛋白基因、SV40、腺病毒、牛***瘤病毒、巨细胞病毒等衍生的启动子。参见Co等,J.Immunol.148:1149(1992)。
一旦合成(化学或重组方式),可以依照本领域的标准规程,包括硫酸铵沉淀、亲和柱、柱层析、高效液相层析(HPLC)、凝胶电泳等来纯化本发明所述的纤维蛋白溶酶原或纤维蛋白溶酶。该纤维蛋白溶酶原或纤维蛋白溶酶是基本上纯的,例如至少约80%至85%纯的,至少约85%至90%纯的,至少约90%至95%纯的,或98%至99%纯的或更纯的,例如不含污染物,所述污染物如细胞碎片,除主题抗体以外的大分子,等等。
药物配制剂
可以通过将具有所需纯度的纤维蛋白溶酶原或纤维蛋白溶酶与可选的药用载体、赋形剂,或稳定剂(Remington's Pharmaceutical Sciences,16版,Osol,A.ed.(1980))混合形成冻干制剂或水溶液制备治疗配制剂。可接受的载体、赋形剂、稳定剂在所用剂量及浓度下对受者无毒性,并包括缓冲剂例如磷酸盐,柠檬酸盐及其它有机酸;抗氧化剂包括抗坏血酸和蛋氨酸;防腐剂(例如十八烷基二甲基苄基氯化铵;氯化己烷双胺;氯化苄烷铵(benzalkonium chloride),苯索氯铵;酚、丁醇或苯甲醇;烷基对羟基苯甲酸酯如甲基或丙基对羟基苯甲酸酯;邻苯二酚;间苯二酚;环己醇;3-戊醇;间甲酚);低分子量多肽(少于约10个残基);蛋白质如血清白蛋白,明胶或免疫球蛋白;亲水聚合物如聚乙烯吡咯烷酮;氨基酸如甘氨酸,谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖,二糖及其它碳水化合物包括葡萄糖、甘露糖、或糊精;螯合剂如EDTA;糖类如蔗糖、甘露醇、岩藻糖或山梨醇;成盐反离子如钠;金属复合物(例如锌-蛋白复合物);和/或非离子表面活性剂,例如TWEENTM,PLURONICSTM或聚乙二醇(PEG)。优选冻干的抗-VEGF抗体配制剂在WO 97/04801中描述,其包含在本文中作为参考。
本发明的配制剂也可含有需治疗的具体病症所需的一种以上的活性化合物,优选活性互补并且相互之间没有副作用的那些。例如,抗肿瘤药物、抗癌药物、抗感染药、免疫增强剂、止痛药、营养剂和解毒剂等。
本发明的纤维蛋白溶酶原或纤维蛋白溶酶可包裹在通过诸如凝聚技术或界面聚合而制备的微胶囊中,例如,可置入在胶质药物传送***(例如,脂质体,白蛋白微球,微乳剂,纳米颗粒和纳米胶囊)中或置入粗滴乳状液中的羟甲基纤维素或凝胶-微胶囊和聚-(甲基丙烯酸甲酯)微胶囊中。这些技术公开于Remington's Pharmaceutical Sciences 16thedition,Osol,A.Ed.(1980)。
用于体内给药的本发明的纤维蛋白溶酶原或纤维蛋白溶酶必需是无菌的。这可以通过在冷冻干燥和重新配制之前或之后通过除菌滤膜过滤而轻易实现。
本发明的纤维蛋白溶酶原或纤维蛋白溶酶可制备缓释制剂。缓释制剂的适当实例包括具有一定形状且含有糖蛋白的固体疏水聚合物半通透基质,例如膜或微胶囊。缓释基质实例包括聚酯、水凝胶(如聚(2-羟基乙基-异丁烯酸酯)(Langer等,J.Biomed.Mater.Res.,15:167-277(1981);Langer,Chem.Tech.,12:98-105(1982))或聚(乙烯醇)、聚交酯(美国专利3773919,EP58,481)、L-谷氨酸与γ乙基-L-谷氨酸的共聚物(Sidman,等,Biopolymers22:547(1983))、不可降解的乙烯-乙烯乙酸酯(ethylene-vinylacetate)(Langer,等,出处同上),或可降解的乳酸-羟基乙酸共聚物如Lupron DepotTM(由乳酸-羟基乙酸共聚物和亮氨酰脯氨酸(leuprolide)乙酸酯组成的可注射的微球体),以及聚D-(-)-3-羟丁酸。聚合物如乙烯-乙酸乙烯酯和乳酸-羟基乙酸能持续释放分子100天以上,而一些水凝胶释放蛋白的时间却较短。可以根据相关机理来设计使蛋白稳定的合理策略。例如,如果发现凝聚的机理是通过硫代二硫键互换而形成分子间S-S键,则可通过修饰巯基残基、从酸性溶液中冻干、控制湿度、采用合适的添加剂、和开发特定的聚合物基质组合物来实现稳定。
给药和剂量
可以通过不同方式,例如通过静脉内,腹膜内,皮下,颅内,鞘内,动脉内(例如经由颈动脉),肌内,鼻内,表面或皮内施用或脊髓或脑投递来实现本发明药物组合物的施用。气溶胶制剂如鼻喷雾制剂包含活性剂的纯化的水性或其它溶液及防腐剂和等渗剂。将此类制剂调节至与鼻粘膜相容的pH和等渗状态。
用于胃肠外施用的制备物包括无菌水性或非水性溶液、悬浮液和乳剂。非水性溶剂的例子是丙二醇、聚乙二醇、植物油如橄榄油,和可注射有机酯,如油酸乙酯。水性载体包括水、醇性/水性溶液、乳剂或悬浮液,包括盐水和缓冲介质。胃肠外媒介物包含氯化钠溶液、林格氏右旋糖、右旋糖和氯化钠、或固定油。静脉内媒介物包含液体和营养补充物、电解质补充物,等等。也可以存在防腐剂和其他添加剂,例如,抗微生物剂、抗氧化剂、螯合剂、和惰性气体,等等。
医务人员会基于各种临床因素确定剂量方案。如医学领域中公知的,任一患者的剂量取决于多种因素,包括患者的体型、体表面积、年龄、要施用的具体化合物、性别、施用次数和路径、总体健康、和同时施用的其它药物。本发明包含纤溶酶原的药物组合物的剂量范围可以为例如每天约0.0001至2000mg/kg,或约0.001至500mg/kg(例如0.02mg/kg,0.25mg/kg,0.5mg/kg,0.75mg/kg,10mg/kg,50mg/kg等等)受试者体重。例如,剂量可以是1mg/kg体重或50mg/kg体重或在1-50mg/kg的范围,或至少1mg/kg。高于或低于此例示性范围的剂量也涵盖在内,特别是考虑到上述的因素。上述范围中的中间剂量也包含在本发明的范围内。受试者可以每天、隔天、每周或根据通过经验分析确定的任何其它日程表施用此类剂量。例示性的剂量日程表包括连续几天1-10mg/kg。在本发明的药物施用过程中需要实时评估、定期评估放射性和化学性损伤及其相关病症的治疗效果和安全性。
治疗效力和治疗安全性
本发明的一个实施方案涉及使用纤维蛋白溶酶原或纤维蛋白溶酶治疗受试者后,对治疗效力和治疗安全性的判断。其中对所述治疗效力的判断方法包括但不限于:1)免疫***恢复的检查,具体地,例如白细胞、血小板数量的恢复,预期受试者在接受本发明的纤维蛋白溶酶原或纤维蛋白溶酶治疗后上述检测恢复至正常值范围或得到改善,如白细胞恢复至4~10×109/L,血小板恢复至100~300×109/L;2)消化***的不良表现得到改善,包括食欲不振、恶心呕吐、腹泻、便秘等症状具有改善;3)机体各器官功能的改善,包括肝功能如谷丙转氨酶(ALT)、总胆红素水平、肾功能等的改善,具体地,预期受试者在接受本发明的纤维蛋白溶酶原或纤维蛋白溶酶治疗后上述检测恢复至正常值范围或得到改善,如例如,谷丙转氨酶(ALT):0~40μ/L、总胆红素:3.4~20.5μmol/L;4)静脉炎、溃疡等其他症状的改善。此外,本发明还涉及使用纤维蛋白溶酶原或纤维蛋白溶酶对受试者进行治疗过程中和治疗后,所述该治疗方案安全性的判断,包括但不限于对受试者的血清半衰期、治疗半衰期、半数中毒量(TD50)、半数致死量(LD50)进行统计,或对在治疗过程中或治疗后发生的各种不良事件如致敏反应进行观察。
制品或药盒
本发明的一个实施方案涉及一种制品或药盒,其包含可用于治疗放射性和化学性损伤及其相关病症的本发明纤维蛋白溶酶原或纤维蛋白溶酶。所述制品优选包括一个容器,标签或包装插页。适当的容器有瓶子、小瓶、注射器等。容器可由各种材料如玻璃或塑料制成。所述容器含有组合物,所述组合物可有效治疗本发明的疾病或病症并具有无菌入口(例如所述容器可为静脉内溶液包或小瓶,其含有可被皮下注射针穿透的塞子的)。所述组合物中至少一种活性剂为纤维蛋白溶酶原或纤维蛋白溶酶。所述容器上或所附的标签说明所述组合物用于治疗本发明所述放射性和化学性损伤及其相关病症。所述制品可进一步包含含有可药用缓冲液的第二容器,诸如磷酸盐缓冲的盐水,林格氏溶液以及葡萄糖溶液。其可进一步包含从商业和使用者角度来看所需的其它物质,包括其它缓冲液,稀释剂,过滤物,针和注射器。此外,所述制品包含带有使用说明的包装插页,包括例如指示所述组合物的使用者将纤维蛋白溶酶原或纤维蛋白溶酶组合物以及治疗伴随的疾病的其它药物给药患者。
附图简述
图1显示给予纤溶酶原对5.0Gy X射线辐射后小鼠体重的变化。
图2显示5.0Gy X射线辐射过的小鼠给予纤溶酶原10天后肾脏的HE染色观察结果。
图3显示5.0Gy X射线辐射过的小鼠给予纤溶酶原10天后肾脏的巨噬细胞标志物F4/80免疫组化染色观察结果。
图4显示5.0Gy X射线辐射过的小鼠给予纤溶酶原10天后十二指肠的HE染色观察结果。
图5显示5.0Gy X射线辐射过的小鼠给予纤溶酶原10天后十二指肠巨噬细胞标志物F4/80免疫组化染色观察结果。
图6显示5.0Gy X射线辐射过的小鼠给予纤溶酶原10天后肝脏巨噬细胞标志物F4/80免疫组化染色观察结果。
图7显示5.0Gy X射线辐射过的小鼠给予纤溶酶原1、4、7、14天后肝脏HE染色观察结果。
图8显示10mg/kg顺铂化疗损伤模型小鼠给予纤溶酶原7天后体重的变化。
图9显示10mg/kg顺铂化疗损伤模型小鼠给予纤溶酶原7天后肾脏HE染色观察结果。
图10显示10mg/kg顺铂化疗损伤模型小鼠给予纤溶酶原7天后肾脏纤维蛋白免疫组化染色观察结果。
图11显示10mg/kg顺铂化疗损伤模型小鼠给予纤溶酶原7天后肾脏Bcl-2免疫组化染色观察结果。
图12显示10mg/kg顺铂化疗损伤模型小鼠给予纤溶酶原7天后肝脏的HE染色观察结果。
图13显示10mg/kg顺铂化疗损伤模型小鼠给予纤溶酶原7天后肝脏纤维蛋白免疫组化染色观察结果。
图14显示10mg/kg顺铂化疗损伤模型小鼠给予纤溶酶原7天后睾丸和附睾的HE染色观察结果。
实施例
材料与方法:
放射性损伤模型:
实验动物:7-8周龄SPF级健康雄性C57小鼠用于5.0Gy照射后研究脾肝肾等器官的病理组织学改变。动物适应性饲养7天后随机分成三组,分别为空白对照组、单纯辐照组和给纤溶酶原组。
实验方法:采用直线加速器6MV X射线5.0Gy小鼠全身单次均匀照射,吸收剂量率2.0Gy/min,吸收剂量为5.0Gy为亚致死量照射,用于研究脾肝肾等器官的病理组织学改变、造血和免疫功能及自由基检测,源皮距100cm,照射面积30cm×30cm,正常对照组盖以铅块保护。受照后给药至小鼠死亡或特定时间处死,对照组给予相应体积的溶媒。观察受照小鼠大体情况、并在光镜下观察肝、肠组织、肾组织HE染色病理组织学改变以及F4/80的免疫组化染色。
观察指标:
1.肝、肠、肾病理组织学观察:
小鼠摘眼球取血处死后取脾肝、肠、肾组织,用10%中性***固定、经梯度酒精脱水、二甲苯透明、石蜡包埋、石蜡切片(片厚5μm),常规HE染色后中性树胶封片,镜下观察各组织病理学改变。
