CN101155577B - 神经纤维瘤的局部治疗 - Google Patents
神经纤维瘤的局部治疗 Download PDFInfo
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- CN101155577B CN101155577B CN200680011113.5A CN200680011113A CN101155577B CN 101155577 B CN101155577 B CN 101155577B CN 200680011113 A CN200680011113 A CN 200680011113A CN 101155577 B CN101155577 B CN 101155577B
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Abstract
本文公开了用于治疗有治疗需要的个体中神经纤维瘤(例如皮肤神经纤维瘤、皮下神经纤维瘤或浅表丛状神经纤维瘤)的方法。所述方法包括局部或病灶内向神经纤维瘤局部施用组合物。所述方法不包括向所述个体全身给药所述组合物以对所述神经纤维瘤产生效应。本文公开了用于这样的治疗的组合物及制备所述组合物的方法。
Description
发明背景
1型神经纤维瘤病(NF1)为影响人神经系统的最常见的单基因病症。其以常染色体显性方式遗传。在世界范围内，NF1影响约1500万人，且该病症没有种族、人种或地区偏好。NF1由NF1基因突变引起，所述突变产生神经纤维瘤蛋白，一种肿瘤抑制剂。NF1基因座的高自发突变率(50％)确保所述病症不可能由于遗传病筛查而在人群中显著减少。
受NF1影响的人发生多种神经系统肿瘤的危险增大，所述肿瘤包括皮肤、皮下和丛状神经纤维瘤；视通路(optic pathway)星形细胞瘤和恶性周围神经鞘瘤(“MPNST”)，并且学习无能、脊柱侧凸和某些形式的白血病的危险增大。这些肿瘤可导致外貌损伤、神经系统损伤和慢性疼痛。皮肤神经纤维瘤为NF1中最常见的损伤，并在90％的受影响个体中出现。皮肤神经纤维瘤典型地较小(直径小于2cm)、多发并在青春期第一次发生。典型地，它们的胶原含量高，具有极低的代谢活性，且与丛状神经纤维瘤相反，从不经历恶性变性。从来没有报道过在皮肤神经纤维瘤中自发的恶性变性病例或者在接受用于各种恶性肿瘤的局部放射治疗的患者中或接受用于恶性肿瘤的化学治疗的患者中的恶性变性病例。
某些患者可发生与象人病相关的一些相同的外貌损伤病征，象人病为一种原来被认为是NF1的另外的病症。目前唯一的治疗为外科去除。然而，肿瘤通常不能在不导致大的神经和/或美容问题的情况下被去除，并且通常再生。它们对放射治疗或已知的化疗药不敏感。
皮肤和皮下神经纤维瘤可在生命中的任何时期发生，但它们的数量在青春期之前通常较少。见于成年人中的神经纤维瘤的总量从少数到数千不等。另外的皮肤和皮下神经纤维瘤在整个生命过程中发生，但出现比率可年年有较大不同。除了实际治愈该病症，对于在美国受NF1影响的100000人，用于皮肤神经纤维瘤的有效非外科治疗为唯一最优先的。皮肤神经纤维瘤导致明显的外貌损伤、疼痛、心理和财政压力，并应被认为是这一人群中的大的未满足的医疗需求。因为包括相对于其他肿瘤而言相对低的增殖指数在内的几个因素和该肿瘤存在于皮肤稍深处(尤其是与基底细胞癌和鳞状细胞癌相比时)的事实，之前尚未研究开发用于皮肤神经纤维瘤的局部治疗。这一局部治疗包括在神经纤维瘤部位的局部治疗和病灶内或真皮内治疗。因此，尽管这些皮肤神经纤维瘤的这样的局部治疗对于未满足的医疗需求而言会是有价值的治疗，但之前在该领域尚未开展工作。
发明概述
本发明的一个方面为用于治疗有治疗需要的个体中神经纤维瘤(例如皮肤神经纤维瘤、皮下神经纤维瘤或浅表(superficial)丛状神经纤维瘤的方法。所述方法包括向神经纤维瘤局部施用组合物。这一方法不包括向所述个体全身给药所述组合物以对所述神经纤维瘤产生效应。所述方法包括向肿瘤部位局部给药组合物，其中所述组合物包含(a)至少一种用于减轻所述神经纤维瘤对所述个体的负面影响的药物，和任选的(b)药学可接受的赋形剂，其帮助将所述药物转运进入所述肿瘤，优选所述药物在所述肿瘤中保持一段足够的时间以负面影响所述神经纤维瘤。
更具体而言，所述方法包括向肿瘤部位的皮肤表面局部施用组合物，其中所述组合物包含(a)至少一种用于减轻神经纤维瘤对所述个体的负面影响的药物，和任选的(b)药学可接受的局部赋形剂，其帮助将所述药物转运透过皮肤进入所述肿瘤，且优选将所述药物在所述个体的皮肤上保持一段时间。
本发明的另一方面为用于治疗个体中神经纤维瘤(例如皮肤神经纤维瘤、皮下神经纤维瘤或浅表丛状神经纤维瘤)的组合物。所述组合物包含(a)至少一种用于减轻所述神经纤维瘤对所述个体的负面影响的药物，和任选的(b)药学可接受的局部赋形剂，其帮助将所述药物转运透过皮肤进入所述肿瘤，且优选将所述药物在所述个体的皮肤上保持一段时间。或者，所述组合物包含(a)至少一种用于减轻所述神经纤维瘤对所述个体的负面影响的药物，和任选的(b)适于注射的药学可接受的载体。
本发明的再一方面为制备用于局部治疗神经纤维瘤(例如皮肤神经纤维瘤、皮下神经纤维瘤或浅表丛状神经纤维瘤)的药剂的方法。所述方法包括混合至少一种药物与药学可接受的局部赋形剂，所述药物用于减轻所述神经纤维瘤对个体的负面影响，所述赋形剂帮助将所述药物转运透过皮肤进入所述肿瘤，且优选将所述药物在所述个体的皮肤上保持一段时间。
