CN1307681A - 癌的早期诊断方法 - Google Patents
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Abstract
本发明涉及癌及癌前期的早期诊断方法,包括在一机体样品中确定细胞周期调节蛋白的过表达。本发明还涉及可用于所述方法的试剂盒。
Description
本发明涉及癌及癌前期的早期诊断方法,特别是上呼吸道或肛殖道癌的早期诊断方法。
自50年代中期以来对大多数不同的癌已提供了预防计划。关于宫颈癌,主要是基于宫颈的细胞涂片的形态学和细胞学检查,即所谓的Pap测试,其基于妇女从20岁起定期进行的妇科学常规检查。通过细胞的形态学,涂片被分成各种强度程度的发育异常细胞变化。根据Pap I-V,这些强度程度分别代表正常、清度发育异常、稍严重发育异常、严重发育异常和浸润性癌。如果Pap测试产生令人震惊的结果,则进行小规模活组织检查并进行组织病理学检查,由此将发育异常的种类和强度确定并划分为宫颈上皮内癌(CINI-III)。
尽管有预防计划,但是每年增加400000个新病例的宫颈癌仍是妇女中发生频率为第二位的癌症。这特别是由于Pap测试结果的近30%是假阴性所致。
因此,本发明的目的是提供一种可以早期和可靠诊断宫颈癌的方法。另外,由此方法应可以区分肿瘤形成前发育异常的良性炎性改变或化生改变。
根据本发明,这可通过权利要求书中定义的本发明主题实现。
本发明基于申请人的如下观察:即细胞周期调节蛋白在许多癌,例如上呼吸道或肛殖道癌、特别是宫颈癌以及这些癌的前期中过表达。细胞周期调节蛋白的例子为细胞周期蛋白。特别提及的是调节细胞周期蛋白的细胞周期蛋白依赖性激酶,更特别提及的是调节细胞周期蛋白依赖性激酶的细胞周期蛋白依赖性激酶抑制蛋白。细胞周期蛋白依赖性激酶抑制蛋白的例子为蛋白质p14,p15,p16,p19,p21和p27。本申请人发现细胞周期调节蛋白的过表达的强度与细胞发育异常程度相关。
根据本发明,本申请人的观察用作一种癌及癌前期的早期诊断方法,其包括在一机体样品中确定细胞周期蛋白的过表达。
术语“癌及癌前期”包括任何种类和任何起源的癌及其前期。例如,它们可以是上呼吸道或肛殖道癌,特别是宫颈癌。宫颈癌中,特别提及的是其前期,例如宫颈上皮内癌(CINI-III),原位癌(CIS)等。
术语“细胞周期调节蛋白”包括任何种类和起源的细胞周期调节蛋白。例如,这些蛋白可以是细胞周期蛋白。特别是,它们可以是调节细胞周期蛋白的细胞周期蛋白依赖性激酶。细胞周期蛋白依赖性激酶的例子是蛋白质cdk4和cdk6。更特别地,它们可以是调节细胞周期蛋白依赖性激酶的细胞周期蛋白依赖性激酶抑制蛋白。细胞周期蛋白依赖性激酶抑制蛋白的例子是蛋白质p14,p15,p16,p19,p21和p27,优选的是p16。
术语“机体样品”包括可以检测细胞周期调节蛋白的任何机体样品,这种机体样品的例子是血、涂片、痰、尿、粪便、液体(liquor)、胆汁、胃肠道分泌物、淋巴、骨髓、器官穿刺物或抽吸物和活组织检查样品。当检查肛殖道癌例如宫颈癌时,特别提及的是涂片和活检样品。
术语“确定细胞周期调节蛋白的过表达”包括适于检测细胞周期调节蛋白或其编码mRNA的表达和相应基因的扩增的任何方法。为确定过表达,显然是将待检查的机体样品与来自健康人的相应机体样品相比较,这种样品可作为标准形式存在。细胞周期调节蛋白的(过)表达可在核酸水平和蛋白质水平检测。对于蛋白质水平的检测,可以使用例如针对细胞周期调节蛋白的抗体,这些抗体可用于大多数不同方法中,如Western印迹、ELISA或免疫沉淀。有利的是抗体固定在固相载体如测试条或乳胶颗粒上。
通过本发明,可以早期诊断癌症,即在其前期诊断。
本发明的另一主题涉及进行本发明方法的试剂盒,这种试剂盒包括:
(a)检测细胞周期调节蛋白的表达的试剂,例如针对这种蛋白的抗体,或编码这种蛋白或其部分的核酸,
