CN101217961A - 前列腺环素类似物的用途 - Google Patents
前列腺环素类似物的用途 Download PDFInfo
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- CN101217961A CN101217961A CNA2006800249889A CN200680024988A CN101217961A CN 101217961 A CN101217961 A CN 101217961A CN A2006800249889 A CNA2006800249889 A CN A2006800249889A CN 200680024988 A CN200680024988 A CN 200680024988A CN 101217961 A CN101217961 A CN 101217961A
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- prostacyclin analogs
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Abstract
本发明提供了用于通过施用治疗有效量的前列腺环素类似物在具有较高风险因素的受试者中预防或减少癌症或恶化前发育异常进展的风险的方法。
Description
发明领域
本发明涉及前列腺环素类似物的用途,包括但不限于,减少发生癌症或恶化前发育异常的进展的风险。
发明背景
癌症是主要的死因之一。特别地,肺癌不仅在美国而且在全世界的男性和女性中是癌症死亡的头号原因。肺癌是医学上首要重视的问题,因为普通人群中的高烟瘾率和对烟草产品的高度暴露。此外,肺癌在暴露于化学药物例如橙剂(Agent Orange)和其他致癌物例如煤炭粉末、石棉和辐射的受试者中发生。
即使使现时吸烟者戒烟,肺癌将仍保持流行许多年。事实上,如今大部分肺癌是在曾吸烟者中诊断的。目前,没有已建立的针对肺癌的早期检测的筛查试验,低于25%的患者存在可通过手术治疗的这种疾病。肺癌的累计五年存活率大约只为15%。因为存活率如此低,所以预防肺癌的发生而不是在受试者已发生肺癌后试图治疗其将更加有效。
发明概述
在一个方面,本发明提供了减少受试者发生癌症的风险。该方法在相对于不具有类似的风险因素的人具有发生癌症的更高风险因素的受试者中特别有用。所述方法包括对受试者施用治疗有效量的前列腺环素类似物。这样,可预防多种癌症,包括,但不限于肺癌、肝癌、脑癌、胰腺癌、肾癌、前列腺癌、乳腺结肠癌、膀胱癌、卵巢癌和头-颈癌。通常,在具有高风险因素的受试者中,发生癌症的风险减少至少大约10%。
本发明的另一个方面提供了用于在受试者中减少发生晚期恶化前发育异常的风险的方法。
发明详述
由于增长的医疗保健费用和升高的癌症发病率,医疗保健提供者需要容易施用的预防癌症的方法。如果可阻止或预防癌症的发病,那么可避免作为疾病的结果而进行的治疗例如化疗。一些化学保护或化学预防努力集中在饮食因素例如维生素和微量营养素上。尽管维生素补充物可预防或减少癌症的风险,但在一些研究中发现情况相反。一些研究者也已发现富含水果和蔬菜的饮食与肺癌发生率之间的负相关性。例如,通常认为β-胡萝卜素对减少癌症发生率具有正效应;然而,一个研究显示在人中肺癌增加。动物中的另一个研究似乎显示维生素A和β-胡萝卜素补充物都增加肺腺瘤。对于这些表面上矛盾的结果,很明显需要预防癌症发生的其他有效方法。
肺癌在美国是个重大的健康问题,是美国和世界范围内男性和女性中癌症死亡的头号原因。据认为每年发生大约160,000例肺癌导致的死亡。超过一半的这些肺癌病例发生在曾吸烟者中。
在一个方面,本发明提供了用于在受试者中减少癌症发生的风险或预防癌症发生的方法。本发明的方法适合用于,但不限于,减少发生肺癌、肝癌、脑癌、胰腺癌、肾癌、前列腺癌、乳腺癌、结肠癌或头-颈癌的风险。在一个特定的实施方案中,本发明的方法用于减少发生肺癌的风险。通常,本发明的方法包括对具有高风险因素的受试者施用治疗有效量的前列腺环素类似物。