本发明的另一方面为制备用于病灶内注射神经纤维瘤的药剂的方法。所述方法包括混合至少一种药物与药学可接受的赋形剂，所述药物用于减轻所述神经纤维瘤对个体的负面影响，所述赋形剂帮助病灶内递送进入所述肿瘤，从而使所述药物接触所述个体的肿瘤一段时间。
在阅读下述详细说明后，本发明的其他方面对本领域技术人员可能是清楚的。
详细说明
在实施本发明的方法中，将组合物施用于肿瘤部位的皮肤表面。可以将所述组合物以用于施用组合物的任意已知方法施用。因此，可以将所述组合物喷雾、轻轻地抹上、擦上或者使用贴剂粘附在皮肤上等。此外，可以使用微注射、电泳、超声或射频机制将其施用于皮肤并转运透过所述皮肤。其可以使用病毒系(viral-based)或气动(pneumatic)递送系统递送。可以将所述药物配制成毫微粒、树枝状聚合物或脂质体。所述组合物可以采取散剂、液体溶液剂或混悬剂、乳膏、洗剂、软膏剂、凝胶剂的形式，或者采取另一组合物的形式，其允许将所述组合物在所述皮肤上保持一段时间，所述时间足够导致所述药物迁移透过所述皮肤并到达所述肿瘤。
将所述组合物施用于肿瘤部位的皮肤或者病灶内注射入所述肿瘤中。通常，所述肿瘤为易于显现的，并且会导致所述皮肤变形。因此，所述组合物会直接施用于肿瘤部位的皮肤表面。该部位将是皮肤上任意这样的部位，其会被转运透过所述皮肤并进入所述肿瘤以导致所述组合物中的活性剂作用于所述肿瘤。一旦将所述组合物施用于所述皮肤上，其就被保持在所述皮肤上一段时间，所述时间足够将所述药物转运透过所述皮肤进入所述肿瘤以减轻神经纤维瘤对所述个体的负面影响。
对于病灶内注射，存在多种“主动”药物递送方法和被动药物递送(含有或不含渗透促进剂的制剂)。所有技术都用某种类型的能量或者机械地扰乱表皮的角蛋白层以改善药物递送。所述方法包括：离子电渗疗法；超声、射频(RF)和显微针(皮肤磨削术)。也可以使用无针注射技术，其为连接于CO2药筒的显微针，其推动药物穿透所述皮肤。
减轻负面影响指(1)肿瘤的尺寸可稳定而不增加，(2)肿瘤尺寸可降低，或(3)与肿瘤相关的疼痛和/或痒感可减少。优选肿瘤的尺寸显著降低，因为由神经纤维瘤导致的外貌损伤为该病症的主要损害。用于确定组合物是否起减轻对个体的负面影响的作用的标志包括在治疗期内测量肿瘤的尺寸和回访所述个体以确定是否所述个体的疼痛程度降低。可以开发其他标志，比如显示肿瘤生长速率的增殖指数，显示肿瘤细胞死亡速率的细胞凋亡指数，或者血管密度。也可以使用对本领域技术人员显而易见的其他生物标记来测量本发明的组合物的成效。例如，监测Ras-Raf-MEK-MAPK途径的活化状态的生物标记可以用于测量本发明的组合物在肿瘤组织中的目标抑制。在大多数情形下，在治疗前通过使用测径器或者使用MRI成像技术测量肿瘤的尺寸来建立基线，或者建立未治疗的肿瘤的指数。一旦建立了基线，就可以开始治疗并定期进行测量以确定所述治疗的成效。
作为单一药物或者一种或多种药物的组合用于组合物中以施用于皮肤表面或病灶内注射入肿瘤中的药物为会减轻神经纤维瘤对个体的负面影响的药物。在本发明中有用的优选药物为非致癌的药物。FDA或IARCMonographs已经列出了被认为是致癌的且不建议或允许人使用的化合物/药物。虽然博来霉素作为药物在下文中列出，但是作为优选的药物是不期望的，因为它是致癌的。例如，如果这样的药物可以为化疗药(例如抗肿瘤药、细胞毒素或抗增殖药)；硬化剂；免疫调节药(例如免疫调节剂、免疫抑制剂或免疫增强药)或抗炎药，比如非甾体抗炎药(NSAID)或Cox-1&2抑制剂；调节基因转录的药物，例如HDAC(组蛋白脱酰酶)抑制剂(例如丙戊酸、FK228、trapoxin)、血管发生抑制剂；改变小GTP酶的结构、功能、定位或翻译后修饰的药物(例如法尼基转移酶抑制剂[R115777]、异戊二烯基半胱氨酸转移酶抑制剂(cysmethnil)；充当化学预防药的药物，比如维生素、维生素衍生物、抗氧剂、营养补剂(例如芬维A胺、包含EGCG的绿茶提取物)、抗纤维变性药、靶向于细胞凋亡或抗细胞凋亡信号转导的药物；激酶抑制剂(例如蛋白激酶抑制剂或脂质激酶抑制剂)；烷基磷脂；蛋白质陪伴分子抑制剂，比如热激蛋白抑制剂(例如HSP90)；抗真菌剂；恢复突变基因功能的药物，比如抑制无义突变的药物(例如庆大霉素)；核酸系治疗剂、磷酸酶抑制剂、蛋白酶抑制剂或抑制皮肤增生(例如光化性角化病、黑素瘤、卡波西肉瘤、基底细胞癌或鳞状细胞癌或者其他癌症的皮肤转移)的药物。对于局部治疗，所述组合物优选含有帮助推动所述药物透过皮肤进入肿瘤的皮肤渗透剂。
有用的化疗药的实例为(1)通过抑制拓扑异构酶干扰DNA复制的药物；(2)破坏微管和/或有丝分裂纺锤体的药物；(3)充当DNA的烷化剂或破坏剂的药物，或(4)干扰核苷酸合成的药物，即抗代谢药。具体的化疗药包括5-氟尿嘧啶(5-FU)和噻替派。这些物质的每一种都是本领域普通技术人员已知的，且可从标准来源获得。
蛋白激酶抑制剂为靶向于在神经纤维瘤中超活化的激酶的化合物，比如Ras激活的促细胞分裂剂激活的蛋白激酶途径(例如MEK和Raf激酶)、受体和非受体酪氨酸激酶及AKT-mTOR途径的组分，其分别促进细胞增殖和存活。脂质激酶抑制剂为靶向于磷脂酰肌醇3-激酶途径的化合物，所述途径在神经纤维瘤中超活化并导致细胞存活延长。
蛋白质陪伴分子抑制剂为抑制热激蛋白或肽基脯氨酰异构酶功能的抑制剂。需要热激蛋白活性来保持Raf和KSR以及许多其他信号分子的生理蛋白水平，Raf和KSR为Ras-促细胞分裂剂激活的蛋白激酶途径的两种组分。