2.肝、肠、肾F4/80免疫组化染色观察。
肝、肠、肾石蜡切片(片厚5μm),免疫组化染色后镜下观察其在各组织中的表达情况。
化学性损伤模型:
实验动物:7-8周龄SPF级健康雄性C57小鼠用于抗顺铂毒副作用效果观察,动物适应性饲养7天后随机分成三组,分别为空白对照组、单纯模型组和给纤溶酶原组。
实验方法:
顺铂组:将顺铂针剂用生理盐水配成质量浓度为1mg/ml的水溶液,按3.5ml/kg体重经腹腔注射给药。对照组小鼠每次腹腔注射等体积的生理盐水。连续给药5d造模,造模后治疗组按1mg/只给予纤溶酶原,对照组和模型组给予同体积的溶媒,在给纤溶酶原后的第7天处死动物。分别取血和肾组织等进行指标检测。
观察指标:
1.体重变化曲线:每天在给药前测量小鼠体重,观察各组小鼠体重的变化。
2.肾脏系数:处死小鼠后,立即取肾组织,新鲜称重,计算肾脏系数[肾脏系数Z(脏器质量/体重)×100%]。
3.肾脏组织HE观察:用10%中性***固定、经梯度酒精脱水、二甲苯透明、石蜡包埋、石蜡切片(片厚5μm),常规HE染色后中性树胶封片,镜下观察各组织病理学改变。
4.动物胸腺系数和脾脏系数:处死小鼠后,立即取胸腺和脾脏,新鲜称重,计算胸腺系数和脾脏系数[脏器系数Z(脏器质量/体重)×100%]。
5.睾丸和附睾重量:处死各组小鼠后,取材睾丸和附睾,称重后进行统计学分析。
6.睾丸组织形态学观察:睾丸组织经常规固定、脱水、包埋、切片后,进行HE染色观察睾丸组织形态学变化。
实施例1纤溶酶原对5.0Gy X射线辐射后小鼠体重的影响
本实验使用6-8周龄健康的雄性C57小鼠10只,随机分为两组,给溶媒PBS对照组和给纤溶酶原组,每组各5只。分组完成后,建立放射损伤模型,采用直线加速器6MV X射线按5.0Gy对小鼠全身单次均匀照射,吸收剂量率2.0Gy/min,吸收剂量为5.0Gy(照射2.5分钟)。建立模型后,3个小时内给予纤溶酶原。实验开始当天为第0天,称量体重并分组,第1天开始辐射处理并给予纤溶酶原或溶媒PBS,给药期为10天,给药完成后对动物进行停药观察11天,整个实验期为21天。给纤溶酶原组按1mg/0.1mL/只/天经尾静脉注射给药,给溶媒PBS对照组给予相同体积的PBS。在实验的第0、5、12、21天称量记录小鼠的体重。
给溶媒PBS对照组和给纤溶酶原组,在第0、5、12、21天的体重数据统计均无明显差异(图1)。说明X射线辐射和给药处理不影响小鼠体重。
实施例2纤溶酶原对5.0Gy X射线辐射小鼠肾脏的保护作用
本实验使用6-8周龄健康的雄性C57小鼠10只,随机分为两组,给溶媒PBS对照组和给纤溶酶原组,每组各5只。分组完成后,建立放射损伤模型,采用直线加速器6MV X射线按5.0Gy对小鼠全身单次均匀照射,吸收剂量率2.0Gy/min,吸收剂量为5.0Gy(照射2.5分钟)。建立模型后,3个小时内给予纤溶酶原。实验开始当天为第0天称量体重并分组,第1天开始辐射处理并给予纤溶酶原或溶媒PBS,给药期为10天给药完成后对动物进行停药观察11天,整个实验期为21天。给纤溶酶原组按1mg/0.1mL/只/天经尾静脉注射给药,给溶媒PBS对照组给予相同体积的PBS。在第21天处死解剖小鼠并取肾脏在10%中性***固定液中固定24-48小时。固定后的肾脏组织经酒精梯度脱水和二甲苯透明后进行石蜡包埋。组织切片厚度为5μm,切片脱蜡复水并用苏木素和伊红染色(HE染色),1%盐酸酒精分化,氨水返蓝,并酒精梯度脱水封片,切片在显微镜下200倍观察。
结果显示,对于给溶媒PBS对照组(图2A),可见肾小球萎缩(*),肾小管蛋白管型(◤);而对于给纤溶酶原组(图2B),肾小球毛细血管腔通畅,球囊腔清晰可见。给纤溶酶原组肾脏的损伤明显轻于给溶媒PBS对照组,说明注射纤溶酶原能够促进X射线辐射所致的肾损伤的修复。
实施例3纤溶酶原促进5.0Gy X射线辐射小鼠肾脏炎症的修复
本实验使用6-8周龄健康的雄性C57小鼠10只,随机分为两组,给溶媒PBS对照组和给纤溶酶原组,每组各5只。分组完成后,建立放射损伤模型,采用直线加速器6MV X射线按5.0Gy对小鼠全身单次均匀照射,吸收剂量率2.0Gy/min,吸收剂量为5.0Gy(照射2.5分钟)。建立模型后,3个小时内给予纤溶酶原。实验开始当天为第0天称量体重并分组,第1天开始辐射处理并给予纤溶酶原或溶媒PBS,给药期为10天给药完成后对动物进行停药观察11天,整个实验期为21天。给纤溶酶原组按1mg/0.1mL/只/天经尾静脉注射给药,给溶媒PBS对照组给予相同体积的PBS。在第21天处死解剖小鼠并取肾脏在10%中性***固定液中固定24-48小时。固定后的肾脏组织经酒精梯度脱水和二甲苯透明后进行石蜡包埋。组织切片厚度为5μm,切片脱蜡复水后水洗1次。Tris-EDTA修复30分钟,室温冷却20分钟后水轻柔冲洗。以3%双氧水孵育15分钟,用PAP笔圈出组织。10%的正常羊血清(Vectorlaboratories,Inc.,USA)封闭1小时;时间到后,弃除羊血清液。兔抗小鼠F4/80抗体(Abcam)4℃孵育过夜,TBS洗2次,每次5分钟。山羊抗兔IgG(HRP)抗体(Abcam)二抗室温孵育1小时,TBS洗2次,每次5分钟。按DAB试剂盒(Vector laboratories,Inc.,USA)显色,水洗3次后苏木素复染30秒,流水冲洗5分钟。梯度脱水透明并封片,切片在显微镜下200倍下观察。
F4/80巨噬细胞标志物,可以表示炎症反应的程度和阶段。结果显示,给溶媒PBS对照组(图3A)的小鼠巨噬细胞标志物F4/80的表达量高于给纤溶酶原组(图3B),说明给纤溶酶原后,动物肾脏组织的炎症显著减轻。定量分析结果与镜检观察一致,且统计差异显著(图3C),表明纤溶酶原能够促进X射线辐射所致的肾脏炎症的修复。
实施例4纤溶酶原对5.0Gy X射线辐射小鼠十二指肠的保护作用
本实验使用6-8周龄健康的雄性C57小鼠10只,随机分为两组,给溶媒PBS对照组和给纤溶酶原组,每组各5只。分组完成后,建立放射损伤模型,采用直线加速器6MV X射线按5.0Gy对小鼠全身单次均匀照射,吸收剂量率2.0Gy/min,吸收剂量为5.0Gy(照射2.5分钟)。建立模型后,3个小时内给予纤溶酶原。实验开始当天为第0天称量体重并分组,第1天开始辐射处理并给予纤溶酶原或溶媒PBS,给药期为10天给药完成后对动物进行停药观察11天,整个实验期为21天。给纤溶酶原组按1mg/0.1mL/只/天经尾静脉注射给药,给溶媒PBS对照组给予相同体积的PBS。在第21天处死解剖小鼠并取十二指肠在10%中性***固定液中固定24-48小时。固定后的十二指肠组织经酒精梯度脱水和二甲苯透明后进行石蜡包埋。组织切片厚度为5μm,切片脱蜡复水并用苏木素和伊红染色(HE染色),1%盐酸酒精分化,氨水返蓝,并酒精梯度脱水封片,切片在显微镜下200倍下观察。
结果显示,对于给溶媒PBS对照组(图4A),局部肠壁粘膜上皮脱离,变性坏死,脱落处正常粘膜层结构消失;而对于给纤溶酶原组(图4B),可见红染折光的纹状缘,粘膜上皮可见杯状细胞,绒毛中心为固有层,结构清晰,层次分明。给纤溶酶原组十二指肠的损伤明显轻于给溶媒PBS对照组,注射纤溶酶原能够促进X射线辐射所致的十二指肠损伤的修复。
实施例5纤溶酶原促进5.0Gy X射线辐射小鼠十二指肠炎症的修复
本实验使用6-8周龄健康的雄性C57小鼠10只,随机分为两组,给溶媒PBS对照组和给纤溶酶原组,每组各5只。分组完成后,建立放射损伤模型,采用直线加速器6MV X射线按5.0Gy对小鼠全身单次均匀照射,吸收剂量率2.0Gy/min,吸收剂量为5.0Gy(照射2.5分钟)。建立模型后,3个小时内给予纤溶酶原。实验开始当天为第0天称量体重并分组,第1天开始辐射处理并给予纤溶酶原或溶媒PBS,给药期为10天给药完成后对动物进行停药观察11天,整个实验期为21天。给纤溶酶原组按1mg/0.1mL/只/天经尾静脉注射给药,给溶媒PBS对照组给予相同体积的PBS。在第21天处死解剖小鼠并取十二指肠在10%中性***固定液中固定24-48小时。固定后的十二指肠组织经酒精梯度脱水和二甲苯透明后进行石蜡包埋。组织切片厚度为5μm,切片脱蜡复水后水洗1次。Tris-EDTA修复30分钟,室温冷却20分钟后水轻柔冲洗。以3%双氧水孵育15分钟,用PAP笔圈出组织。10%的正常羊血清(Vectorlaboratories,Inc.,USA)封闭1小时;时间到后,弃除羊血清液。兔抗小鼠F4/80抗体(Abcam)4℃孵育过夜,TBS洗2次,每次5分钟。山羊抗兔IgG(HRP)抗体(Abcam)二抗室温孵育1小时,TBS洗2次,每次5分钟。按DAB试剂盒(Vector laboratories,Inc.,USA)显色,水洗3次后苏木素复染30秒,流水冲洗5分钟。梯度脱水透明并封片,切片在显微镜下200倍下观察。
结果显示,给溶媒PBS对照组(图5A)的小鼠F4/80表达量明显高于给纤溶酶原组(图5B),说明给纤溶酶原后,十二指肠的炎症显著减轻,反映纤溶酶原能够促进X射线辐射所致的十二指肠炎症的修复。
实施例6纤溶酶原促进5.0GyX射线辐射小鼠肝脏炎症的修复
本实验使用6-8周龄健康的雄性C57小鼠10只,随机分为两组,给溶媒PBS对照组和给纤溶酶原组,每组各5只。分组完成后,建立放射损伤模型,采用直线加速器6MV X射线按5.0Gy对小鼠全身单次均匀照射,吸收剂量率2.0Gy/min,吸收剂量为5.0Gy(照射2.5分钟)。建立模型后,3个小时内给予纤溶酶原。实验开始当天为第0天称量体重并分组,第1天开始辐射处理并给予纤溶酶原或溶媒PBS,给药期为10天给药完成后对动物进行停药观察11天,整个实验期为21天。给纤溶酶原组按1mg/0.1mL/只/天经尾静脉注射给药,给溶媒PBS对照组给予相同体积的PBS。在第21天处死解剖小鼠并取肝脏在10%中性***固定液中固定24-48小时。固定后的肝脏组织经酒精梯度脱水和二甲苯透明后进行石蜡包埋。组织切片厚度为5μm,切片脱蜡复水后水洗1次。Tris-EDTA修复30分钟,室温冷却20分钟后水轻柔冲洗。以3%双氧水孵育15分钟,用PAP笔圈出组织。10%的正常羊血清(Vectorlaboratories,Inc.,USA)封闭1小时;时间到后,弃除羊血清液。兔抗小鼠F4/80抗体(Abcam)4℃孵育过夜,TBS洗2次,每次5分钟。山羊抗兔IgG(HRP)抗体(Abcam)二抗室温孵育1小时,TBS洗2次,每次5分钟。按DAB试剂盒(Vector laboratories,Inc.,USA)显色,水洗3次后苏木素复染30秒,流水冲洗5分钟。梯度脱水透明并封片,切片在显微镜下200倍下观察。
F4/80免疫组化结果显示,5.0Gy X射线照射造模后给溶媒PBS对照组(图6A)的小鼠巨噬细胞标志物F4/80的表达量高于给纤溶酶原组(图6B)。说明给纤溶酶原后,动物肝脏组织的炎症显著减轻。、
实施例7纤溶酶原对5.0Gy X射线辐射小鼠肝脏的保护作用