发生癌症中的“减少风险” 是指相对于具有相似高风险因素但未用前列腺环素类似物治疗或用安慰剂治疗的对照组,减少受试者发生癌症的可能性。本领域技术人员可容易地确定风险减少的功效。该分析通常需要病例对照研究,其中用前列腺环素类似物治疗具有发生癌症的高风险的组的一些成员(病例组),而不治疗相同组内的其他成员(对照组)或为所述成员提供安慰剂。为确定前列腺环素在减少癌症发生的发生率(或风险)中的功效,观察病例对照组,进行被认为足以提供统计学上显著的分析的一段时间。如将被认识到的,为了提供统计学上显著的结果,病倒对照中的受试者人数应当在数量上是足够的。此外,可使用动物模型研究确定前列腺环素类似物减少癌症风险的功效。
通常通过在一定的时间后比较对照组和病例组之间癌症发生的发生率或恶化前发育异常的进展的差异来确定风险的减少。比较可包括但不限于,比较组织样品、细胞样品、痰样品、x-射线、血液样品等。用于这些类型的细胞样品的比较的任何已知的方法可用于评估发生癌症的风险的相对变化。
如此处所用的,“高风险因素”是指增加受试者发生癌症的可能性的因素。示例性高风险因素包括,但不限于,环境因素、易感染的遗传因素、暴露于烟草产品、暴露于化学药物、辐射或石棉、和已知增加各种癌症的风险的其他因素。例如,与非吸烟者相比,吸烟者处于发展肺癌的更高风险中。在一个特定的实施方案中,高风险因素是指每天吸至少1/2至1包香烟,进行至少1年,优选至少3年,更优选至少5年,更优选至少10年和最优选至少20年的受试者。为了简短和清楚起见,现以香烟烟雾暴露作为高风险因素来举例说明本发明;然而,应当理解,本发明的范围包括其他高风险因素例如上面公开的高风险因素。
通常,本发明的方法在受试者中减少发生癌症的风险至少10%(相对于具有相似风险因素的对照组)。优选地,风险减少至少15%,更优选至少20%和最优选至少30%。
前列腺环素类似物是指以与前列腺环素(前列腺素I2,PGI2)相似的方式起作用的化合物或其药学上可接受的盐。特别地,前列腺环素类似物是指模拟PGI2的体内作用或调节与PGI2调节的酶相同的酶的化合物。存在多种可获得的确定特定化合物是否可被当作前列腺环素类似物的体外测定法。可将目前可获得的任何已知的前列腺环素类似物用于本发明的方法。在一个特定的实施方案中,所述前列腺环素类似物选自伊洛前列素、贝拉普罗、treprostenil(Remodulin)和其组合。特别优选的前列腺环素类似物是伊洛前列素。有趣地,已发现对小鼠施用伊洛前列素不阻止癌症转移至肺。参见,例如,美国专利5,545,671。然而,与过去的研究不同,本发明涉及预防癌症在第一位置的发生而不阻止其转移。
伊洛前列素是化学稳定的并且具有比天然发生的物质更长的半衰期的合成的前列腺环素(PGI2)的类似物。伊洛前列素由Schering AG(美国的Berlex实验室)生产。其可通过口服、胃肠外或通过吸入施用。伊洛前列素可以伊洛前列素酸、伊洛前列素钠和伊洛前列素包合物以及速释放片剂和胶囊以及缓释胶囊的形式口服施用。
本发明的方法也可用于在具有发生恶化前发育异常的高风险因素的受试者中减少恶化前发育异常的进程(相对于具有相似风险因素的人)。
也可将前列腺环素类似物与其他治疗有用试剂例如环氧合酶(COX)抑制剂和过氧化物酶体增生物激活受体(PPAR)γ激动剂(例如,噻唑烷二酮类例如罗西格列酮、匹格列酮和环格列酮)一起施用。
制剂
可对受试者施用前列腺环素类似物以获得希望的生理效应。优选地,受试者是动物,更优选是哺乳动物和最优选是人。可以多种适合于选择的给药途径例如口服或胃肠外途径的多种形式施用前列腺环素类似物。在该方面,胃肠外给药包括通过下列途径的给药:静脉内、肌内、皮下、眼内、滑膜内、经皮(包括经真皮)、眼部、舌下和口腔途径、局部途径(包括眼部、真皮、眼睛、直肠和通过鼻吸入剂和烟雾剂施用的鼻吸入)、腹膜内和直肠系统途径。
可将前列腺环素类似物与例如惰性稀释剂或与可同化食用的载体一起口服施用,或可将其封装在硬壳或软壳明胶胶囊内,或可压制成片剂,或可将其直接与日常饮食的食物混合。对于口服治疗给药,可将前列腺环素类似物与赋形剂混合和以可摄入的片剂、含片、药片、胶囊剂、酏剂、混悬剂、糖浆剂、糯米纸囊剂等形式使用。这样的组合物和制剂可包含至少0.1%的活性前列腺环素类似物。当然,组合物和制剂的百分比可以变化并且可方便地在大约1%至大约10%的单位重量之间。这样的治疗上有用的组合物中的活性前列腺环素类似物的量是可获得合适的剂量的量。这样制备本发明的优选组合物或制剂以使口服单位剂型包含大约1至大约1000mg的活性前列腺环素类似物.在一个特定的实施方案中,口服或通过烟雾剂递送系统施用前列腺环素类似物。
