CN1531441A - 抑制血管增殖的药物组合物及其使用方法 - Google Patents
抑制血管增殖的药物组合物及其使用方法 Download PDFInfo
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- CN1531441A CN1531441A CNA02803564XA CN02803564A CN1531441A CN 1531441 A CN1531441 A CN 1531441A CN A02803564X A CNA02803564X A CN A02803564XA CN 02803564 A CN02803564 A CN 02803564A CN 1531441 A CN1531441 A CN 1531441A
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Abstract
本发明涉及一种在患者需要时，治疗其血管增殖的方法。该方法包括给予所述患者治疗有效量的1－型促生长素抑制素激动剂的步骤。
Description
发明背景
血管生成，即由先前已存在的血管形成新的毛细血管，在实体瘤和许多其它病理性疾病，如糖尿病性视网膜病和类风湿性关节炎的发展中是一种危险的病变(Folkman，J.，Nature Medicine 1995，1：27-31)。人们已经广泛研究过抑制血管形成的不同策略，在血管生成研究的体外模型系统中，模型的可靠有效性对于具体抑制剂的研究是至关重要的(Jain，R.K.，et al.，，NatureMedicine 1997，3：1203-120)。
现在人们已经普遍认识到肿瘤诱导宿主新血管增殖的能力对于癌的发展和转移具有深远的影响。肿瘤血管生成的过程是由微血管生长的正调节物与负调节物的平衡介导的，新血管的形成可分为3个不同的顺序步骤：1)由细胞-介导，基膜的蛋白水解降解；2)内皮细胞从血管内到周围胞外基质的迁移和增殖；3)细胞到管-状结构的组构(Folkman，J.，Nature Medicine1995，1：27-31)。
促生长素抑制素(somatostatin)(促生长素释放抑制因子或SRIF)具有一个14氨基酸的同种型(促生长素抑制素-14)和一个28氨基酸的同种型(促生长素抑制素-28)。见Wilson，J.& Foster，D.，Williams Textbook ofEndocrinology，p，510(1985年第7版)。该化合物是一种生长激素分泌的抑制剂，它最初是从下丘脑中分离出来的。Brazeau，et al.，，Science179：77(1973)。天然的促生长素抑制素在体内维持有效的时间非常短，这是因为它会被内肽酶和外肽酶迅速灭活。为了提高这种激素的作用持续时间、生物活性、和选择性(例如，对于特定的促生长素抑制素受体的选择性)，已经制备了许多新的类似物(例如，肽和非-肽化合物)。此处将这种促生长素抑制素的类似物称为“促生长素抑制素激动剂”。
人们已经分离出了各种促生长素抑制素受体(SSTRs)，例如，SSTR-1，SSTR-2，SSTR-3，SSTR-4，和SSTR-5。因此，促生长素抑制素激动剂可以是SSTR-1激动剂，和/或SSTR-2激动剂，和/或SSTR-3激动剂，和/或SSTR-4激动剂和/或SSTR-5激动剂。
先前已经在某些体外和体内实验模型中证实了促生长素抑制素类似物的抗血管生成的活性(Danesi，R.，et al.，，Clinical Cancer Research 1997，3：265-272；Woltering，E.A.，et al.，Investigational New Drug 1997，15：77-86)。除此之外，长期的奥曲肽(octreotide)治疗能够减少由糖尿病患者严重的增殖性视网膜病所引起的新血管形成的进一步发展(Mallet，et al.，1992)。
确定了涉及促生长素抑制素抗血管生成性质的促生长素抑制素亚型，利于研制出具有最大功效和最小副作用的治疗组合物。然而，关于5种促生长素抑制素受体亚型中的每一种在促生长素抑制素的抗血管生成活性方面的作用，本领域以前的研究得出了相反和/或不确定的结论。
发明概述