本实验使用6-8周龄健康的雄性C57小鼠24只,随机分为两组,给溶媒PBS对照组和给纤溶酶原组,每组各12只。分组完成后,建立放射损伤模型,采用直线加速器6MV X射线按5.0Gy对小鼠全身单次均匀照射,吸收剂量率2.0Gy/min,吸收剂量为5.0Gy(照射2.5分钟)。建立模型后,3个小时内给予纤溶酶原。给纤溶酶原组按1mg/0.1mL/只/天经尾静脉注射给药,给溶媒PBS对照组给予相同体积的PBS。实验开始当天为第0天称量体重并分组,第1天开始辐射处理并给予纤溶酶原或溶媒PBS,给药期为14天。照射后第1、4、7、14天,每个时间点处死3只动物,取小鼠肝脏在10%中性***固定液中固定24-48小时。固定后的肝脏组织经酒精梯度脱水和二甲苯透明后进行石蜡包埋。组织切片厚度为5μm,切片脱蜡复水并用苏木素和伊红染色(HE染色),1%盐酸酒精分化,氨水返蓝,并酒精梯度脱水封片,切片在显微镜下200倍下观察。
结果显示,对于给溶媒PBS对照组(图7a-d)第1天肝脏,肝索以中央静脉为中心放射状向四周扩散,纹理规则,肝窦清晰,部分肝细胞变性坏死,核溶解,胞浆淡染(↓);第4天肝窦内轻度炎细胞浸润(),肝窦变窄;第7天肝细胞坏死进一步加重,并且肝细胞呈现了轻度水样变性(◤),胞浆溶解,肝索紊乱;第14天肝脏已有较大的好转,肝索较规则,肝窦清晰,但仍在临近中央静脉处肝窦内有少量炎细胞浸润。
给纤溶酶原组(图7e-g)第1天肝脏,肝索规则,肝窦清晰,有少量肝细胞坏死(↓);第4天肝脏在中央静脉周围肝细胞出现了轻度的水样变性(◤);从第7天开始,肝脏病变开始好转,肝索以中央静脉为中心放射状排列,肝窦清晰;第14天肝脏也呈现不断好转,坏死较第一天明显减轻,肝索比之第7天也更加规则。
总而言之,PBS对照组从第1天至第7天,肝脏呈现渐进性损伤,到了第14天才有好转的趋势;而给药组虽然从第1天至第4天肝脏有损伤的趋势,但是从第7天开始肝脏就已经出现了较大幅度的好转。说明纤溶酶原能够促进修复X射线辐射所致的肝脏损伤。
实施例8纤溶酶原对顺铂化疗损伤模型小鼠体重的影响
本实验使用8-9周龄健康的雄性C57小鼠10只,随机分为两组,给溶媒PBS对照组和给纤溶酶原组,每组各5只。分组完成后,建立化疗损伤模型,按10mg/Kg体重单次腹腔注射顺铂。建立模型后,给纤溶酶原组按1mg/0.1mL/只/天经尾静脉注射给予纤溶酶原,给溶媒PBS对照组给予相同体积的PBS。实验开始当天为第0天称量体重并分组,第1天开始腹腔注射顺铂造模,造模后3小时内给予纤溶酶原或溶媒PBS,给药期为7天,在第0天和7天称重。结果显示,给溶媒PBS对照组小鼠体重显著减轻,并有统计学差异;而给纤溶酶原组小鼠体重虽有减轻但并不明显(图8)。说明纤溶酶原能够显著减轻化疗药物顺铂对动物体重的影响。
实施例9纤溶酶原对顺铂化疗损伤模型小鼠肾脏的保护作用
本实验使用8-9周龄健康的雄性C57小鼠10只,随机分为两组,给溶媒PBS对照组和给纤溶酶原组,每组各5只。分组完成后,建立化疗损伤模型,按10mg/Kg体重单次腹腔注射顺铂。建立模型后,给纤溶酶原组按1mg/0.1mL/只/天1mg/只/天经尾静脉注射给予纤溶酶原,给溶媒PBS对照组给予相同体积的PBS。实验开始当天为第0天称量体重并分组,第1天开始腹腔注射顺铂造模,造模后3小时内给予纤溶酶原或溶媒PBS,给药期为7天。第8天处死小鼠,取肾脏在10%中性***固定液中固定24-48小时。固定后的肾脏组织经酒精梯度脱水和二甲苯透明后进行石蜡包埋。组织切片厚度为5μm,切片脱蜡复水并用苏木素和伊红染色(HE染色),1%盐酸酒精分化,氨水返蓝,并酒精梯度脱水封片,切片在显微镜下200倍下观察。
HE结果显示,给溶媒PBS对照组(图9A)出现肾小管上皮细胞坏死(◤),并伴有炎症细胞浸润(↓);而给纤溶酶原组(图9B)肾小管未有明显坏死,仅伴有少量炎症细胞的浸润。说明纤溶酶原能够减轻化疗药顺铂所致的肾脏损伤。
实施例10纤溶酶原促进顺铂化疗损伤模型小鼠肾脏纤维蛋白的降解
本实验使用8-9周龄健康的雄性C57小鼠10只,随机分为两组,给溶媒PBS对照组和给纤溶酶原组,每组各5只。分组完成后,建立化疗损伤模型,按10mg/Kg体重单次腹腔注射顺铂。建立模型后,给纤溶酶原组按1mg/0.1mL/只/天经尾静脉注射给予纤溶酶原,给溶媒PBS对照组给予相同体积的PBS。实验开始当天为第0天称量体重并分组,第1天开始腹腔注射顺铂造模,造模后3小时内给予纤溶酶原或溶媒PBS,给药期为7天。第8天处死小鼠,取肾脏在10%中性***固定液中固定24-48小时。固定后的肾脏组织经酒精梯度脱水和二甲苯透明后进行石蜡包埋。组织切片厚度为5μm,切片脱蜡复水后水洗1次。柠檬酸修复30分钟,室温冷却10分钟后水轻柔冲洗。以3%双氧水孵育15分钟,用PAP笔圈出组织。10%的正常羊血清(Vector laboratories,Inc.,USA)封闭1小时;时间到后,弃除羊血清液。兔抗小鼠纤维蛋白抗体(Abcam)4℃孵育过夜,TBS洗2次,每次5分钟。山羊抗兔IgG(HRP)抗体(Abcam)二抗室温孵育1小时,TBS洗2次,每次5分钟。按DAB试剂盒(Vector laboratories,Inc.,USA)显色,水洗3次后苏木素复染30秒,流水冲洗5分钟。梯度脱水透明并封片,切片在显微镜下200倍下观察。
纤维蛋白原是纤维蛋白的前体,在组织存在损伤的情况下,作为机体对损伤的一种应激反应,纤维蛋白原水解成纤维蛋白沉积在损伤部位[22-24]。因此,可将损伤局部纤维蛋白水平作为损伤程度的一个标志。
结果显示,给溶媒PBS对照组(图10A)纤维蛋白的阳性着色显著深于给纤溶酶原组(图10B)。说明纤溶酶原能够显著减轻化疗药物顺铂所致的纤维蛋白沉积,有助于化疗药物顺铂所致的肾脏损伤的修复。
实施例11纤溶酶原促进顺铂化疗损伤模型小鼠肾脏凋亡抑制蛋白Bcl-2的表达
本实验使用8-9周龄健康的雄性C57小鼠10只,随机分为两组,给溶媒PBS对照组和给纤溶酶原组,每组各5只。分组完成后,建立化疗损伤模型,按10mg/Kg体重单次腹腔注射顺铂。建立模型后,给纤溶酶原组按1mg/0.1mL/只/天经尾静脉注射给予纤溶酶原,给溶媒PBS对照组给予相同体积的PBS。实验开始当天为第0天称量体重并分组,第1天开始腹腔注射顺铂造模,造模后3小时内给予纤溶酶原或溶媒PBS,给药期为7天。第8天处死小鼠,取肾脏在10%中性***固定液中固定24-48小时。固定后的肾脏组织经酒精梯度脱水和二甲苯透明后进行石蜡包埋。组织切片厚度为5μm,切片脱蜡至水后水洗1次。柠檬酸修复30分钟,室温冷却10分钟后水轻柔冲洗。以3%双氧水孵育15分钟,用PAP笔圈出组织。10%的正常羊血清(Vector laboratories,Inc.,USA)封闭1小时;时间到后,弃除羊血清液。兔抗小鼠Bcl-2抗体(Abcam)4℃孵育过夜,TBS洗2次,每次5分钟。山羊抗兔IgG(HRP)抗体(Abcam)二抗室温孵育1小时,TBS洗2次,每次5分钟。按DAB试剂盒(Vector laboratories,Inc.,USA)显色,水洗3次后苏木素复染30秒,流水冲洗5分钟。梯度脱水透明并封片,切片在显微镜下200倍下观察。
Bcl-2为细胞凋亡抑制蛋白,在凋亡刺激因子作用下会下调表达[25,26]。结果显示,给溶媒PBS对照组(图11A)肾脏组织中Bcl-2的阳性着色明显低于给纤溶酶原组(图11B)。说明纤溶酶原能显著提高化疗药物顺铂所致的肾脏组织中凋亡抑制蛋白Bcl-2的表达,从而有助于抑制肾脏组织细胞的凋亡。
实施例12纤溶酶原对顺铂化疗损伤模型小鼠肝脏的保护作用
本实验使用8-9周C57小鼠10只,给溶媒PBS对照组和给纤溶酶原组各5只。分组完成后,建立化疗损伤模型,按10mg/Kg体重单次腹腔注射顺铂。建立模型后,给纤溶酶原组按1mg/0.1mL/只/天尾静脉注射纤溶酶原,给溶媒PBS对照组给予相同体积的PBS。实验开始当天为第0天称量体重并分组,第1天开始腹腔注射顺铂并给予纤溶酶原或溶媒PBS,给药期为7天。第8天处死小鼠,取肝脏在10%中性***固定液中固定24-48小时。固定后的肝脏组织经酒精梯度脱水和二甲苯透明后进行石蜡包埋。组织切片厚度为5μm,切片脱蜡复水并用苏木素和伊红染色(HE染色),1%盐酸酒精分化,氨水返蓝,并酒精梯度脱水封片,切片在显微镜下200倍下观察。
HE结果显示,给溶媒PBS组(图12A)肝脏中央静脉扩张,内皮细胞坏死,周围轻度炎细胞浸润,还可见较大的炎性灶(↓),肝细胞点状坏死,核碎裂,胞浆淡染,肝索紊乱;而给纤溶酶组(图12B)肝脏肝索以中央静脉为中心向四周发散,肝窦清晰,胞浆红染,肝细胞坏死和炎细胞浸润明显减轻。说明纤溶酶原能够显著减轻化疗药顺铂所致的肝脏损伤。
实施例13纤溶酶原促进顺铂化疗损伤模型小鼠肝脏纤维蛋白的降解
本实验使用8-9周龄健康的雄性C57小鼠10只,随机分为两组,给溶媒PBS对照组和给纤溶酶原组,每组各5只。分组完成后,建立化疗损伤模型,按10mg/Kg体重单次腹腔注射顺铂。建立模型后,给纤溶酶原组按1mg/0.1mL/只/天经尾静脉注射给予纤溶酶原,给溶媒PBS对照组给予相同体积的PBS。实验开始当天为第0天称量体重并分组,第1天开始腹腔注射顺铂造模,造模后3小时内给予纤溶酶原或溶媒PBS,给药期为7天。第8天处死小鼠,取肝脏在10%中性***固定液中固定24-48小时。固定后的肝脏组织经酒精梯度脱水和二甲苯透明后进行石蜡包埋。组织切片厚度为5μm,切片脱蜡复水后水洗1次。柠檬酸修复30分钟,室温冷却10分钟后水轻柔冲洗。以3%双氧水孵育15分钟,用PAP笔圈出组织。10%的正常羊血清(Vector laboratories,Inc.,USA)封闭1小时;时间到后,弃除羊血清液。兔抗小鼠纤维蛋白抗体(Abcam)4℃孵育过夜,TBS洗2次,每次5分钟。山羊抗兔IgG(HRP)抗体(Abcam)二抗室温孵育1小时,TBS洗2次,每次5分钟。按DAB试剂盒(Vector laboratories,Inc.,USA)显色,水洗3次后苏木素复染30秒,流水冲洗5分钟。梯度脱水透明并封片,切片在显微镜下200倍下观察。
纤维蛋白原是纤维蛋白的前体,在组织存在损伤的情况下,作为机体对损伤的一种应激反应,纤维蛋白原水解成纤维蛋白沉积在损伤部位[22-24]。因此,可将损伤局部纤维蛋白水平作为损伤程度的一个标志。
结果显示,给溶媒PBS照组(图13A)肝脏组织中纤维蛋白阳性着色明显深于给纤溶酶原组(图13B)。说明纤溶酶原能够显著减轻纤维蛋白的沉积,从而促进化疗药顺铂所致的肝脏损伤的修复。
实施例14纤溶酶原降低顺铂处理对小鼠的生殖器官的毒性