片剂、含片、丸剂、胶囊剂等也可包含下列物质:粘合剂例如黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂例如磷酸二钙;崩解剂例如玉米淀粉、土豆淀粉、海藻酸等;润滑剂例如硬脂酸镁;和可加入甜味剂例如蔗糖、乳糖或糖精或增香剂例如薄荷、冬青油或樱桃香料。当单位剂型是胶囊时,其可包含,除了上述类型的材料外,液体载体。各种其他材料可以以包衣的形式存在或修饰剂量单位的物理形式。例如,可用紫胶、糖或两者包被片剂、丸剂或胶囊。糖浆或酏剂可包含前列腺环素类似物,蔗糖作为甜味剂,对羟苯甲酸甲酯和对羟苯甲酸丙酯作为防腐剂,染料和香料为例如樱桃香料或柑橘香料。当然,用于制备任何单位剂型的任何材料在使用的量上应当是药学上纯的和基本上无毒性。此外,可将前列腺环素类似物整合入缓释制剂和组分中。
也可胃肠外施用前列腺环素类似物。可在水中适当地与表面活性剂例如羟丙基纤维素混合来制备前列腺环素类似物的溶液。也可在甘油、液体聚乙二醇和其混合物以及油中制备分散体。在通常的贮存和使用条件下,这些制剂包含防止微生物生长的防腐剂。
适合用于可注射使用的药物形式包括无菌水溶液或分散体或用于无菌可注射溶液或分散相的临时配制的无菌粉剂。在所有情况下,所述形式必须是无菌的并且必须是流体,以达到容易以可注射性的程度存在。其在生产和贮存条件下可以是稳定的并且必须保护其免受微生物例如细菌和真菌的污染作用。载体可以是分散介质的溶剂,其包含水、乙醇、多元醇(例如,甘油、丙二醇和液体聚乙二醇等)、其合适的混合物和植物油。可通过例如使用包衣例如卵磷脂,通过在分散体的情况下保持所需的颗粒大小和通过使用表面活性剂来保持适当的流动性。可通过各种抗菌剂和抗真菌剂例如对羟苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等产生对微生物作用的预防。在许多情况下,优选地包含等渗剂,例如,糖或氯化钠。延缓吸收的试剂(例如,单硬脂酸铝和明胶)的可注射组合物的延缓吸收。
通过将前列腺环素类似物以需要的量与各种其他上面列举的组分(按需要)在适当溶剂中混合,然后过滤灭菌来制备无菌注射液。通常,通过将各种灭菌的活性组分整合入无菌媒介物来制备分散体,所述媒介物包含基本分散介质和来自上面列举的所需的其他组分。在用于制备无菌注射液的无菌粉剂的情况下,优选制备方法是真空干燥和冷冻干燥技术,所述技术从之前的无菌过滤溶液产生活性组分和任何额外的所希望组分的粉剂。
可将前列腺环素类似物单独地或与上面指出的药学上可接受的载体一起对哺乳动物施用,可通过前列腺环素类似物的溶解性和化学性质、选择的给药途径和标准的药物实践确定其比例。
医生将确定最适合于预防或治疗的前列腺环素类似物的剂量,并且其可随选择的给药形式和特定的前列腺环素类似物的变化而变化,同样,其随被治疗的特定患者的变化而变化。医生通常希望使用小剂量开始治疗,然后逐步少量增加剂量直至在所述状况下达到最佳效果。治疗剂量通常为大约0.1至大约1000mg/天,和优选大约10至大约100mg/天,或每天大约0.1至大约50mg/Kg的体重和优选每天大约0.1至大约20mg/Kg的体重,并且可以几种不同的剂量单位施用。可需要更高的剂量(在大约2X至大约4X的等级上)进行口服给药。
本发明的其他目的、有利方面和新特征,在检查下列其实施例(不希望被限定)后,对于本领域技术人员来说是很显然的。以现在式时态描述被建设性地减少到实践中的方法,和以过去式时态显示已在实验室中进行的方法。
实施例
大约20%的肺癌是小细胞肺癌(SCLC)。这些肺癌是所有肺癌中最具侵袭性和快速生长的肺癌。SCLC与吸烟具有强相关性,只有1%的这些肿瘤在非吸烟者中发生。SCLC快速地转移至身体内的许多部位,并且通常在它们已广泛扩散后才被发现。当提及通常见于SCLC中的特定细胞类型时,这些癌症有时称为燕麦细胞癌。
非小细胞肺癌(NSCLC)是最常见的肺癌,其占据所有肺癌的大约80%。NSCLC具有3种主要的、基于肿瘤中发现的细胞类型命名的类型即腺癌、鳞状细胞癌和大细胞癌。
在美国腺癌是最常见的NSCLC类型,其包括大约50%的NSCLC。虽然腺癌和其他肺癌一样与吸烟相关,但尤其在发生肺癌的非吸烟者中观察到该类型。大多数腺癌出现在肺的外部或周围区域。细支气管肺泡癌是在肺的多个部位频繁发生并沿预先存在的肺泡壁扩散的腺癌的亚型。鳞状细胞癌以前比腺癌更常见;目前其占到NSCLC的大约30%。也称为表皮样癌,鳞状细胞癌最常见地出现在支气管中的中部胸区域并且与香烟烟雾暴露强烈相关。