本发明涉及含有促生长素抑制素1-型受体激动剂的组合物，它可用于抑制受试者的血管增殖。本发明还涉及在患者(例如，哺乳动物，如人)需要时，治疗其血管增殖，例如血管生成和再狭窄的方法。该方法包括给予所述患者治疗有效量的促生长素抑制素1-型受体(SSTR-1)激动剂(例如，促生长素抑制素1-型选择性激动剂)的步骤。
本发明还涉及一种在患者需要时，抑制其平滑肌增殖，内皮细胞增殖，和新血管生长的方法。该方法包括给予所述患者治疗有效量的促生长素抑制素1-型受体(SSTR-1)激动剂(例如，促生长素抑制素1-型选择性激动剂)的步骤。
可通过本发明进行治疗的临床适应症的例子包括，但不受限于，自身免疫性疾病(例如，关节炎，硬皮病等)，癌性肿瘤，角膜移植片新血管形成，糖尿病性视网膜病，血管瘤，肥大性瘢痕，和牛皮癣，以及由外科手术过程，例如血管成形术或AV分流术所引起的血管增殖。
可使用本发明的治疗组合物和方法进行治疗的疾病的其它例子，就皮肤来说是：疣，肉芽肿，卡波济氏肉瘤(Kaposi’s sarcoma)，过敏性水肿及类似疾病；就子宫和卵巢来说是：子宫内膜异位，机能障碍性子宫出血，或滤泡囊肿及类似疾病；就眼睛来说是：早熟的视网膜病，脉络膜疾病和其它眼内疾病，黄斑变性，与年龄有关的黄斑变性及类似疾病。
可使用本发明的治疗组合物和方法进行治疗的疾病的其它例子在Folkman，J.，Seminars in Medicine of the Beth Israel Hospital，Boston，Vol.333，No.26，pp.1757-1763中公开。
事实上，正如本领域所熟知的，所述药剂具有的抑制血管生成，平滑肌增殖，内皮细胞增殖，和/或新血管生长作用，可用于治疗已知的所列疾病外，还可治疗的疾病包括，但不受限于：实体瘤、瘤转移、良性瘤，例如，听神经瘤、神经纤维瘤，和沙眼、白血病、脓性肉芽肿、心肌血管生成、血小板新血管形成(plaque neovascularization)、动脉粥样硬化、冠状侧突(coronarycollaterals)、脑侧突(cerebral collaterals)、动静脉畸形、局部缺血性四肢血管生成，眼睛和角膜的血管生成疾病，例如，角膜移植片排斥、Osler-Webber综合征、潮红、新血管性青光眼、晶状体后纤维组织形成，和糖尿病性视网膜病，糖尿病性新血管形成、伤口愈合、骨折、血管发生、血细胞生成、排卵、月经、胎盘形成、猫抓伤(Rochele minalia quintosa)、溃疡(消化性溃疡，与幽门螺旋杆菌有关的溃疡)、牛皮癣(包括，例如，毛细管扩张性牛皮癣)、类风湿性关节炎、克罗恩氏病(Crohn’s disease)、肠粘连、瘢痕形成(即高密度组织，包括细胞和结缔组织的形成)、肥大性瘢痕(即瘢痕瘤)、毛细管扩张、血友病性关节、血管纤维瘤；和伤口肉芽发生。这些疾病和病症在如下美国专利和国际专利公开各文献中已作详细讨论：6,323,228，6,294,532，6,288,228，6,288,024，6,284,726，6,280,739，6,265,407，6,265,403，6,258,812，6,255,355，6,255,353，6,251,867，6,242,481，6,235,756，6,235,741，6,228,879，6,228,871，6,225,340，6,214,800，6,201,104，6,177,401，6,174,861，6,150,407，6,150,362，6,117,862，6,114,355，6,090,794，6,086,865，6,071,948，6,057,290，6,057,122，6,028,061，6,025,353，6,025,331，6,024,688，6,017,949，5,997,868，5,994,388，5,994,292，5,990,280，5,985,878，5,985,330，5,981,484，5,972,922，5,972,896，5,948,403，5,932,611，5,902,790，5,874,081，5,847,002，5,843,925，5,837,680，5,807,731，5,801,146，5,766,591，5,753,230，5,744,492，5,733,876，5,721,226，5,712,291，5,698,586，5,696,147，5,677,181，5,646,136，5,629,340，5,629,327，5,610,166，5,593,990，5,574,026，5,567,693，5,567,417，5,563