(b)常规助剂,如缓冲剂、载体、标记物等,和任选地
(c)用于对照反应的制剂,例如一种细胞周期调节蛋白,编码这种蛋白及其部分的核酸,或细胞制备物,例如组织切片或固定在玻片上的细胞。
以上陈述相应地适于所述试剂盒的各组分。另外,可存在各个组分的一或几个代表。
通过本发明,可以早期诊断癌,特别是可以早期诊断癌前期。还可以区分肿瘤形成前发育异常的良性炎性改变或化生改变。另一个特征是本发明方法获得的结果不进行主观评价,因而Pap测试或组织学制备的假阴性和假阳性结果可以避免。另外,本发明可以快速简便地操作,因而可用于深入筛选措施,特别是在第三世界国家中。因此,本发明对现今癌症诊断作出了重要贡献。
附图简述
图1示出在HPV16转化的宫颈癌细胞CaSki中cdk4过表达的检测。4h,8h,12h,24h是指取细胞抽提物的时间。co代表对照,arr代表加入血清。
图2示出在HPV16转化的NIH3T3细胞中cdk6和p19的过表达的检测。co代表对照。
本发明通过以下实施例解释。实施例1 在子宫颈活检样品中检测p16的过表达(A)从20个子宫颈活检样品产生厚度为3-5微米的石蜡切片,其包括所有程度的发育异常进程,从正常组织(n=2)经CIN I(n=4),II(n=4),III(n=5)病变至浸润性癌(n=5)。它们在二甲苯中脱石蜡2×10分钟并用乙醇再氢化。抗原于10mM柠檬酸盐缓冲液(pH6.0)中在高压灭菌器中于110℃、10分钟解蔽。之后用在PBS中的0.25%H2O2失活内源性过氧化物酶。用马血清(Vectastain ABC检测试剂盒,VectroLaboratories,Burlingame,美国加利福尼亚州)在室温封闭非特异性结合位点20分钟,随后切片在存在3%胎牛血清时与p16特异性单克隆抗体(Neomarkers,Fremont,美国加利福尼亚州)在室温保温45分钟。为检测p16抗体结合,加入生物素化第二抗体(马抗鼠IgG,Vectastain试剂盒,同上)保温30分钟,之后,用Vectastain试剂盒的试剂根据其指导检测结合的第二抗体,并用Mayer苏木精明矾溶液进行核心复染。
结果示出p16的过表达存在于发育异常细胞中,还示出p16过表达强度与细胞发育异常程度相关。(B)另外,从78个子宫颈活检样品制备石蜡切片,活检样品涉及正常组织(n=12),CIN I(n=15),II(n=14),III(n=18)阶段的发育异常病变及浸润性癌(n=19)。石蜡切片如上(A)所述处理。获得表1所示数据。
表1
p16表达强度组织学 n= - + ++ +++正常 12 9 3CIN I 15 10 3 2CIN II 14 1 4 9CIN III 18 9 9CxCa 19 1 18总计 78 20 10 21 27
由表1数据可看出,p16在发育异常和浸润性癌的细胞中过表达,过表达随着发育异常程度向浸润性癌发展而增加。(C)另外,来自180个子宫颈癌生物活检样品的石蜡切片如上述(A)方式处理。另外,测定与上述p16特异性单克隆抗体反应的细胞百分数。在HPV阳性和HPV阴性发育异常和浸润性癌之间也进行区分,获得表2所示数据。
表2
过表达p16的细胞百分数
n 平均百分数±标准偏差CIN I 32 54.9±24.0
HPV阴性 17 54.0±27.2
HPV阳性 15 55.9±21.0CIN II 32 70.8±18.9
HPV阴性 14 76.0±15.8
HPV阳性 18 66.8±20.5CIN III 60 92.4±10.2
HPV阴性 9 94.4±7.5
HPV阳性 51 92.1±10.7浸润性癌 58 97.8±5.2
HPV阴性 5 96.4±8.1
HPV阳性 53 97.9±4.9