大细胞癌,有时称作未分化癌,是最不常见的NSCLC类型。也见到不同类型NSCLC的混合癌。肺中可出现其他类型的癌症。这些类型远没有NSCLC和SCLC常见,占据大约5-10%的肺癌。
吸烟是肺癌的主要风险因素。气流阻塞、慢性支气管炎或慢性阻塞性肺疾患(COPD)在大约25%的吸烟者中发生。与具有相似吸烟历史但不具有气流阻塞的吸烟者相比,该亚群具有显著增加的肺癌发生率。可用前列腺环素类似物治疗具有气流阻塞、慢性支气管炎或COPD的具有发生肺癌的增加的风险的受试者,然后可将所述受试者与具有相似气流阻塞、慢性支气管炎或COPD的对照受试者比较,从而评估发生肺癌的风险的减少。
对化学物质的暴露可导致对呼吸系统的有害作用,所述呼吸系统由鼻道、咽、气管、支气管和肺组成。呼吸毒性可包括多种急性和慢性肺病症,包括局部刺激、支气管炎、肺水肿、肺气肿和癌症。众所周知,对环境和工业化学物质的暴露可损害呼吸功能包括引起肺癌。地面水平的臭氧(烟雾的主要成分)引起呼吸问题、加重哮喘和增加呼吸道感染的严重性和发病率。对呼吸有毒物的急性暴露可触发从轻微刺激至窒息死亡的效应。对呼吸有毒物的长期暴露可产生对肺的结构性破坏,从而导致慢性疾病例如肺纤维化、肺气肿和癌症。肺纤维化是其中气道受到限制、发炎,从而导致呼吸困难的严重肺病。其可由对煤炭粉末、铝、铍和钨的碳化物的暴露引起。
肺气肿(退化和潜在的不治之症)的特征在于肺不能完全扩张和收缩。肺气肿的最常原因是重度吸烟,但该疾病也可由对铝、氧化镉、臭氧和氧化氮的暴露引起。此外,已知几种有毒物引起呼吸系统癌症。明确确定的人肺致癌物的实例是香烟、石棉、砷和镍。香烟包含4,000多种不同的化学物质,这些物质中的许多物质经证明是引起癌症的物质或致癌物。吸雪茄或吸烟斗也增加肺癌的风险。
氡在当今美国被认为是致肺癌的第二大病因。氡气可通过住宅或建筑物下面的土壤向上进入或通过地基或隔离物中的缝隙和裂缝以及通过管道、排水沟、墙壁或其他开口进入。在美国氡每年导致大量的肺癌死亡。在每一个州都发现了氡的问题。在学校和工作场所氡也是个问题。对氡的暴露和吸烟一起大大增加了肺癌的风险。这意味着对于吸烟者,对氡的暴露是甚至更大的健康风险。
肺癌的另一个主要病因是对引起癌症的物质或致癌物的在职暴露。石棉是众所周知的可导致肺癌的与工作相关的物质,但存在许多其他致癌物质,包括铀、砷和某些石油产品。存在可涉及暴露的许多不同的工作。一些实例是用某些类型的绝缘物工作,在炼焦炉中工作和修理车闸。当对工作相关性致癌物暴露同时又吸烟时,患肺癌的风险急剧增加。肺癌要花费多年时间来发生,但肺的改变几乎在人一暴露于引起癌症的物质时就开始发生。
对氯甲基醚和氡的职业性暴露优先影响小细胞肺癌。关于饮食,已看到与脂质消费、脂肪和胆固醇相关的一些正相关性,以及与各种类胡萝卜素、维生素C和视黄醇和与作为一类的水果和蔬菜的负相关性。也已表明免疫和激素因素影响腺癌的风险。
鼠类肺癌发生的化学预防
使用人表面活性剂蛋白C(SPC)启动子和大鼠PGIS cDNA的构建体产生具有肺前列环素合酶(PGIS)过度表达的转基因小鼠。据认为人SPC启动子指导转基因在II型肺泡和克拉拉细胞中表达,所述细胞被认为是人和小鼠肺腺癌的祖细胞。为确定基因分量效应,产生两个不同的转基因品系并将其暴露于致癌物质,低表达小鼠在肺PGIS活性上具有50%的增加(由与野生型同窝出生仔畜比较,1.5倍的PGI2的增加所展示的),高表达品系在肺PGI2上具有3倍的增加。
将8至12周龄的转基因小鼠(Tg+)和野生型同窝出生仔畜(Tg-)经历两种不同的肺癌发生方案。在第一模型中,以单一腹膜内(ip)剂量施用尿烷(氨基甲酸乙酯)(通过癌基因ras的基因突变选择性地诱导肺腺癌的致癌物)。在诱发/促进模型中,以单一ip剂量提供3-甲基胆蒽(MCA)(在香烟中发现的显示对鼠类肺肿瘤的剂量依赖性诱发的稠环芳烃),然后使用丁羟甲苯(BHT)进行6周的ip处理。BHT是肿瘤启动剂并且诱导特征在于I型肺泡细胞坏死、选择性肺炎和II型肺泡细胞超常增生的可逆肺损伤。两种模型的对照由只用媒介物注射的小鼠组成。