血管发生抑制剂为阻断下述的抑制剂：(1)血管发生信号级联，比如血管内皮生长因子(VEGF)受体信号转导，(2)细胞外基质破坏，比如由基质金属蛋白酶(例如卤夫酮(halofuginone))诱导的细胞外基质破坏，(3)内皮细胞的生长、存活和迁移，或(4)未知作用机理。这些化合物中的一些也归属于其他种类。其中这些血管发生过程被需要以确保生长中的肿瘤的足够血供，目为NF1治疗干预的有吸引力的模式。
许多细胞类型(包括施万细胞、肥大细胞和成纤维细胞)之间的化学和物理两种细胞-细胞通讯对于神经纤维瘤疾病进程可能是必不可少的。阻断细胞因子和生长因子转录的免疫调节药(比如钙调磷酸酶抑制剂)为干扰细胞-细胞信号转导的有效工具。
用于修复无义突变的矫正特定突变的药物，比如基因置换或庆大霉素，也是有用的。
通过下述优选实施方案来更具体地描述本发明：
1、治疗有治疗需要的个体中皮肤神经纤维瘤、皮下神经纤维瘤或浅表丛状神经纤维瘤的方法，所述方法包括向肿瘤部位局部给药组合物，其中所述组合物包含(a)至少一种用于减轻所述神经纤维瘤对所述个体的负面影响的药物，和任选的(b)药学可接受的赋形剂，其帮助将所述药物转运进入所述肿瘤，优选所述药物在所述肿瘤中保持一段足够的时间以负面影响所述神经纤维瘤。2、1的方法，其中所述局部给药为向肿瘤部位的皮肤表面局部施用所述组合物，并且其中所述赋形剂帮助将所述药物转运透过皮肤并到达所述肿瘤，且优选将所述药物保持在所述个体的皮肤上。3、1的方法，其中所述局部给药为将所述组合物病灶内注射入所述肿瘤。4、1-3之任一项的方法，其中所述药物包括化疗药，其中(1)所述药物通过抑制拓扑异构酶干扰DNA复制；(2)所述药物破坏微管和/或有丝分裂纺锤体；(3)所述药物充当DNA的烷化剂或破坏剂；(4)所述药物干扰核苷酸合成，或它们的组合。5、1-3之任一项的方法，其中所述药物包括硬化剂。6、1-3之任一项的方法，其中所述药物为免疫调节药、免疫调节剂、免疫抑制剂、免疫增强药或非甾体抗炎药。7、1-3之任一项的方法，其中所述药物调节基因转录。1-3之任一项的方法，其中所述药物为血管发生抑制剂。9、1-3之任一项的方法，其中所述药物改变小GTP酶的结构、功能、定位或翻译后修饰。10、1-3之任一项的方法，其中所述药物为化学预防药。1 1、1-3之任一项的方法，其中所述药物为选自下述的抑制剂：蛋白激酶抑制剂、脂质激酶抑制剂、热激蛋白抑制剂、蛋白质陪伴分子抑制剂、磷酸酶抑制剂或蛋白酶抑制剂。12、1-3之任一项的方法，其中所述药物为抗纤维变性药。13、1-3之任一项的方法，其中所述药物为烷基磷脂。14、1-3之任一项的方法，其中所述药物靶向于细胞凋亡或抗细胞凋亡信号转导。15、1-3之任一项的方法，其中所述药物为核酸系治疗剂。16、1-3之任一项的方法，其中所述药物恢复突变基因的功能。17、1-3之任一项的方法，其中所述药物抑制皮肤增生。18、1-3之任一项的方法，其中所述药物为烷化剂，比如噻替派或卡铂；抗代谢药或核苷类似物，比如5-氟尿嘧啶、曲西立滨、桑吉瓦霉素或杀结核菌素(tubercidin)；拓扑异构酶抑制剂，比如鬼臼毒素；微管抑制剂，比如甲苯达唑，硬化剂，比如博来霉素、多西环素或其类似物；抗炎药或非甾体抗炎药(NSAID)，比如双氯芬酸；调节基因转录的药物，比如HDAC抑制剂，包括tricostatin A或丙戊酸；化学预防药，比如类维生素A，比如芬维A胺；烷基磷脂，比如米替福新；HSP90抑制剂，比如格尔德霉素衍生物，比如17-AAG、根赤壳菌素或其类似物；卤夫酮、庆大霉素、雷帕霉素，或其组合。19、1-18的方法，其中所述赋形剂包括皮肤渗透剂。
还公开了用于治疗神经纤维瘤的优选组合物。20、用于治疗个体中皮肤神经纤维瘤、皮下神经纤维瘤或浅表丛状神经纤维瘤的组合物，所述组合物包含(a)至少一种用于减轻所述神经纤维瘤对所述个体的负面影响的药物，和任选的(b)药学可接受的局部赋形剂，其帮助将所述药物转运透过皮肤进入所述肿瘤，且优选将所述药物在所述个体的皮肤上保持一段时间。21、20的组合物，其中所述药物为化疗药，其中(1)所述药物通过抑制拓扑异构酶干扰DNA复制；(2)所述药物破坏微管和/或有丝分裂纺锤体；(3)所述药物充当DNA的烷化剂或破坏剂；(4)所述药物干扰核苷酸合成，或它们的组合。22、20的组合物，其中所述药物包括硬化剂。23、20的组合物，其中所述药物为免疫调节药、免疫调节剂、免疫抑制剂、免疫增强药或非甾体抗炎药。24、20的组合物，其中所述药物调节基因转录。25、20的组合物，其中所述药物为血管发生抑制剂。26、20的组合物，其中所述药物改变小GTP酶的结构、功能、定位或翻译后修饰。27、20的组合物，其中所述药物为化学预防药。28、20的组合物，其中所述药物为选自下述的抑制剂：蛋白激酶抑制剂、脂质激酶抑制剂、热激蛋白抑制剂、蛋白质陪伴分子抑制剂、磷酸酶抑制剂或蛋白酶抑制剂。29、20的组合物，其中所述药物为抗纤维变性药。30、20的组合物，其中所述药物为烷基磷脂。31、20的组合物，其中所述药物靶向于细胞凋亡或抗细胞凋亡信号转导。32、20的组合物，其中所述药物为核酸系治疗剂。33、20的组合物，其中所述药物恢复突变基因的功能。34、20的组合物，其中所述药物抑制皮肤增生。