本实验使用8-9周龄健康的雄性C57小鼠10只,随机分为两组,给溶媒PBS对照组和给纤溶酶原组,每组各5只。分组完成后,建立化疗损伤模型,按10mg/Kg体重单次腹腔注射顺铂。建立模型后,给纤溶酶原组按1mg/0.1mL/只天经尾静脉注射给予纤溶酶原,给溶媒PBS对照组给予相同体积的PBS。实验开始当天为第0天称量体重并分组,第1天开始腹腔注射顺铂造模,造模3小时内给予纤溶酶原或溶媒PBS,给药期为7天。第8天处死小鼠,取睾丸和附睾在10%中性***固定液中固定24-48小时。固定后的睾丸和附睾组织经酒精梯度脱水和二甲苯透明后进行石蜡包埋。组织切片厚度为5μm,切片脱蜡复水并用苏木素和伊红染色(HE染色),1%盐酸酒精分化,氨水返蓝,并酒精梯度脱水封片,切片在显微镜下200倍下观察。
结果显示,溶媒PBS对照组附睾输精管(图14A)中***数减少,并伴有附睾组织多处坏死,***数目较之于给纤溶酶组明显减少,睾丸(图14C)间质多处坏死();与给溶媒PBS对照组相比,给纤溶酶原组附睾输精管(图14B)中***数也明显多于给溶媒PBS对照组,***(图14D)坏死病灶(单处坏死病灶)也明显减少。说明纤溶酶原能够减轻化疗药顺铂所致的生殖器官毒性。
参考文献:
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序列表
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Ser Gly His Thr Cys Gln His Trp Ser Ala Gln Thr Pro His Thr His
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Pro Arg Lys Leu Tyr Asp Tyr Cys Asp Val Pro Gln Cys Ala Ala Pro
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Ser Phe Asp Cys Gly Lys Pro Gln Val Glu Pro Lys Lys Cys Pro Gly
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gatggacaga gctaccgagg cacatcctcc accaccacca caggaaagaa gtgtcagtct 1200
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ctgacaatga actactgcag gaatccagat gccgataaag gcccctggtg ttttaccaca 1320
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aatccacggg cgggtctgga aaaaaattac tgccgtaacc ctgatggtga tgtaggtggt 1620
ccctggtgct acacgacaaa tccaagaaaa ctttacgact actgtgatgt ccctcagtgt 1680
gcggcccctt catttgattg tgggaagcct caagtggagc cgaagaaatg tcctggaagg 1740
gttgtagggg ggtgtgtggc ccacccacat tcctggccct ggcaagtcag tcttagaaca 1800
aggtttggaa tgcacttctg tggaggcacc ttgatatccc cagagtgggt gttgactgct 1860
gcccactgct tggagaagtc cccaaggcct tcatcctaca aggtcatcct gggtgcacac 1920
caagaagtga atctcgaacc gcatgttcag gaaatagaag tgtctaggct gttcttggag 1980
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gtaatcccag cttgtctgcc atccccaaat tatgtggtcg ctgaccggac cgaatgtttc 2100
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<210> 4
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<213> 含有信号肽的天然纤溶酶原(来源于swiss prot)的氨基酸序列
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Met Glu His Lys Glu Val Val Leu Leu Leu Leu Leu Phe Leu Lys Ser
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Lys Ser Ser Ile Ile Ile Arg Met Arg Asp Val Val Leu Phe Glu Lys
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Lys Val Tyr Leu Ser Glu Cys Lys Thr Gly Asn Gly Lys Asn Tyr Arg
100 105 110
Gly Thr Met Ser Lys Thr Lys Asn Gly Ile Thr Cys Gln Lys Trp Ser
115 120 125
Ser Thr Ser Pro His Arg Pro Arg Phe Ser Pro Ala Thr His Pro Ser
130 135 140
Glu Gly Leu Glu Glu Asn Tyr Cys Arg Asn Pro Asp Asn Asp Pro Gln
145 150 155 160
Gly Pro Trp Cys Tyr Thr Thr Asp Pro Glu Lys Arg Tyr Asp Tyr Cys
165 170 175
Asp Ile Leu Glu Cys Glu Glu Glu Cys Met His Cys Ser Gly Glu Asn
180 185 190
Tyr Asp Gly Lys Ile Ser Lys Thr Met Ser Gly Leu Glu Cys Gln Ala
195 200 205
Trp Asp Ser Gln Ser Pro His Ala His Gly Tyr Ile Pro Ser Lys Phe
210 215 220
Pro Asn Lys Asn Leu Lys Lys Asn Tyr Cys Arg Asn Pro Asp Arg Glu
225 230 235 240
Leu Arg Pro Trp Cys Phe Thr Thr Asp Pro Asn Lys Arg Trp Glu Leu
245 250 255
Cys Asp Ile Pro Arg Cys Thr Thr Pro Pro Pro Ser Ser Gly Pro Thr
260 265 270
Tyr Gln Cys Leu Lys Gly Thr Gly Glu Asn Tyr Arg Gly Asn Val Ala
275 280 285
Val Thr Val Ser Gly His Thr Cys Gln His Trp Ser Ala Gln Thr Pro
290 295 300
His Thr His Asn Arg Thr Pro Glu Asn Phe Pro Cys Lys Asn Leu Asp
305 310 315 320
Glu Asn Tyr Cys Arg Asn Pro Asp Gly Lys Arg Ala Pro Trp Cys His
325 330 335
Thr Thr Asn Ser Gln Val Arg Trp Glu Tyr Cys Lys Ile Pro Ser Cys
340 345 350
Asp Ser Ser Pro Val Ser Thr Glu Gln Leu Ala Pro Thr Ala Pro Pro
355 360 365
Glu Leu Thr Pro Val Val Gln Asp Cys Tyr His Gly Asp Gly Gln Ser
370 375 380
Tyr Arg Gly Thr Ser Ser Thr Thr Thr Thr Gly Lys Lys Cys Gln Ser
385 390 395 400
Trp Ser Ser Met Thr Pro His Arg His Gln Lys Thr Pro Glu Asn Tyr
405 410 415
Pro Asn Ala Gly Leu Thr Met Asn Tyr Cys Arg Asn Pro Asp Ala Asp
420 425 430
Lys Gly Pro Trp Cys Phe Thr Thr Asp Pro Ser Val Arg Trp Glu Tyr
435 440 445
Cys Asn Leu Lys Lys Cys Ser Gly Thr Glu Ala Ser Val Val Ala Pro
450 455 460
Pro Pro Val Val Leu Leu Pro Asp Val Glu Thr Pro Ser Glu Glu Asp
465 470 475 480
Cys Met Phe Gly Asn Gly Lys Gly Tyr Arg Gly Lys Arg Ala Thr Thr
485 490 495
Val Thr Gly Thr Pro Cys Gln Asp Trp Ala Ala Gln Glu Pro His Arg
500 505 510
His Ser Ile Phe Thr Pro Glu Thr Asn Pro Arg Ala Gly Leu Glu Lys
515 520 525
Asn Tyr Cys Arg Asn Pro Asp Gly Asp Val Gly Gly Pro Trp Cys Tyr
530 535 540
Thr Thr Asn Pro Arg Lys Leu Tyr Asp Tyr Cys Asp Val Pro Gln Cys
545 550 555 560
Ala Ala Pro Ser Phe Asp Cys Gly Lys Pro Gln Val Glu Pro Lys Lys
565 570 575
Cys Pro Gly Arg Val Val Gly Gly Cys Val Ala His Pro His Ser Trp
580 585 590
Pro Trp Gln Val Ser Leu Arg Thr Arg Phe Gly Met His Phe Cys Gly
595 600 605
Gly Thr Leu Ile Ser Pro Glu Trp Val Leu Thr Ala Ala His Cys Leu