PGIS的转基因过度表达在两种致癌模型中显著减少了肿瘤的多样性(multiplicity)和发生率。表达低水平PGIS的Tg+小鼠展示的尿烷诱导的肿瘤多样性的减少50%(3.4对6.8个肿瘤/小鼠,p<0.001)和在MCA/BHT模型中66%的减少(2.5对7.5肿瘤/小鼠,p<0.001)。未处理的小鼠不能产生肿瘤。表达高水平PGIS的Tg+小鼠展示甚至更大的化学保护作用,与Tg-同窝出生仔畜相比,展示85%的肿瘤多样性的减少(0.8对5.2肿瘤/小鼠,p<0.0001)。在这些高表达小鼠中,肺肿瘤发生率也减少了,与Tg-同窝出生仔畜中的100%的发生率相比,44%(8/18)的Tg+小鼠保持无肿瘤(p=0.01,Fisher氏精确检验)。
烟草烟雾暴露模型中的化学预防。
可使用作为已建立的诱导肺腺癌的模型的鼠类暴露于烟草烟雾。据认为,该肺癌发生模型与人疾病状况非常相似。将PGIS过度表达者暴露于主流香烟烟雾22周,然后保持不暴露,进行另外的20周。当与暴露于烟雾的Tg-同窝出生仔畜相比时,Tg+小鼠具有显著减少的肿瘤发生率和多样性。与野生型同窝出生仔畜(16/19,84%)相比,显著更少的转基因(6/15,40%)产生了肿瘤(Fisher氏精确检验,p=0.012)。在转基因动物中也显著地减少了肿瘤多样性(tg+=0.4+/-0.5对wt=1.2+/-0.86个肿瘤/小鼠,p<0.001)。
这些不同的致癌模型中由PGIS的过度表达产生的保护作用证明了化学预防的通用性。这些研究说明了控制COX远端的前列腺素的代谢产生了比单独的COX抑制更大的肺癌减少。
提高的PGI2水平
确定Tg+动物的基线6-酮PGF1α(PGI2的稳定断裂产物)水平,和在两种癌发生方案结束时,同时测量6-酮PGF1α和PGE2的水平。在两种致癌模型中,在处死时,保持显著高于基线的6-酮PGF1α,然而在MCA/BHT模型中未观察到减少的PGE2水平。在用于PGIS过度表达的许多致癌模型中,对于发生的化学预防,观察到PGI2的提高(PGE2未减少)。
肺肿瘤发生的预防
调查伊洛前列素的口服给药,发现具有与PGIS的过度表达相似的有益效应。在整个实验中连续给FVB/N小鼠喂食低(0.1%)或高(3.0%)剂量的伊洛前列素,然后将其经历使用尿烷或MCA/BHT的肿瘤发生方案。在实验结束时,对动物实施无痛致死术并对肿瘤计数。两种致癌方案中的动物在肿瘤多样性中都具有显著的减少。在使用3.0%伊洛前列素的小鼠中观察到更大的多样性的减少。
在处于肺癌的高风险的患者中进行的伊洛前列素的化学预防研究
伊洛前列素是长效的、口服可用的前列腺环素类似物。已在具有各种病状、已接受6个月或更长时间的药物的受试者中确定了口服伊洛前列素的长期安全性,所述症状包括原发性肺动脉高压、具有雷诺现象的硬皮病、具有下肢溃疡的外周血管病/动脉粥样硬化和Buerger病(血栓闭塞性脉管炎)。
肺的鳞状细胞癌(SCC)是4种主要肺癌亚型中的一种,其是仅次于腺癌的第二常见的NSCLC形式。SCC通常起于中央气道(包括气管、主支气管和亚段支气管),组织学/细胞学研究已清楚地显示最终可发展成支气管癌的系列可预测的病理变化。可使用荧光支气管镜检查法检测支气管上皮损伤。荧光支气管镜检查法依赖于自发荧光,以在中央气道中检测癌前损伤。已发展了用于提高恶化前发育异常的检测的LIFE(激光诱导荧光内窥镜检查法(Laser Induced FluorescenceEndoscopy))。在白光支气管镜检查过程中显现的发育异常损伤较不可靠。与白光支气管镜检查法相比,LIFE支气管镜检查法对于检测中度或更高的发育异常具有提高大约6倍的灵敏性增加。LIFE支气管镜检查法是用于检测血管生成性鳞状上皮不典型增生(ASD)(特征在于毛细血管突入化生性或发育异常鳞状支气管上皮)的优选方法。关于ASD的自然历史的研究表明其可在发生鳞状细胞肺癌的患者中更频繁地发生。
试验包括在为期6个月的双盲、随机化前瞻性试验中给处于肺癌高风险的患者(基于痰的细胞非典型性和吸烟年包数)施用伊洛前列素或安慰剂。将选出的患者分配至各阶层内的积极疗法或安慰剂疗法组。反应的测量包括:使用针对支气管上皮的世界卫生组织(WHO)分类进行的治疗前和治疗后的组织学(第一终末点);Ki-67标记指数(第二终末点);和系列生物标记(包括针对PGIS、COX-2、PPARδ、PPARγ、MCM2、p53、酪氨酸激酶受体蛋白[EGFR、HER2/neu、ErbB3、ErbB4,、Akt]的免疫组织化学和定量聚合酶链式反应(qPCR)以及通过CD-31染色测量的微血管密度)。
体外测定法