35、20的组合物，其中所述药物为烷化剂，比如噻替派或卡铂；抗代谢药或核苷类似物，比如5-氟尿嘧啶、曲西立滨、桑吉瓦霉素或杀结核菌素；拓扑异构酶抑制剂，比如鬼臼毒素；微管抑制剂，比如甲苯达唑，硬化剂，比如博来霉素、多西环素或其类似物；抗炎药或非甾体抗炎药(NSAID)，比如双氯芬酸；调节基因转录的药物，比如HDAC抑制剂，包括tricostatin A或丙戊酸；化学预防药，比如类维生素A，比如芬维A胺；烷基磷脂，比如米替福新；HSP90抑制剂，比如格尔德霉素衍生物，比如17-AAG、根赤壳菌素或其类似物；卤夫酮、庆大霉素、雷帕霉素，或其组合。36、20-36的组合物，其中所述赋形剂包括皮肤渗透剂。37、20-36之任一项的组合物在制备用于治疗个体中神经纤维瘤的药物组合物中的用途。38、制备用于局部治疗皮肤神经纤维瘤、皮下神经纤维瘤、浅表丛状神经纤维瘤的药剂的方法，所述药剂包含20-36之任一项的组合物，所述方法包括混合至少一种药物与药学可接受的局部赋形剂，所述药物用于减轻所述神经纤维瘤对所述个体的负面影响，所述赋形剂帮助将所述药物转运透过皮肤进入该肿瘤，且优选将所述药物在所述个体的皮肤上保持一段时间。
在本发明中单独或组合用作用于减轻神经纤维瘤对个体的负面影响的药物的具体化合物的实例包括噻替派、多西环素、博来霉素、双氯芬酸、卡铂、5-氟尿嘧啶(5-FU)、甲苯达唑、卤夫酮(halfuginone)、庆大霉素、雷帕霉素、米替福新等。
而且，作为单一药学活性剂或与一种或多种药学活性剂加或不加药学可接受的局部赋形剂包含于所述组合物中的用于减轻所述神经纤维瘤对个体的负面影响的药物包括但不限于下述药物：
1.化疗药，比如细胞毒素、抗肿瘤药或抗增殖药，例如：药物，比如：烷化剂，比如噻替派，
拓扑异构酶抑制剂，比如喜树碱，
卡铂，
抗代谢药，比如5-氟尿嘧啶(5-FU)，
拓扑异构酶抑制剂，比如鬼臼毒素，
微管抑制剂，比如甲苯达唑，
抗代谢药或核苷类似物，比如克拉屈滨，
拓扑异构酶抑制剂，比如XK469(2-(4-((7-氯-2-喹喔啉基)氧基)苯氧基)丙酸)，
核苷类似物，比如桑吉瓦霉素，
核苷类似物，比如杀结核菌素，
2.硬化剂，例如：
博来霉素，一种抗肿瘤抗生素，
四环素类似物或抗生素，比如多西环素，
3.免疫调节药或免疫调节剂或免疫增强药或免疫抑制剂，例如：
免疫增强药，比如咪喹莫特(免疫应答调节剂或TLR7/8配体或激动剂)，
免疫抑制剂，比如他克莫司(FK506)，
4.抗炎药或非甾体抗炎药(NSAID)，比如：
双氯芬酸，
塞来考昔(也是Cox-1&2抑制剂或抗炎药)，
5.调节基因转录的药物；例如HDAC(组蛋白脱酰酶)抑制剂，例如：
脂肪酸类HDAC抑制剂，比如丙戊酸，
异羟肟酸类HDAC抑制剂，比如Tricostatin A(TSA)，
卡马西平(下述)及其衍生物比如卡马西平环氧化物，
环状四肽类HDAC抑制剂，比如缩酚酸肽FK228(FR901228)，
6.血管发生抑制剂，例如：
烟曲霉素，其由真菌烟曲霉(Aspergillus fumigatus)分泌，及其类似物比如TNP-470[O-(氯乙酰基氨基甲酰基)烟曲霉醇]，如下所示：
沙立度胺，也是免疫调节药，
7.抑制修饰小GTP酶所需要的细胞过程的药物，比如：
法尼基转移酶抑制剂[例如R115777，(B)-6-[氨基(4-氯苯基)(1-甲基-1H-咪唑-5-基)甲基]-4-(3-氯苯基)-1-甲基-2(1H)-喹啉酮]，
异戊二烯基半胱氨酸转移酶抑制剂[例如cysmethnil]，
HMG-CoA抑制剂(他汀类，例如洛伐他汀)，
双膦酸盐(例如阿仑膦酸盐，如甲羟戊酸途径抑制剂)
8.化学预防药，例如：
合成的类维生素A(芬维A胺)，
视黄酸[3，7-二甲基-9-(2，6，6-三甲基-1-环己烯基)-壬-2，4，6，8-四烯酸]及类似物，
姜黄素及衍生物，
EGCG，(-)-表儿茶素棓酸酯(见下述)及类似物，
I3C(吲哚-3-甲醇)，
环杷明，
甲基乙二醛，
激酶抑制剂、MEK抑制剂、Raf抑制剂、mTOR抑制剂、PI3K抑制剂，例如，比如：
MEK抑制剂，比如U0126[1，4-二氨基2，3-二氰基-1，4-双(2-氨基苯硫基)丁二烯]，
P13K抑制剂，比如Ly294002[2-(4-吗啉基)-8-苯基-4H-1-苯并吡喃-4-酮]，
EGFR/ErbB2抑制剂，比如4-(4-苄氧基苯胺基)-6，7-二甲氧基喹唑啉，
AG1478(EGFR抑制剂)，4-(3-氯苯胺基)-6，7-二甲氧基喹唑啉，
多种酪氨酸激酶的抑制剂，例如PDGFR抑制剂，比如KN2941(4-(6.7-二甲氧基-4-喹唑啉基)-N-(3，4-亚甲二氧基苄基)-1-哌嗪硫代甲酰胺)，
多种激酶的抑制剂，比如SU11652，5-[(Z)-(5-氯-2-氧代-1，2-二氢-3H-吲哚-3-亚基)甲基]-N-[2-(二乙氨基)乙基]-2，4-二甲基-1H-吡咯-3-甲酰胺，
多种激酶的抑制剂，比如SU11248[(商品名为Sutent)，5-[(Z)-(5-氟-2-氧代-1，2-二氢-3H-吲哚-3-亚基)甲基]-N-[2-(二乙氨基)乙基]-2，4-二甲基-1H-吡咯-3-甲酰胺，
多种激酶的抑制剂，比如VEGFR2和Raf激酶，比如Bay43-9006(NEXAVAR或Sorafenib)，4-(4-{3-[4-氯-3-(三氟甲基)苯基]脲基}苯氧基)-N2-甲基吡啶-2-甲酰胺，
mTOR抑制剂，比如雷帕霉素(也是免疫抑制剂，参见下述)和前药或类似物，