,130，5,512,550，5,506,208，WO02/02609，WO02/02593，WO02/00877，WO02/00690，WO02/00017，WO01/93806，WO01/85796，WO01/81579，WO01/81311，WO01/79157，WO01/74299，WO01/72699，WO01/72297，WO01/66127，WO01/62799，WO01/62725，WO01/59100，WO01/58899，WO01/51048，WO01/46110，WO01/45751，WO01/35977，WO01/34195，WO01/29085，WO01/28577，WO01/25433，WO01/23375，WO01/21831，WO01/19987，WO01/19868，WO01/12809，WO01/12226，WO01/12210，WO01/10859，WO01/09113，WO01/07057，WO01/04157，WO01/03720，WO01/00201，WO00/75124，WO00/73445，WO00/73340，WO00/59532，WO00/54770，WO00/54762，WO00/53757，WO00/53753，WO00/53752，WO00/52158，WO00/48591，WO00/47212，WO00/47193，WO00/43393，WO00/40597，WO00/35407，WO00/32221，WO00/32180，WO00/30628，WO00/27866，WO00/27415，WO00/27340，WO00/24415，WO00/21561，WO00/20577，WO00/20026，WO00/19995，WO00/15792，WO00/12089，WO00/10507，WO00/10506，WO00/09657，WO00/09495，WO00/05356，WO00/02902，WO00/02871，WO00/02585，WO00/01383，WO99/62549，WO99/61590，WO99/61432，WO99/60984，WO99/58139，WO99/48495，WO99/45909，WO99/37776，WO99/31088，WO99/26622，WO99/26480，WO99/23105，WO99/22760，WO99/16755，WO99/16465，WO99/14234，WO99/10349，WO99/09982，WO99/04806，WO99/04803，WO98/58929，WO98/58919，WO98/54093，WO98/51326，WO98/41205，WO98/36760，WO98/35958，WO98/31688，WO98/19712，WO98/19649，WO98/17796，WO98/13071，WO98/12226，WO98/05323，WO98/05293，WO97/45137，WO97/41824，WO97/35567，WO97/32583，WO97/30085，和WO97/26258。前述专利和专利公开的内容全部引入此处作为参考。
下面给出“促生长素抑制素1-型受体激动剂”和“促生长素抑制素1-型受体选择性激动剂”的定义。治疗有效量取决于所治疗的疾病，所选择的给药途径，和所用化合物的具体的活性，且最终由主治医生或兽医决定(例如，5g/天-5mg/天)。在其中一个实施方案中，给予患者促生长素抑制素激动剂，直到治疗的病症已经消退。在另一个实施方案中，终生给予患者促生长素抑制素激动剂。
促生长素抑制素激动剂可非肠道注射给药，例如，静脉内注射到被治疗者的血流中。然而，本领域那些技术人员可很容易地根据所治疗的疾病和所用促生长素抑制素激动剂的活性及生物可利用度改变给药途径，如静脉内，皮下，肌内，腹膜内，肠内，经皮，经粘膜，持续释放的聚合物组合物(例如，乳酸聚合物或乳酸与羟基乙酸共聚物的微颗粒或植入物)，profusion，鼻，口腔等。
促生长素抑制素激动剂还可以用作植入体装置的表面涂层或涂层成分。例如，提供于血管斯腾氏固定模(stent)之内或之上的促生长素抑制素激动剂可用于治疗通常由于斯腾氏固定模的植入所引起的再狭窄。
如果需要，SSTR-1激动剂可全身性系统地和/或局部地给药。为防止粘连，SSTR-1激动剂通常在手术时使用，优选以控释制剂的形式使用和/或使用屏障技术。