可对细胞例如培养的鳞状细胞肺癌细胞系施用前列腺环素类似物以检测前列腺环素类似物的抑制性质。在另一个示例性方法中,可对小鼠施用前列腺环素类似物以在描述的鳞状细胞肺癌的鼠类模型中评估抗潜在的癌症例如肺癌发生发展的化学预防能力。这些研究的结果可用于在受试者例如动物或人受试者中评估前列腺环素类似物单独地或与其他疗法一起抑制癌症发展的功效。
PGIS过度表达的保护作用
为确定前列腺环素膜爱体对化学预防的效果,产生双转基因小鼠。首先,将具有前列腺环素受体(PGIR)被靶向破坏的小鼠回交10代成为FVB/N品系,以使之与PGIS Tg+动物同类系。然后进行系列杂交以产生双转基因动物(即,过度表达PGIS的PGIR基因敲除动物)。在该策略中,可确定通过PGIR进行的信号转导的影响。然后将动物经历尿烷癌发生方案。化学预防不依赖于PGIR。具有PGIR-/-或PGIR-/+的动物具有与野生型相同的肿瘤多样性。此外,即使在PGIR不存在的情况下PGIS转基因具有保护作用。不受任何理论束缚,有人认为该观察表明化学预防不依赖于细胞膜PGI2受体。
癌症的化学预防和减少恶化前支气管发育异常
小鼠肺肿瘤发生模型取决于鼠类品系,使用NTCU模型评估大量品系。检验FVB小鼠(经基因修饰的小鼠的品系)并基于肺的鳞状细胞癌(SCC)(4/9,44%)、原位SCC(7/9,78%)、细支气管组织化生(9/9,100%)和细支气管超常增生(8/9,89%)的发生率将其分类为“中度易感性的”。这模拟了现时吸烟者和曾吸烟者的气道中发现的各种病理损伤。因此,该SCC模型允许评估PGIS过度表达和/或伊洛前列素在SSC和恶化前支气管发育异常发生中的功效。
为确定前列腺环素是否能够改变恶化前鼠类损伤和鼠类SCC的发展,一个示例性方法是将NTCU模型用于接受口服伊洛前列素的FVB/NPGIS的过度表达者和野生FVB/N小鼠。在诱发癌发生方案前1周开始进行伊洛前列素治疗并在整个实验中持续进行。
PGIS化学保护Arm
喂养无抗氧化剂饲料(AIN-76A)的动物
局部应用NTCU,2次/周,共8个月 动物安乐死,并计数肿瘤数
↓↓↓↓ ↓
←——→
8个月
伊洛前列素化学保护Arm
给饲料中添加3.0%的伊洛前列素
局部应用NTCU,2次/周,共8个月 动物安乐死,并计数肿瘤数
↓↓↓↓ ↓
1周
←——→
8个月
实验组(具有20只FVB/N小鼠/组)是:
1.用NTCU处理的PGIS过度表达者
2.用丙酮(NTCU的递送媒介物)处理的PGIS过度表达者
3.用NTCU处理的野生型同窝出生仔畜
4.用丙酮处理的野生型同窝出生仔畜
5.接受用NTCU处理的3.0%伊洛前列素饲料的野生型动物
6.接受用NTCU处理的对照饲料的野生型动物
如下概述实验方案:NTCU SCC模型:在诱发处理之前48小时将8-10龄的动物的背部皮肤的毛剃光。使用局部NTCU(0.04M,每滴25μl)处理一组小鼠,每周2次,处理之间间隔3天。用1滴丙酮(用于溶解NTCU的溶剂)处理对照动物。在用NTCU诱发处理后8个月,使用过量戊巴比妥无痛杀死动物,收获肺以确定肿瘤发生率、多样性和原位SCC的存在以及支气管发育异常。将肿瘤和周围的肺保存在10%福尔马林中以进行常规H&E染色。从福尔马林固定的组织产生连续切片(每片5μm),每20张切片中有1张用H&E染色,然后用光学显微镜检查。将肿瘤和周围的肺的另外的样品在液氮中快速冷冻并贮存以待将来的DNA和蛋白质分析,或置于RNA保存液(RNAlater)中以待将来用于潜在的基因表达研究。
关于癌发生方案,对于α=0.05显著水平,使用双尾独立样本T检验确定20个动物的样本量。通过在各实验组中包含20只小鼠,置信(power)分析显示大于90%的检测肿瘤数目的显著差异的机会。将数据接受非配对t检验和泊松检验(肿瘤数目,肿瘤体积)以验证显著性。通过Student’s T检验检验肿瘤数目的差异的统计学显著性。在p值为0.05,各组中标准差为1,组大小为20的情况下,与另一个组相比,检测一个组中肿瘤数目从5个增加至6个的置信力经计算为0.86。
生长比
受伊洛前列素影响的各路径的共同终末点是细胞增殖。Ki-67标记是增殖指数的指示剂,其可在支气管活检材料中被容易地检测到。Ki-67标记评分随支气管发育异常的等级增加而增加,正常样品中具有4%的平均值,在增生样品中Ki-67标记评分在具有中度或严重发育异常的活检组织中增加至38%。参见表1。此外,现时吸烟者与曾吸烟者(平均18%)相比,具有较高的Ki-67标记评分(平均31%)。当就一段时间内的改变检查系列组的匹配的活检材料时,组织学改变和Ki-67标记评分之间存在相关性。因此,用于评估在治疗性处理的受试者中的发展癌症的减少的风险的方法是分析Ki-67生长比。