Rho激酶抑制剂，比如Fasudil，[1-(5-异喹啉磺酰基)高哌嗪]，
10.新的抗纤维变性药，其可以包括也为血管发生抑制剂的药物，例如
卤夫酮氢溴酸盐[(+/-)-反式-7-溴-6-氯-3-[3-(3-羟基-2-哌啶基)-2-氧代丙基]-4(3H)-喹唑啉酮氢溴酸盐]，
吡非尼酮(5-甲基-N-苯基2-1H-吡啶酮-d5)，
11.烷基磷脂，例如：
A.米替福新(HePC)
B.依地福新(Et-18-OCH3)
C.哌立福辛(D21266)
12.HSP90抑制剂(热激蛋白抑制剂)
格尔德霉素类似物/衍生物，比如17-AAG及其衍生物，17-AAG，17-(烯丙基氨基)-17-脱甲氧基格尔德霉素，
根赤壳菌素及类似物，
金丝桃素，
13.抗真菌剂：
克霉唑及类似物，
14.恢复突变基因功能的药物，例如抑制无义突变的药物，例如：
庆大霉素，
在制备本发明的组合物中，可由下述文献的教导来指导：(1)Remingtons Pharmaceutical Sciences，Mack Publishing Co.，第17、18或19版，ISBN：0-912734-04.3，(也称为“Remington：The Science and Practice ofPharmacy″)；(2)Pharmaceutics-The Science of Dosage Form Design，Aulton，Churchill Livingston；(3)Appleton and Lange Review of Pharmacy(第7或第8版)by Hall and Reiss，Appleton and Lange；等，所有这些文献均引入本文作为参考。关于毫微粒或脂质体递送，更多信息可在http://www.happ1.com/special/mar013.htm和http://www.collabo.com/liposome.htm获得。关于树枝状聚合物的信息见http://www.ringer.com/dedrimer/one.htm。
实施例
在本发明中用于治疗神经纤维瘤的药物可通过本文描述的几种方法选择。例如，在基于细胞的测定中测试本文描述的各种化合物/药物以及可选择的其他药物抑制NF1相关细胞系组(panel)的细胞增殖的效力，测试它们以确定对皮肤神经纤维瘤外植块测定的效应，并测测试它们以确定对皮肤神经纤维瘤异种移植物模型的效应。
I.体外测定
1)细胞增殖测定
在细胞增殖测定中，使用几种生理上相关的细胞或细胞系来测量化合物效力。这些细胞包括：(1)NF1-缺陷人恶性周围神经鞘瘤(MPNST)细胞，(2)NF1-/-小鼠胚胎施万细胞，和(3)Nf1-和p53-缺陷小鼠细胞。小鼠施万细胞生长在用层粘连蛋白涂敷的平板上，并在Dulbecco’s Modified Eagle’s培养基(DMEM)/Ham’s F12培养基(F12)中培养，培养基为DMEM和F12培养基的1∶1混合物，并补充有重组heregulin-β1(10ng/ml)、福斯高林(forskolin)(2μM)和N2增补剂(Invitrogen，California.Cat#17502-048)。所有其他细胞均在含有10％胎牛血清(FBS)的DMEM中生长。下述出版物公开了在细胞增殖测定中使用的细胞系的制备。
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为了进行细胞增殖测定，将在3天中可以达到～70％铺满的合适数目的细胞(例如，对于人MPNST细胞和小鼠Nf1/p53-缺陷细胞为3000-6000个细胞/孔，对于小鼠胚胎施万细胞为8000-10000个细胞/孔)铺在96孔板上。将要测试的各种浓度的每种化合物/药物加入到培养基中，接着将细胞培养3天。在培养完成后，轻轻地除去培养基，并将100μl ATPlite溶液(PerkinElmer，Boston Cat.#6016941)加入到每孔中。通过检测ATPlite溶液和细胞中的ATP反应产生的发光来测量活细胞。测定各种化合物/药物抑制几种NF1相关细胞系的细胞增殖的效力范围。作为用于局部治疗神经纤维瘤的良好候选物有用的药物/化合物的选择标准基于选择IC50等于或低于10μM的任意化合物(IC50被定义为抑制细胞增殖50％所需的抑制剂的浓度)。满足这样的标准的化合物为：烷化剂(例如噻替派)、抗代谢药或核苷类似物(例如5-氟尿嘧啶、桑吉瓦霉素、杀结核菌素、曲西立滨、克拉屈滨)、拓扑异构酶抑制剂(例如喜树碱、鬼臼毒素、XK469)、微管抑制剂(例如甲苯达唑)、硬化剂(例如博来霉素、多西环素及类似物)、调节基因转录的药物(HDAC抑制剂，比如Tricostatin A)、化学预防药(例如类维生素A比如芬维A胺、视黄酸及类似物、姜黄素及衍生物、EGCG及类似物以及甲基乙二醛)、激酶抑制剂(例如U0126、LY294002、EGFR/ErbB2抑制剂、KN2941、SU11652、Bay43-9006、雷帕霉素及其类似物)、烷基磷脂(例如米替福新)、HSP90抑制剂(例如格尔德霉素衍生物，比如17-AAG、根赤壳菌素及类似物、金丝桃素)、抗真菌剂(例如克霉唑)、抑制无义突变的药物(例如庆大霉素)。此外，如果相信化合物具有非细胞自发的(例如免疫调节或抗血管发生)或未知的作用机理，则不可将它们记分为阳性，但是，它们将在外植块模型、异种移植物模型中进行测试，并且如果可能在用NF1患者的原理验证(proof-of-principle)临床试验中进行测试。