610 615 620
Glu Lys Ser Pro Arg Pro Ser Ser Tyr Lys Val Ile Leu Gly Ala His
625 630 635 640
Gln Glu Val Asn Leu Glu Pro His Val Gln Glu Ile Glu Val Ser Arg
645 650 655
Leu Phe Leu Glu Pro Thr Arg Lys Asp Ile Ala Leu Leu Lys Leu Ser
660 665 670
Ser Pro Ala Val Ile Thr Asp Lys Val Ile Pro Ala Cys Leu Pro Ser
675 680 685
Pro Asn Tyr Val Val Ala Asp Arg Thr Glu Cys Phe Ile Thr Gly Trp
690 695 700
Gly Glu Thr Gln Gly Thr Phe Gly Ala Gly Leu Leu Lys Glu Ala Gln
705 710 715 720
Leu Pro Val Ile Glu Asn Lys Val Cys Asn Arg Tyr Glu Phe Leu Asn
725 730 735
Gly Arg Val Gln Ser Thr Glu Leu Cys Ala Gly His Leu Ala Gly Gly
740 745 750
Thr Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Val Cys Phe Glu
755 760 765
Lys Asp Lys Tyr Ile Leu Gln Gly Val Thr Ser Trp Gly Leu Gly Cys
770 775 780
Ala Arg Pro Asn Lys Pro Gly Val Tyr Val Arg Val Ser Arg Phe Val
785 790 795 800
Thr Trp Ile Glu Gly Val Met Arg Asn Asn
805 810
<210> 5
<211> 2145
<212> DNA
<213> LYS77-PLG(Lys-纤溶酶原)核酸序列
<400> 5
aaagtgtatc tctcagagtg caagactggg aatggaaaga actacagagg gacgatgtcc 60
aaaacaaaaa atggcatcac ctgtcaaaaa tggagttcca cttctcccca cagacctaga 120
ttctcacctg ctacacaccc ctcagaggga ctggaggaga actactgcag gaatccagac 180
aacgatccgc aggggccctg gtgctatact actgatccag aaaagagata tgactactgc 240
gacattcttg agtgtgaaga ggaatgtatg cattgcagtg gagaaaacta tgacggcaaa 300
atttccaaga ccatgtctgg actggaatgc caggcctggg actctcagag cccacacgct 360
catggataca ttccttccaa atttccaaac aagaacctga agaagaatta ctgtcgtaac 420
cccgataggg agctgcggcc ttggtgtttc accaccgacc ccaacaagcg ctgggaactt 480
tgtgacatcc cccgctgcac aacacctcca ccatcttctg gtcccaccta ccagtgtctg 540
aagggaacag gtgaaaacta tcgcgggaat gtggctgtta ccgtgtccgg gcacacctgt 600
cagcactgga gtgcacagac ccctcacaca cataacagga caccagaaaa cttcccctgc 660
aaaaatttgg atgaaaacta ctgccgcaat cctgacggaa aaagggcccc atggtgccat 720
acaaccaaca gccaagtgcg gtgggagtac tgtaagatac cgtcctgtga ctcctcccca 780
gtatccacgg aacaattggc tcccacagca ccacctgagc taacccctgt ggtccaggac 840
tgctaccatg gtgatggaca gagctaccga ggcacatcct ccaccaccac cacaggaaag 900
aagtgtcagt cttggtcatc tatgacacca caccggcacc agaagacccc agaaaactac 960
ccaaatgctg gcctgacaat gaactactgc aggaatccag atgccgataa aggcccctgg 1020
tgttttacca cagaccccag cgtcaggtgg gagtactgca acctgaaaaa atgctcagga 1080
acagaagcga gtgttgtagc acctccgcct gttgtcctgc ttccagatgt agagactcct 1140
tccgaagaag actgtatgtt tgggaatggg aaaggatacc gaggcaagag ggcgaccact 1200
gttactggga cgccatgcca ggactgggct gcccaggagc cccatagaca cagcattttc 1260
actccagaga caaatccacg ggcgggtctg gaaaaaaatt actgccgtaa ccctgatggt 1320
gatgtaggtg gtccctggtg ctacacgaca aatccaagaa aactttacga ctactgtgat 1380
gtccctcagt gtgcggcccc ttcatttgat tgtgggaagc ctcaagtgga gccgaagaaa 1440
tgtcctggaa gggttgtagg ggggtgtgtg gcccacccac attcctggcc ctggcaagtc 1500
agtcttagaa caaggtttgg aatgcacttc tgtggaggca ccttgatatc cccagagtgg 1560
gtgttgactg ctgcccactg cttggagaag tccccaaggc cttcatccta caaggtcatc 1620
ctgggtgcac accaagaagt gaatctcgaa ccgcatgttc aggaaataga agtgtctagg 1680
ctgttcttgg agcccacacg aaaagatatt gccttgctaa agctaagcag tcctgccgtc 1740
atcactgaca aagtaatccc agcttgtctg ccatccccaa attatgtggt cgctgaccgg 1800
accgaatgtt tcatcactgg ctggggagaa acccaaggta cttttggagc tggccttctc 1860
aaggaagccc agctccctgt gattgagaat aaagtgtgca atcgctatga gtttctgaat 1920
ggaagagtcc aatccaccga actctgtgct gggcatttgg ccggaggcac tgacagttgc 1980
cagggtgaca gtggaggtcc tctggtttgc ttcgagaagg acaaatacat tttacaagga 2040
gtcacttctt ggggtcttgg ctgtgcacgc cccaataagc ctggtgtcta tgttcgtgtt 2100
tcaaggtttg ttacttggat tgagggagtg atgagaaata attaa 2145
<210> 6
<211> 714
<212> PRT
<213> LYS77-PLG(Lys-纤溶酶原)氨基酸序列
<400> 6
Lys Val Tyr Leu Ser Glu Cys Lys Thr Gly Asn Gly Lys Asn Tyr Arg
1 5 10 15
Gly Thr Met Ser Lys Thr Lys Asn Gly Ile Thr Cys Gln Lys Trp Ser
20 25 30
Ser Thr Ser Pro His Arg Pro Arg Phe Ser Pro Ala Thr His Pro Ser
35 40 45
Glu Gly Leu Glu Glu Asn Tyr Cys Arg Asn Pro Asp Asn Asp Pro Gln
50 55 60
Gly Pro Trp Cys Tyr Thr Thr Asp Pro Glu Lys Arg Tyr Asp Tyr Cys
65 70 75 80
Asp Ile Leu Glu Cys Glu Glu Glu Cys Met His Cys Ser Gly Glu Asn
85 90 95
Tyr Asp Gly Lys Ile Ser Lys Thr Met Ser Gly Leu Glu Cys Gln Ala
100 105 110
Trp Asp Ser Gln Ser Pro His Ala His Gly Tyr Ile Pro Ser Lys Phe
115 120 125
Pro Asn Lys Asn Leu Lys Lys Asn Tyr Cys Arg Asn Pro Asp Arg Glu
130 135 140
Leu Arg Pro Trp Cys Phe Thr Thr Asp Pro Asn Lys Arg Trp Glu Leu
145 150 155 160
Cys Asp Ile Pro Arg Cys Thr Thr Pro Pro Pro Ser Ser Gly Pro Thr
165 170 175
Tyr Gln Cys Leu Lys Gly Thr Gly Glu Asn Tyr Arg Gly Asn Val Ala
180 185 190
Val Thr Val Ser Gly His Thr Cys Gln His Trp Ser Ala Gln Thr Pro
195 200 205
His Thr His Asn Arg Thr Pro Glu Asn Phe Pro Cys Lys Asn Leu Asp
210 215 220