表1.高风险受试者的支气管上皮的组织学
组织学 | Ki-67(平均值%) | |
研究群体 | 1-2级(N=14个活检样本) | 4% |
3-4级(N=16个活检样本) | 20% | |
5-6级(N=39个活检样本) | 38% | |
现时吸烟者(N=11) | 平均等级4.4 | 31% |
曾吸烟者(N=5) | 平均等级3.0 | 18% |
系列活组织检查:无变化(N=7) | 平均等级改变0 | -17% |
进展(N=10) | 平均等级改变+2 | +17% |
改善(N=4) | 平均等级改变-2.5 | -21% |
因此Ki-67是容易进行的为本研究的第一终末点的增殖指数。
细胞附着和增殖
将等数目的细胞涂板在96孔板(5000/小孔)中。在不同的时间,用Hank漂洗板,使用MTT细胞生活力测定法定量细胞附着。使用未包被的标准组织培养皿进行初步研究。检测对特定的细胞外基质的附着。用I型胶原、纤连蛋白或基质胶包被培养皿,然后确定附着。以标准的组织培养条件下细胞(涂板在塑料培养皿上的细胞)数目的变化作为时间的函数来测量生长。在完全培养基[10%胎牛血清(FCS)]和生长因子耗尽的培养基中进行实验以确定自主生长。72小时后通过CellTiter 96 Aqueous One Solution Cell Proliferation测定(Promega;MTT Assay)就活细胞对板进行测定。结果计算为活细胞的百分比。
迁移
在纤连蛋白迁移能力测定中使用Transwell测定法测量细胞迁移。使用30μl 10μg/ml贮液,在24孔板中用纤连蛋白包被包含8μm孔的插入物(Falcon)。将等数目(~30,000)的稳定地过量表达PPARγ、PGIS或空载体的各NSCLC细胞涂板在transwell上,然后进行不同时间长度的孵育。在各时间点上,取出transwell,固定在4%的多聚甲醛中。用棉花拭子除去附着至transwell上端的细胞,用结晶紫染色存在于transwell底部的细胞。通过计数至少3个独立的视野/小孔定量迁移的细胞。在初步实验中,transwell的底部包含具有0.5%FCS的培养基。以不断增加的浓度(始于1μM,增加至5μM)向底部小室中加入伊洛前列素。
侵袭
使用基质胶侵袭池测定法(Matrigel invasion chamber assay)(BD Biosciences)确定细胞侵入基质胶。在该测定法中,将细胞涂板在已用基质胶包被的Transwell、或用牛血清白蛋白(BSA)包被的Transwell(对照)上。如对于迁移测定所描述的进行细胞定量。对于各细胞系,将%侵袭计算为迁移通过基质胶膜的细胞除以迁移通过对照膜的细胞的分数。对于过度表达PPARγ或PGIS的细胞,则将侵袭指数计算为过量表达PPAR的细胞的%侵袭/用空载体转染的细胞的%侵袭。
划痕测定
作为对Transwell迁移测定的另一选择,可通过细胞填充入培养皿上的划痕的能力检查细胞迁移。将细胞培养至汇合,然后通过在无FCS的培养基中孵育使其静止。使用移液管尖头在培养基上产生30-100μm的划痕。通过拍摄相同的细胞视野的照片将细胞填充由移液管尖头产生的空隙的能力确定为时间的函数。如果过量表达PPARγ或PGIS的细胞的附着率存在显著差异,那么Transwell测定的结果反映了附着和迁移的差异,从而使解释更困难。
提出本发明的上述讨论是为了举例说明和描述。上述内容不希望将本发明限定于此处公开的形式。尽管本发明的描述已包括了一个或多个实施方案的描述,但在理解本公开内容后,某些改变和修饰、其他变化形式和改变在本发明的范围内,例如,如可在本领域技术人员的能力范围内的改变。希望获得包括对允许的范围可选择的实施方案(包括针对权利要求的实施方案的备选的、可互换的和/或等同的结构、功能、范围或步骤),无论这些可选择的、可互换的和/或可等同的结构、功能、范围或步骤是否是此处公开的,和不希望公开展示可授予专利的客体。
Claims (12)