2)外植块测定
如下在离体(ex vivo)肿瘤外植块模型中测试所述化合物/药物的功效。将新鲜人皮肤神经纤维瘤切成八小片，并在标准细胞培养板上用含有DMEM/F12、10％FBS、heregulin和福斯高林的培养基培养。将所述片分成治疗组和对照组。第一天将不同剂量的化合物加入到所述培养基中。在阴性对照组中不加入化合物。第3天收集所有的肿瘤片，并通过福尔马林固定和石蜡包埋加工用于组织学。切开组织切片，并用苏木精-曙红染色用于组织学分析。双盲进行成对外植块样品的组织学分析。使用三个参数组织学参数从“-”至“+++”记分样品：1)全面组织完整性；我们通过比较经处理的样品与阴性对照样品的细胞结构来评价组织完整性。低细胞结构面积定义为比对照样品上的类似面积少＞30％的细胞核。使用MagnaFire数字照相机(Optronics，USA)采集在明视场显微镜下40X的各样品的照片，并保存在计算机中。使用Photoshop测量图像中的低细胞结构面积，并计算为长度×宽度，然后表达为对样品总面积的百分数。使用0至2+分记分全面组织完整性。简言之，好的组织完整性计分为0(＜5％)，1+表示中等组织完整性(5-25％)，2+表示低组织完整性(＞25％)。对于最终的总分，仅2+病例被认为是阳性“+”。2)细胞死亡-用明视场显微镜评价载玻片。计算至少100个细胞/图。使用0至3+分半定量记分细胞死亡。不存在凝缩或成碎片的细胞核计分为0，1+表示最低水平的可检测细胞死亡(＜10％)，2+表示中等细胞死亡(10-20％)，而3+表示高细胞死亡(＞30％)。对于最终的总分，所有的2+和3+病例均被认为是阳性“+”；和3)对脉管系统的效应-用明视场显微镜评价载玻片。通过与对照阴性样品中的脉管系统比较来确定对经处理的样品中脉管系统的效应。计数至少20个脉管系统/样品。使用0至3+分半定量计分对脉管系统的效应。简言之，没有或最低水平的脉管系统损伤计分为0(＜5％)，1+表示一些脉管系统损伤(5-25％)，2+表示高(＞25％)。对于最终的总分，所有的1+和2+病例均被认为是阳性“+”。最终的组织学得分为上述三个参数得分的总和，表达为“-”至“+++”。组织学得分为“+”或更高的任意化合物都会是局部治疗神经纤维瘤的潜在的良好候选者。满足这样的标准的化合物为：烷化剂(例如噻替派、卡铂)、抗代谢药或核苷类似物(例如5-氟尿嘧啶、桑吉瓦霉素、杀结核菌素)、拓扑异构酶抑制剂(例如鬼臼毒素)、微管抑制剂(例如甲苯达唑)、硬化剂(例如博来霉素)、抗炎药或非甾体抗炎药(NSAID)(例如双氯芬酸)、调节基因转录的药物(HDAC抑制剂，比如Tricostatin A、丙戊酸)、化学预防药(例如类维生素A，比如芬维A胺)、HSP90抑制剂(例如格尔德霉素衍生物，比如17-AAG、根赤壳菌素及类似物)。
3)异种移植物测定
如下在小鼠皮肤神经纤维瘤(DNF)异种移植物模型中在荷瘤减少研究(tumor burden reduction study)中测试所述化合物的功效。雌性SCID小鼠从Charles River Laboratories(Wilmington，MA)获得，5至6周龄，重量约为20g。将新鲜人DNF碎片皮下植入动物中。接种后3天，将所述动物随机分成治疗组和对照组。每组包括6只肿瘤小鼠。在整个实验过程中，将每只小鼠耳标并单独追踪。在随机化后第一天开始给药。以每周两次持续4周的方案病灶内给药所述化合物。以50μl体积以不同剂量给药化合物加载体。仅给药载体以充当阴性对照。从第一天开始，每周两次称重小鼠，并每周两侧使用测径器获得肿瘤尺寸。通过标准公式(W2×L)/2计算肿瘤体积，其中L为长度，而W为宽度。(Blaskovich MA，Lin Q，Delarue FL，SunJ，Park HS，Coppola D，Hamilton AD，Sebti SM(2000)，Design of GFB-111，aplatelet-derived growth factor binding molecule with antiangiogenic andanticancer activity against human tumors in mice.Nat Biotechnol 18：1065-1070)。在接种前和处死后称重肿瘤碎片。将该差表达为原始肿瘤重量的百分比。通过福尔马林固定和石蜡包埋来加工所收集的肿瘤用于组织学。切开组织切片，并用苏木精-曙红染色用于组织学分析。通过下述之一来确定所述化合物对异种移植物的效应：1)肿瘤重量测量-使用私式t检验分析治疗组和对照组处理前后的肿瘤重量差。当肿瘤重量差为统计学上显著性的(p＜0.05)时，认为某一剂量的化合物的结果为“+”。2)组织学分析-使用三个组织学参数计分样品。A)组织坏死-使用MagnaFire数字照相机(Optronics，USA)采集在明视场显微镜下40X的各样品的照片，并保存在计算机中。使用Photoshop测量照片中的坏死面积，计算为长度×宽度，然后表达为对样品总面积的百分数。使用0至2+分计分全面组织坏死。简言之，没有坏死计分为0(＜5％)，1+表示中等组织坏死(5-25％)，2+表示高组织坏死(＞25％)。对于最终的总分，仅2+病例被认为是阳性“+”。B)组织细胞结构-在经处理的样品中的低细胞结构面积定义为比对照样品上的类似面积少＞30％的细胞核。