Glu Asn Tyr Cys Arg Asn Pro Asp Gly Lys Arg Ala Pro Trp Cys His
225 230 235 240
Thr Thr Asn Ser Gln Val Arg Trp Glu Tyr Cys Lys Ile Pro Ser Cys
245 250 255
Asp Ser Ser Pro Val Ser Thr Glu Gln Leu Ala Pro Thr Ala Pro Pro
260 265 270
Glu Leu Thr Pro Val Val Gln Asp Cys Tyr His Gly Asp Gly Gln Ser
275 280 285
Tyr Arg Gly Thr Ser Ser Thr Thr Thr Thr Gly Lys Lys Cys Gln Ser
290 295 300
Trp Ser Ser Met Thr Pro His Arg His Gln Lys Thr Pro Glu Asn Tyr
305 310 315 320
Pro Asn Ala Gly Leu Thr Met Asn Tyr Cys Arg Asn Pro Asp Ala Asp
325 330 335
Lys Gly Pro Trp Cys Phe Thr Thr Asp Pro Ser Val Arg Trp Glu Tyr
340 345 350
Cys Asn Leu Lys Lys Cys Ser Gly Thr Glu Ala Ser Val Val Ala Pro
355 360 365
Pro Pro Val Val Leu Leu Pro Asp Val Glu Thr Pro Ser Glu Glu Asp
370 375 380
Cys Met Phe Gly Asn Gly Lys Gly Tyr Arg Gly Lys Arg Ala Thr Thr
385 390 395 400
Val Thr Gly Thr Pro Cys Gln Asp Trp Ala Ala Gln Glu Pro His Arg
405 410 415
His Ser Ile Phe Thr Pro Glu Thr Asn Pro Arg Ala Gly Leu Glu Lys
420 425 430
Asn Tyr Cys Arg Asn Pro Asp Gly Asp Val Gly Gly Pro Trp Cys Tyr
435 440 445
Thr Thr Asn Pro Arg Lys Leu Tyr Asp Tyr Cys Asp Val Pro Gln Cys
450 455 460
Ala Ala Pro Ser Phe Asp Cys Gly Lys Pro Gln Val Glu Pro Lys Lys
465 470 475 480
Cys Pro Gly Arg Val Val Gly Gly Cys Val Ala His Pro His Ser Trp
485 490 495
Pro Trp Gln Val Ser Leu Arg Thr Arg Phe Gly Met His Phe Cys Gly
500 505 510
Gly Thr Leu Ile Ser Pro Glu Trp Val Leu Thr Ala Ala His Cys Leu
515 520 525
Glu Lys Ser Pro Arg Pro Ser Ser Tyr Lys Val Ile Leu Gly Ala His
530 535 540
Gln Glu Val Asn Leu Glu Pro His Val Gln Glu Ile Glu Val Ser Arg
545 550 555 560
Leu Phe Leu Glu Pro Thr Arg Lys Asp Ile Ala Leu Leu Lys Leu Ser
565 570 575
Ser Pro Ala Val Ile Thr Asp Lys Val Ile Pro Ala Cys Leu Pro Ser
580 585 590
Pro Asn Tyr Val Val Ala Asp Arg Thr Glu Cys Phe Ile Thr Gly Trp
595 600 605
Gly Glu Thr Gln Gly Thr Phe Gly Ala Gly Leu Leu Lys Glu Ala Gln
610 615 620
Leu Pro Val Ile Glu Asn Lys Val Cys Asn Arg Tyr Glu Phe Leu Asn
625 630 635 640
Gly Arg Val Gln Ser Thr Glu Leu Cys Ala Gly His Leu Ala Gly Gly
645 650 655
Thr Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Val Cys Phe Glu
660 665 670
Lys Asp Lys Tyr Ile Leu Gln Gly Val Thr Ser Trp Gly Leu Gly Cys
675 680 685
Ala Arg Pro Asn Lys Pro Gly Val Tyr Val Arg Val Ser Arg Phe Val
690 695 700
Thr Trp Ile Glu Gly Val Met Arg Asn Asn
705 710
<210> 7
<211> 1245
<212> DNA
<213> delta-plg(delta-纤溶酶原)核酸序列
<400> 7
gagcctctgg atgactatgt gaatacccag ggggcttcac tgttcagtgt cactaagaag 60
cagctgggag caggaagtat agaagaatgt gcagcaaaat gtgaggagga cgaagaattc 120
acctgcaggg cattccaata tcacagtaaa gagcaacaat gtgtgataat ggctgaaaac 180
aggaagtcct ccataatcat taggatgaga gatgtagttt tatttgaaaa gaaagtgtat 240
ctctcagagt gcaagactgg gaatggaaag aactacagag ggacgatgtc caaaacaaaa 300
aatggcatca cctgtcaaaa atggagttcc acttctcccc acagacctag attctcacct 360
gctacacacc cctcagaggg actggaggag aactactgca ggaatccaga caacgatccg 420
caggggccct ggtgctatac tactgatcca gaaaagagat atgactactg cgacattctt 480
gagtgtgaag aggcggcccc ttcatttgat tgtgggaagc ctcaagtgga gccgaagaaa 540
tgtcctggaa gggttgtagg ggggtgtgtg gcccacccac attcctggcc ctggcaagtc 600
agtcttagaa caaggtttgg aatgcacttc tgtggaggca ccttgatatc cccagagtgg 660
gtgttgactg ctgcccactg cttggagaag tccccaaggc cttcatccta caaggtcatc 720
ctgggtgcac accaagaagt gaatctcgaa ccgcatgttc aggaaataga agtgtctagg 780
ctgttcttgg agcccacacg aaaagatatt gccttgctaa agctaagcag tcctgccgtc 840
atcactgaca aagtaatccc agcttgtctg ccatccccaa attatgtggt cgctgaccgg 900
accgaatgtt tcatcactgg ctggggagaa acccaaggta cttttggagc tggccttctc 960
aaggaagccc agctccctgt gattgagaat aaagtgtgca atcgctatga gtttctgaat 1020
ggaagagtcc aatccaccga actctgtgct gggcatttgg ccggaggcac tgacagttgc 1080
cagggtgaca gtggaggtcc tctggtttgc ttcgagaagg acaaatacat tttacaagga 1140
gtcacttctt ggggtcttgg ctgtgcacgc cccaataagc ctggtgtcta tgttcgtgtt 1200
tcaaggtttg ttacttggat tgagggagtg atgagaaata attaa 1245
<210> 8
<211> 414
<212> PRT
<213> delta-plg(delta-纤溶酶原)氨基酸序列
<400> 8
Glu Pro Leu Asp Asp Tyr Val Asn Thr Gln Gly Ala Ser Leu Phe Ser
1 5 10 15
Val Thr Lys Lys Gln Leu Gly Ala Gly Ser Ile Glu Glu Cys Ala Ala
20 25 30
Lys Cys Glu Glu Asp Glu Glu Phe Thr Cys Arg Ala Phe Gln Tyr His
35 40 45
Ser Lys Glu Gln Gln Cys Val Ile Met Ala Glu Asn Arg Lys Ser Ser
50 55 60
Ile Ile Ile Arg Met Arg Asp Val Val Leu Phe Glu Lys Lys Val Tyr
65 70 75 80
Leu Ser Glu Cys Lys Thr Gly Asn Gly Lys Asn Tyr Arg Gly Thr Met
85 90 95
Ser Lys Thr Lys Asn Gly Ile Thr Cys Gln Lys Trp Ser Ser Thr Ser
100 105 110
Pro His Arg Pro Arg Phe Ser Pro Ala Thr His Pro Ser Glu Gly Leu
115 120 125
Glu Glu Asn Tyr Cys Arg Asn Pro Asp Asn Asp Pro Gln Gly Pro Trp
130 135 140
Cys Tyr Thr Thr Asp Pro Glu Lys Arg Tyr Asp Tyr Cys Asp Ile Leu