1.用于相对于不具有相似风险因素的人,在具有较高的发生癌症的风险因素的受试者中减少发生癌症的风险的方法,所述方法包括对受试者施用治疗有效量的前列腺环素类似物以使受试者中发生癌症的风险相对于具有相似风险因素的对照组减少至少10%。
2.权利要求1的方法,其中所述癌症选自肺癌、肝癌、脑癌、胰腺癌、肾癌、前列腺癌、乳腺癌、结肠癌和头-颈癌。
3.权利要求2的方法,其中所述发生癌症的较高风险因素是暴露于平均每天至少1包烟,进行至少5年。
4.权利要求2的方法,其中所述前列腺环素类似物选自伊洛前列素、贝拉普罗、treprostenil和其组合。
5.权利要求1的方法,其中相对于对照组,受试者中发生癌症的风险减少至少20%。
6.在相对于不具有相似风险因素的人具有发生癌症的较高风险因素的受试者中预防癌症的方法,所述方法包括对受试者施用治疗有效量的前列腺环素类似物,以使相对于具有相似风险因素的对照组,受试者中癌症的发生率减少至少10%,其中所述癌症选自肺癌、肝癌、脑癌、胰腺癌、肾癌、前列腺癌、乳腺癌、结肠癌和头-颈癌。
7.权利要求6的方法,其中所述发生癌症的较高风险因素是暴露于平均每天至少1包烟,进行至少5年。
8.权利要求6的方法,其中所述前列腺环素类似物选自伊洛前列素、贝拉普罗、treprostenil和其组合。
9.权利要求6的方法,其中相对于对照组,受试者中发生癌症的风险减少至少20%。
10.用于在相对于不具有相似风险因素的人具有发生恶化前发育异常的较高风险因素的受试者中减少发生恶化前发育异常的方法,所述方法包括对受试者施用治疗有效量的前列腺环素类似物以使相对于具有相似风险因素的对照组,受试者中恶化前发育异常的风险减少至少10%。
11.权利要求10的方法,其中所述前列腺环素类似物选自伊洛前列素、贝拉普罗、treprostenil和其组合。
12.权利要求10的方法,其中受试者中恶化前发育异常的进展相对于对照组减少至少20%。
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CN109793744A (zh) * | 2019-03-26 | 2019-05-24 | 牡丹江医学院 | 一种介入治疗子宫肌瘤的药物组合物及其制备方法 |
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ES2805367T3 (es) | 2013-01-11 | 2021-02-11 | Corsair Pharma Inc | Profármacos de treprostinil |
US9505737B2 (en) | 2013-01-11 | 2016-11-29 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
AU2016381656A1 (en) | 2015-12-30 | 2018-07-12 | Visiongate, Inc. | System and method for automated detection and monitoring of dysplasia and administration of chemoprevention |
US11069054B2 (en) | 2015-12-30 | 2021-07-20 | Visiongate, Inc. | System and method for automated detection and monitoring of dysplasia and administration of immunotherapy and chemotherapy |
US11065260B1 (en) | 2020-04-13 | 2021-07-20 | Alan C Nelson | Method of treatment for reducing pulmonary inflammation in a patient with pathogen infection using oral prostacyclin analog drugs |
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US8623917B2 (en) | 2014-01-07 |
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