使用MagnaFire数字照相机(Optronics，USA)采集在明视场显微镜下40X的各样品的照片，并保存在计算机中。使用Photoshop测量照片中的低细胞结构面积，并计算为长度×宽度，然后标的为对样品总面积的百分数。使用0至2+分计分全面组织完整性。简言之，好的组织完整性计分为0(＜5％)，1+表示中等组织完整性(5-25％)，2+表示低组织完整性(＞25％)。对于最终的总分，所有的1+和2+病例均被认为是阳性“+”。C)炎性细胞浸润-用明视场显微镜评价载玻片。计数至少100个细胞/图，并将每个样品的每总共100个细胞中炎性细胞的数目计算为百分数。通过经处理的样品的百分数和对照样品的百分数之差确定炎性细胞浸润，并使用0至3+分半定量地计分。简言之，没有炎性细胞浸润或差异极低计分为0(＜5％)，1+表示中等水平的炎性细胞浸润(5-25％)，而2+表示高水平的炎性细胞浸润(＞25％)。对于最终的总分，所有的1+和2+病例均被认为是阳性“+”。最终的组织学得分为上述三个参数得分的总和，表达为“-”至“+++”。肿瘤重量测量为“+”或组织学得分为“+”或更高的任意化合物都会是局部治疗神经纤维瘤的潜在的良好候选者。满足这样的标准的化合物为：烷化剂(例如噻替派、卡铂)、抗代谢药或核苷类似物(例如5-氟尿嘧啶、桑吉瓦霉素、杀结核菌素)、拓扑异构酶抑制剂(例如鬼臼毒素)、微管抑制剂(例如甲苯达唑)、硬化剂(例如博来霉素、多西环素)、抗炎药或非甾体抗炎药(NSAID)(例如双氯芬酸)、调节基因转录的药物(HDAC抑制剂，比如Tricostatin A、丙戊酸)、化学预防药(例如类维生素A，比如芬维A胺)、烷基磷脂(例如米替福新)、HSP90抑制剂(例如格尔德霉素衍生物，比如17-AAG、根赤壳菌素及类似物)。
使用一种或多种上述测定来测试上述化合物/药物以选择在本发明中用于治疗神经纤维瘤的药物：所述测定优选以特定的顺序进行，并且当得到“阳性结果”时，接着进行下一步测定等等。例如，如果在细胞增殖测定中测试药物，并且按上述公开的标准为阳性，则接着在外植块测定中测试该药物，并且如果根据上述标准为阳性，则接着在异种移植物测定中测试该药物。如果特定的药物或化合物的所有三个测定基于所述标准都为阳性结果，那么预计该药物是成功治疗神经纤维瘤特别是NF1的良好候选者。此外，对于相信其具有非细胞自发的(例如免疫调节或抗血管发生)或未知的作用机理的化合物，如果在异种移植物模型或者如果可能在用NF1患者的原理验证临床试验中获得阳性结果，则预计它们为成功治疗神经纤维瘤的良好候选者。
II.体内研究
用药物或化合物局部治疗神经纤维瘤的总体研究设计
A.病灶内给药
该研究为病灶内给药的药物的作用的概念验证(proof-of-concept)、预期的、安全性和功效研究，所述给药为每周一次给药至3个目标皮肤神经纤维瘤，连续给药4周。六名个体参加。所有个体均被诊断患有NF1，并在背上具有至少6处0.5至1.5cm(包括端值)的皮肤神经纤维瘤。所有个体均为18至65岁(包括端值)。所有个体在其他方面均是健康的，或者患有由基础保健医生适当地处理的稳定的伴发的医学病症。在实验室检查和体格检查两者中，除NF1的特征以外，参加的个体均未表现临床上显著的异常。在筛查和登记后，所有个体均每周一次接受规定体积(根据损伤的尺寸)的病灶内药物，给药进入3个目标皮肤神经纤维瘤，所述神经纤维瘤以其最大尺寸计直径为0.5至1.5cm(包括端值)。每个目标皮肤神经纤维瘤的尺寸不同，一个直径为0.5至0.8cm，第二个直径为0.81至1.2cm，而第三个直径为1.21至1.5cm。相伴地，在躯干和/或附肢上发现的尺寸范围相同的三个对照皮肤神经纤维瘤接受无菌生理盐水。用利多卡因1％和肾上腺素1∶100000局部麻醉所有损伤部位，然后注射。在研究期间，个体在6处损伤接受4次每周一次的病灶内注射(3处目标损伤接受药物，3处对照损伤接受生理盐水)，并且在接受研究药物治疗期间和在最后一次给药后的三周期间每周进行追踪。在每次回访时，个体接受体格检查，记录不利事件和相伴的药物治疗，以及目标和对照损伤两者的尺寸和图像。评价包括两个估定损伤的精确测量尺寸(在两个轴的方向上)。照相要求目标和对照损伤的标准化数字图像(伴有标尺)，而不表现个体的任何识别特征。对于每个个体，照相涉及每次回访之间一致的焦距、光和曝光角。在每次回访时，询问每个个体在给药期间或在回访之间接受研究药物治疗的潜在副作用，包括疼痛、瘙痒、刺激、变色、溃疡或在基线中不存在的任何其他新的病征或症状(局部或远离目标和对照损伤)。
在其中多西环素为研究药物的一项局部注射研究中，89％的注射多西环素的肿瘤显示出皮肤神经纤维瘤部分或完全消除，而所有的对照均未显示出变化。类似地，在使用双氯芬酸作为研究药物的另一研究中，48％的注射双氯芬酸的肿瘤显示出皮肤神经纤维瘤部分或完全消除，而所有的对照均未显示变化。
B.局部给药
如在上述A中所述选择患有神经纤维瘤的个体，并用同一个体上的未经处理的神经纤维瘤进行类似的对照。可供选择的给药方法包括通过向覆盖神经纤维瘤的皮肤施用包含任一种或多种本文描述的药物的组合物与5％的凝胶来局部施用，其量足以覆盖该肿瘤，每天施用一次，持续21天。另外，局部施用如下进行：向覆盖所述肿瘤的皮肤施用皮肤磨削装置，其中所述装置的显微针涂敷有包含所述药物的组合物，每天施用一次，持续7天。
Claims (6)