145 150 155 160
Glu Cys Glu Glu Ala Ala Pro Ser Phe Asp Cys Gly Lys Pro Gln Val
165 170 175
Glu Pro Lys Lys Cys Pro Gly Arg Val Val Gly Gly Cys Val Ala His
180 185 190
Pro His Ser Trp Pro Trp Gln Val Ser Leu Arg Thr Arg Phe Gly Met
195 200 205
His Phe Cys Gly Gly Thr Leu Ile Ser Pro Glu Trp Val Leu Thr Ala
210 215 220
Ala His Cys Leu Glu Lys Ser Pro Arg Pro Ser Ser Tyr Lys Val Ile
225 230 235 240
Leu Gly Ala His Gln Glu Val Asn Leu Glu Pro His Val Gln Glu Ile
245 250 255
Glu Val Ser Arg Leu Phe Leu Glu Pro Thr Arg Lys Asp Ile Ala Leu
260 265 270
Leu Lys Leu Ser Ser Pro Ala Val Ile Thr Asp Lys Val Ile Pro Ala
275 280 285
Cys Leu Pro Ser Pro Asn Tyr Val Val Ala Asp Arg Thr Glu Cys Phe
290 295 300
Ile Thr Gly Trp Gly Glu Thr Gln Gly Thr Phe Gly Ala Gly Leu Leu
305 310 315 320
Lys Glu Ala Gln Leu Pro Val Ile Glu Asn Lys Val Cys Asn Arg Tyr
325 330 335
Glu Phe Leu Asn Gly Arg Val Gln Ser Thr Glu Leu Cys Ala Gly His
340 345 350
Leu Ala Gly Gly Thr Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu
355 360 365
Val Cys Phe Glu Lys Asp Lys Tyr Ile Leu Gln Gly Val Thr Ser Trp
370 375 380
Gly Leu Gly Cys Ala Arg Pro Asn Lys Pro Gly Val Tyr Val Arg Val
385 390 395 400
Ser Arg Phe Val Thr Trp Ile Glu Gly Val Met Arg Asn Asn
405 410
<210> 9
<211> 1104
<212> DNA
<213> Mini-plg(小纤维蛋白溶酶原)核酸序列
<400> 9
gtcaggtggg agtactgcaa cctgaaaaaa tgctcaggaa cagaagcgag tgttgtagca 60
cctccgcctg ttgtcctgct tccagatgta gagactcctt ccgaagaaga ctgtatgttt 120
gggaatggga aaggataccg aggcaagagg gcgaccactg ttactgggac gccatgccag 180
gactgggctg cccaggagcc ccatagacac agcattttca ctccagagac aaatccacgg 240
gcgggtctgg aaaaaaatta ctgccgtaac cctgatggtg atgtaggtgg tccctggtgc 300
tacacgacaa atccaagaaa actttacgac tactgtgatg tccctcagtg tgcggcccct 360
tcatttgatt gtgggaagcc tcaagtggag ccgaagaaat gtcctggaag ggttgtaggg 420
gggtgtgtgg cccacccaca ttcctggccc tggcaagtca gtcttagaac aaggtttgga 480
atgcacttct gtggaggcac cttgatatcc ccagagtggg tgttgactgc tgcccactgc 540
ttggagaagt ccccaaggcc ttcatcctac aaggtcatcc tgggtgcaca ccaagaagtg 600
aatctcgaac cgcatgttca ggaaatagaa gtgtctaggc tgttcttgga gcccacacga 660
aaagatattg ccttgctaaa gctaagcagt cctgccgtca tcactgacaa agtaatccca 720
gcttgtctgc catccccaaa ttatgtggtc gctgaccgga ccgaatgttt catcactggc 780
tggggagaaa cccaaggtac ttttggagct ggccttctca aggaagccca gctccctgtg 840
attgagaata aagtgtgcaa tcgctatgag tttctgaatg gaagagtcca atccaccgaa 900
ctctgtgctg ggcatttggc cggaggcact gacagttgcc agggtgacag tggaggtcct 960
ctggtttgct tcgagaagga caaatacatt ttacaaggag tcacttcttg gggtcttggc 1020
tgtgcacgcc ccaataagcc tggtgtctat gttcgtgttt caaggtttgt tacttggatt 1080
gagggagtga tgagaaataa ttaa 1104
<210> 10
<211> 367
<212> PRT
<213> Mini-plg(小纤维蛋白溶酶原)氨基酸序列
<400> 10
Val Arg Trp Glu Tyr Cys Asn Leu Lys Lys Cys Ser Gly Thr Glu Ala
1 5 10 15
Ser Val Val Ala Pro Pro Pro Val Val Leu Leu Pro Asp Val Glu Thr
20 25 30
Pro Ser Glu Glu Asp Cys Met Phe Gly Asn Gly Lys Gly Tyr Arg Gly
35 40 45
Lys Arg Ala Thr Thr Val Thr Gly Thr Pro Cys Gln Asp Trp Ala Ala
50 55 60
Gln Glu Pro His Arg His Ser Ile Phe Thr Pro Glu Thr Asn Pro Arg
65 70 75 80
Ala Gly Leu Glu Lys Asn Tyr Cys Arg Asn Pro Asp Gly Asp Val Gly
85 90 95
Gly Pro Trp Cys Tyr Thr Thr Asn Pro Arg Lys Leu Tyr Asp Tyr Cys
100 105 110
Asp Val Pro Gln Cys Ala Ala Pro Ser Phe Asp Cys Gly Lys Pro Gln
115 120 125
Val Glu Pro Lys Lys Cys Pro Gly Arg Val Val Gly Gly Cys Val Ala
130 135 140
His Pro His Ser Trp Pro Trp Gln Val Ser Leu Arg Thr Arg Phe Gly
145 150 155 160
Met His Phe Cys Gly Gly Thr Leu Ile Ser Pro Glu Trp Val Leu Thr
165 170 175
Ala Ala His Cys Leu Glu Lys Ser Pro Arg Pro Ser Ser Tyr Lys Val
180 185 190
Ile Leu Gly Ala His Gln Glu Val Asn Leu Glu Pro His Val Gln Glu
195 200 205
Ile Glu Val Ser Arg Leu Phe Leu Glu Pro Thr Arg Lys Asp Ile Ala
210 215 220
Leu Leu Lys Leu Ser Ser Pro Ala Val Ile Thr Asp Lys Val Ile Pro
225 230 235 240
Ala Cys Leu Pro Ser Pro Asn Tyr Val Val Ala Asp Arg Thr Glu Cys
245 250 255
Phe Ile Thr Gly Trp Gly Glu Thr Gln Gly Thr Phe Gly Ala Gly Leu
260 265 270
Leu Lys Glu Ala Gln Leu Pro Val Ile Glu Asn Lys Val Cys Asn Arg
275 280 285
Tyr Glu Phe Leu Asn Gly Arg Val Gln Ser Thr Glu Leu Cys Ala Gly
290 295 300
His Leu Ala Gly Gly Thr Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro
305 310 315 320
Leu Val Cys Phe Glu Lys Asp Lys Tyr Ile Leu Gln Gly Val Thr Ser
325 330 335
Trp Gly Leu Gly Cys Ala Arg Pro Asn Lys Pro Gly Val Tyr Val Arg
340 345 350
Val Ser Arg Phe Val Thr Trp Ile Glu Gly Val Met Arg Asn Asn
355 360 365
<210> 11
<211> 750
<212> DNA
<213> Micro-plg(微纤维蛋白溶酶原)核酸序列
<400> 11
gccccttcat ttgattgtgg gaagcctcaa gtggagccga agaaatgtcc tggaagggtt 60
gtaggggggt gtgtggccca cccacattcc tggccctggc aagtcagtct tagaacaagg 120