表2数据显示p16在发育异常和浸润性癌的HPV阳性和HPV阴性细胞中均过表达,这一结果经正常组织的对照而证实。数据还显示与p16反应的细胞百分数随着发育异常程度向浸润性癌发展而增加。实施例2细胞周期调节蛋白在HPV转化细胞中的过表达的检测(A)在无血清存在下培养用HPV16转化的宫颈癌细胞CaSki,培养72小时。加入血清后,在各时间点收集细胞抽提物,进行SDS-PAGE并转移至PVDF膜(Du Pont)。用来自Santa Cruz的多克隆抗血清(1∶1000)确定cdk4的表达。另外,HPV16-E7蛋白的表达用来自Triton的抗HPV16-E7D单克隆抗体(1∶50)测定。经过氧化物酶连接的第二抗体和化学发光检测系统(NEN,Du Pont)检测各免疫应答。
结果是cdk4过表达(参见图1)。(B)用HPV16转化NIH3T3细胞以获得HPV16-E7蛋白的表达。获得该转化细胞的细胞抽提物并如(A)所述处理。为检测cdk6和p19的表达,使用来自Santa Cruz的多克隆抗血清(1∶1000)。HPV16-E7蛋白表达的检测和各免疫应答的检测参照上述(A)所述。
结果是cdk6和p19过表达(参见图2)。
Claims (18)
1、癌及癌前期的早期诊断方法,包括在一机体样品中确定细胞周期调节蛋白的过表达。
2、权利要求1的方法,其中所述的癌是上呼吸道癌。
3、权利要求1的方法,其中所述的癌是肛殖道癌。
4、权利要求3的方法,其中所述的肛殖道癌是宫颈癌。
5、权利要求1-4任一项的方法,其中细胞周期调节蛋白是细胞周期蛋白。
6、权利要求1-4任一项的方法,其中细胞周期调节蛋白是细胞周期蛋白依赖性激酶。
7、权利要求6的方法,其中细胞周期蛋白依赖性激酶是cdk4或cdk6。
8、权利要求1-4任一项的方法,其中细胞周期调节蛋白是细胞周期蛋白依赖性激酶抑制蛋白。
9、权利要求8的方法,其中细胞周期蛋白依赖性激酶抑制蛋白是蛋白质p14,p15,p16,p18,p19,p21或p27。
10、权利要求1-9任一项的方法,其中机体样品分别是是血、涂片、痰、尿、粪便、液体(liquor)、胆汁、骨髓、胃肠道分泌物、器官穿刺物或抽吸物和活组织检查样品,和/或淋巴。
11、权利要求1-10任一项的方法,其中是在核酸水平确定过表达。
12、权利要求1-10任一项的方法,其中是在蛋白质水平确定过表达。
13、权利要求12的方法,其中通过抗细胞周期调节蛋白的抗体确定过表达。
14、进行权利要求1-13任一项的方法的试剂盒,包含:
(a)检测细胞周期调节蛋白的表达的试剂,
(b)常规助剂,如缓冲剂、载体、标记物等,和任选地
(c)用于对照反应的制剂。
15、权利要求14的试剂盒,其中所述试剂是抗细胞周期调节蛋白的抗体。
16、权利要求14的试剂盒,其中所述试剂是编码细胞周期调节蛋白或其部分的核酸。
17、权利要求14-16任一项的试剂盒,其中所述的制剂是一种细胞周期调节蛋白,或编码这种蛋白或其部分的核酸。
18、权利要求14-16任一项的试剂盒,其中所述的制剂是一种细胞制备物。
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DE19829473A DE19829473C2 (de) | 1998-07-01 | 1998-07-01 | Verfahren zur frühen Diagnose von Carcinomen |
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US10180431B2 (en) | 2011-11-15 | 2019-01-15 | University Of Miami | Methods for detecting human papillomavirus and providing prognosis for head and neck squamous cell carcinoma |
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