1.至少一种非致癌的药物在制备用于局部给药以治疗有治疗需要的个体中皮肤神经纤维瘤或皮下神经纤维瘤的组合物中的用途，其中所述组合物包含(a)至少一种用于减轻所述神经纤维瘤对所述个体的负面影响的非致癌的药物，和任选的(b)药学可接受的赋形剂，其帮助将所述药物转运进入所述神经纤维瘤，所述药物在所述神经纤维瘤中保持一段足够的时间以负面影响所述神经纤维瘤；并且所述非致癌的药物为多西环素、双氯芬酸或其组合。
2.权利要求1的用途，其中所述局部给药为向所述神经纤维瘤部位的皮肤表面局部施用所述组合物，并且其中所述赋形剂帮助将所述药物转运透过皮肤并到达所述神经纤维瘤，且将所述药物保持在所述个体的皮肤上。
3.权利要求2的用途，其中所述赋形剂包括皮肤渗透剂。
4.权利要求1的用途，其中所述局部给药为将所述组合物病灶内注射入所述神经纤维瘤。
5.权利要求1-4之任一项的用途，其中所述药物是多西环素。
6.权利要求1-4之任一项的用途，其中所述药物是双氯芬酸。
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| KR102642411B1 (ko) | 2017-05-19 | 2024-02-28 | 엔플렉션 테라퓨틱스, 인코포레이티드 | 피부병 치료를 위한 피롤로피리딘-아닐린 화합물 |
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| EP3883553A4 (en) | 2018-11-20 | 2022-11-02 | NFlection Therapeutics, Inc. | ARYL-ANILINE AND HETEROARYL-ANILINE COMPOUNDS FOR THE TREATMENT OF SKIN CANCERS |
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| US20020119095A1 (en) * | 1992-07-10 | 2002-08-29 | Reinhard Gabathuler | Chemotherapeutic agents conjugated to p97 and their methods of use in treating neurological tumours |
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| JPH08119865A (ja) * | 1994-10-26 | 1996-05-14 | Teijin Ltd | 神経線維腫症治療剤 |
| CA2226623A1 (en) * | 1995-07-13 | 1997-01-30 | University Of Cincinnati | Compounds useful in the treatment of neurofibromatosis |
| ATE493983T1 (de) * | 1996-11-05 | 2011-01-15 | Childrens Medical Center | Thalidomide und dexamethason für die behandlung von tumors |
| GB9809889D0 (en) * | 1998-05-11 | 1998-07-08 | Univ Strathclyde | Prevention of restenosis |
| WO2004001010A2 (en) * | 2002-06-21 | 2003-12-31 | Ptc Therapeutics, Inc. | METHODS FOR IDENTIFYING SMALL MOLECULES THAT MODULATE PREMATURE TRANSLATION TERMINATION AND NONSENSE MEDIATED mRNA DECAY |
| JP4216680B2 (ja) * | 2003-09-25 | 2009-01-28 | 知子 菊井 | 腫瘍・ケロイド等治療剤 |
| WO2006071966A2 (en) * | 2004-12-29 | 2006-07-06 | The Brigham And Women's Hospital, Inc. | Rapamycin compounds in the treatment of neurofibromatosis type 1 |
| CN101155577B (zh) * | 2005-02-02 | 2015-04-22 | 耐克斯詹尼克斯医药有限公司 | 神经纤维瘤的局部治疗 |
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| AU2006210787A1 (en) | 2006-08-10 |
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| CN101155577A (zh) | 2008-04-02 |
| WO2006083979A2 (en) | 2006-08-10 |
| EP1853223A2 (en) | 2007-11-14 |
| US20150182452A1 (en) | 2015-07-02 |
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