tttggaatgc acttctgtgg aggcaccttg atatccccag agtgggtgtt gactgctgcc 180
cactgcttgg agaagtcccc aaggccttca tcctacaagg tcatcctggg tgcacaccaa 240
gaagtgaatc tcgaaccgca tgttcaggaa atagaagtgt ctaggctgtt cttggagccc 300
acacgaaaag atattgcctt gctaaagcta agcagtcctg ccgtcatcac tgacaaagta 360
atcccagctt gtctgccatc cccaaattat gtggtcgctg accggaccga atgtttcatc 420
actggctggg gagaaaccca aggtactttt ggagctggcc ttctcaagga agcccagctc 480
cctgtgattg agaataaagt gtgcaatcgc tatgagtttc tgaatggaag agtccaatcc 540
accgaactct gtgctgggca tttggccgga ggcactgaca gttgccaggg tgacagtgga 600
ggtcctctgg tttgcttcga gaaggacaaa tacattttac aaggagtcac ttcttggggt 660
cttggctgtg cacgccccaa taagcctggt gtctatgttc gtgtttcaag gtttgttact 720
tggattgagg gagtgatgag aaataattaa 750
<210> 12
<211> 249
<212> PRT
<213> Micro-plg(微纤维蛋白溶酶原)氨基酸序列
<400> 12
Ala Pro Ser Phe Asp Cys Gly Lys Pro Gln Val Glu Pro Lys Lys Cys
1 5 10 15
Pro Gly Arg Val Val Gly Gly Cys Val Ala His Pro His Ser Trp Pro
20 25 30
Trp Gln Val Ser Leu Arg Thr Arg Phe Gly Met His Phe Cys Gly Gly
35 40 45
Thr Leu Ile Ser Pro Glu Trp Val Leu Thr Ala Ala His Cys Leu Glu
50 55 60
Lys Ser Pro Arg Pro Ser Ser Tyr Lys Val Ile Leu Gly Ala His Gln
65 70 75 80
Glu Val Asn Leu Glu Pro His Val Gln Glu Ile Glu Val Ser Arg Leu
85 90 95
Phe Leu Glu Pro Thr Arg Lys Asp Ile Ala Leu Leu Lys Leu Ser Ser
100 105 110
Pro Ala Val Ile Thr Asp Lys Val Ile Pro Ala Cys Leu Pro Ser Pro
115 120 125
Asn Tyr Val Val Ala Asp Arg Thr Glu Cys Phe Ile Thr Gly Trp Gly
130 135 140
Glu Thr Gln Gly Thr Phe Gly Ala Gly Leu Leu Lys Glu Ala Gln Leu
145 150 155 160
Pro Val Ile Glu Asn Lys Val Cys Asn Arg Tyr Glu Phe Leu Asn Gly
165 170 175
Arg Val Gln Ser Thr Glu Leu Cys Ala Gly His Leu Ala Gly Gly Thr
180 185 190
Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Val Cys Phe Glu Lys
195 200 205
Asp Lys Tyr Ile Leu Gln Gly Val Thr Ser Trp Gly Leu Gly Cys Ala
210 215 220
Arg Pro Asn Lys Pro Gly Val Tyr Val Arg Val Ser Arg Phe Val Thr
225 230 235 240
Trp Ile Glu Gly Val Met Arg Asn Asn
245
<210> 13
<211> 684
<212> DNA
<213> 丝氨酸蛋白酶(结构)域的核酸序列
<400> 13
gttgtagggg ggtgtgtggc ccacccacat tcctggccct ggcaagtcag tcttagaaca 60
aggtttggaa tgcacttctg tggaggcacc ttgatatccc cagagtgggt gttgactgct 120
gcccactgct tggagaagtc cccaaggcct tcatcctaca aggtcatcct gggtgcacac 180
caagaagtga atctcgaacc gcatgttcag gaaatagaag tgtctaggct gttcttggag 240
cccacacgaa aagatattgc cttgctaaag ctaagcagtc ctgccgtcat cactgacaaa 300
gtaatcccag cttgtctgcc atccccaaat tatgtggtcg ctgaccggac cgaatgtttc 360
atcactggct ggggagaaac ccaaggtact tttggagctg gccttctcaa ggaagcccag 420
ctccctgtga ttgagaataa agtgtgcaat cgctatgagt ttctgaatgg aagagtccaa 480
tccaccgaac tctgtgctgg gcatttggcc ggaggcactg acagttgcca gggtgacagt 540
ggaggtcctc tggtttgctt cgagaaggac aaatacattt tacaaggagt cacttcttgg 600
ggtcttggct gtgcacgccc caataagcct ggtgtctatg ttcgtgtttc aaggtttgtt 660
acttggattg agggagtgat gaga 684
<210> 14
<211> 228
<212> PRT
<213> 丝氨酸蛋白酶(结构)域的氨基酸序列
<400> 14
Val Val Gly Gly Cys Val Ala His Pro His Ser Trp Pro Trp Gln Val
1 5 10 15
Ser Leu Arg Thr Arg Phe Gly Met His Phe Cys Gly Gly Thr Leu Ile
20 25 30
Ser Pro Glu Trp Val Leu Thr Ala Ala His Cys Leu Glu Lys Ser Pro
35 40 45
Arg Pro Ser Ser Tyr Lys Val Ile Leu Gly Ala His Gln Glu Val Asn
50 55 60
Leu Glu Pro His Val Gln Glu Ile Glu Val Ser Arg Leu Phe Leu Glu
65 70 75 80
Pro Thr Arg Lys Asp Ile Ala Leu Leu Lys Leu Ser Ser Pro Ala Val
85 90 95
Ile Thr Asp Lys Val Ile Pro Ala Cys Leu Pro Ser Pro Asn Tyr Val
100 105 110
Val Ala Asp Arg Thr Glu Cys Phe Ile Thr Gly Trp Gly Glu Thr Gln
115 120 125
Gly Thr Phe Gly Ala Gly Leu Leu Lys Glu Ala Gln Leu Pro Val Ile
130 135 140
Glu Asn Lys Val Cys Asn Arg Tyr Glu Phe Leu Asn Gly Arg Val Gln
145 150 155 160
Ser Thr Glu Leu Cys Ala Gly His Leu Ala Gly Gly Thr Asp Ser Cys
165 170 175
Gln Gly Asp Ser Gly Gly Pro Leu Val Cys Phe Glu Lys Asp Lys Tyr
180 185 190
Ile Leu Gln Gly Val Thr Ser Trp Gly Leu Gly Cys Ala Arg Pro Asn
195 200 205
Lys Pro Gly Val Tyr Val Arg Val Ser Arg Phe Val Thr Trp Ile Glu
210 215 220
Gly Val Met Arg
225
Claims (9)
1.纤维蛋白溶酶原在制备治疗和/或消除受试者辐射损伤和化学损伤及其相关病症的药物中的用途。
2.纤维蛋白溶酶原在制备治疗和/或消除受试者放射治疗、化疗或放化疗引起的机体器官和组织损伤及其相关病症的药物中的用途。
3.权利要求1或2的用途,其中所述损伤包括对骨髓造血***、皮肤、粘膜、免疫***和生殖***的损伤。
4.权利要求1-3任一项的用途,其中所述损伤包括对肝脏、脾脏、肾脏、肺脏、胃肠道、胸腺、骨髓、睾丸、附睾的损伤。
5.权利要求1-4任一项的用途,其中所述损伤是放射治疗、化疗或放化疗导致的一般健康状况的下降、全身副作用和局部副作用,包括急性副作用、长期副作用和累积副作用。
6.权利要求1-5任一项的用途,其中所述损伤相关病症包括:粘膜溃疡、免疫功能下降、骨髓抑制、消化功能障碍、心、肝、脾、肺、肾、卵巢、睾丸中毒性功能障碍、神经***中毒性功能障碍。
7.根据权利要求1-6任一项的用途,其中所述纤维蛋白溶酶原与序列2、6、8、10或12具有至少80%、85%、90%、95%、96%、97%、98%或99%的序列同一性,并且仍然具有纤维蛋白溶酶原活性。
8.根据权利要求1-7任一项的用途,其中所述纤维蛋白溶酶原是包含纤溶酶原活性片段、并且仍然具有纤维蛋白溶酶原活性的蛋白质。
9.根据权利1-8任一项的用途,其中所述纤维蛋白溶酶原可与一种或多种其它药物或疗法联合施用,包括:抗癌药物、抗感染药物、免疫增强剂、止痛药、营养剂和解毒剂。
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