促生长素抑制素可以以纯的或基本上纯的化合物进行给药，也可以以药物制剂的形式提供。本发明给人和动物使用的制剂含有下述任何一种促生长素抑制素激动剂，和其一种或多种药学上可接受的载体，及任选的其它治疗性成分。
载体必须是与活性成分相兼容意义上的“可接受的”(例如，能够使肽稳定)，而且对所治疗的受试者无害。人们希望所述制剂不含氧化剂或其它已知不能与肽并存的物质。例如，有环状结构的促生长素抑制素(例如，内半胱氨酸二硫键)可被氧化；因此，作为赋形剂存在的还原剂可导致半胱氨酸二硫桥键断开。另一方面，高度氧化性的条件可导致半胱氨酸亚砜的形成及色氨酸的氧化。因此，仔细选择赋形剂是非常重要的。pH是另一个重要因素，它对于在弱酸条件下(pH5-6)缓冲产物是必需的。
所述制剂可以以单位剂量形式很方便地提供，并可通过制药领域熟知的任何一种方法制备。所有方法均包括加入活性成分，使其与载体联合的步骤，其中所述载体构成一个或多个辅助成分。
通常，片剂或粉剂是通过将活性成分与微细分散的固体载体充分混合均匀而制备的，如果需要，在制备片剂的情况下，还可使所述产品形成所需的形状和大小。
另一方面，适于非肠道(例如，静脉内)给药的制剂适宜含有活性成分的无菌水溶液。优选所述溶液与所治疗受试者的血液等渗。这种制剂可通过使固体活性成分溶解在水中，形成一种水溶液，然后制备上述无菌溶液。所述制剂可以以单位-剂量或多-剂量容器提供，例如，密封的安瓿或小瓶提供。
适于持续释放非肠道给药的制剂(例如，生物可降解的聚合物制剂，如含有乳酸或羟基乙酸残基的聚酯)也是本领域熟知的。见，例如，美国专利US 3,773,919和US 4,767,628及PCT公开WO 94/15587。
处理和/或涂布外科手术用斯腾氏固定模的方法和制剂也是本领域熟知的，其中所述涂层可含有一种药学活性化合物。见，例如，美国专利US6,214,115，US 6,083,257，和国际专利公开WO 01/01957和WO 00/02599。
促生长素抑制素或促生长素抑制素激动剂还可与其它能够降低血液甘油三酯，胆固醇，或甘油水平的化合物，如fibrates(例如，苯扎贝特(bezafibrate)，吉非贝齐(gemfibrozil)，和氯贝特(clofibrate))，HMG-COA还原酶抑制剂(例如，普伐他汀(pravastatin)，辛伐他汀(simvastatin)，和fluorastatin，Atorvastatin，和洛伐他汀(lovastatin))，胆汁酸结合树脂(例如，考来烯胺(cholestyramine)和colestipol)，烟酸化合物(例如，烟酸和戊四烟酯(niceritrol))，和鱼油联合给药。见Workshop Treatment of Hyperlipidemia1996-2(Lakemedelsverket，Uppsala，Sweden，1996)。
本发明的其它特征和有利之处可从下列优选实施方案的描述和权利要求中很明显地看出。
发明详述
本领域的技术人员可基于此处的描述将本发明利用至最完全的程度。因此，下列具体实施方案仅仅是举例说明，无论如何不是对所公开内容剩余部分的限制。
除非另有说明，此处所用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常所理解相同的含义。并且，此处提到的所有出版物，专利申请，专利，和其它参考文献均引入此处作为参考。
促生长素抑制素1-型受体激动剂(即，SSTR-1激动剂)是这样一种化合物，其(1)对SSTR-1具有较高的结合亲和性(例如，Ki小于1000nM，或优选小于100nM或小于10nM)(例如，通过下述受体结合测定法测定)，(2)可降低血管增殖的速度或程度(例如，通过下述生物测定法所示)。
促生长素抑制素1-型受体选择性激动剂是一种促生长素抑制素激动剂，其(1)对于SSTR-1比对SSTR-2，SSTR-3，SSTR-4，或SSTR-5具有更高的结合亲和性(即Ki)(例如通过下述的受体结合测定法确定)，(2)可降低血管增殖的速度或程度(例如，下述生物测定法所示)。
在其中一个实施方案中，促生长素抑制素1-型受体选择性激动剂还是一种SSTR-1激动剂。
促生长素抑制素激动剂的例子是通式所包括的那些，或在下述出版物中特别列举的那些，它们全部引入此处作为参考。
Van Binst，G.，et al.，Peptide Research 5：8(1992)；
Horvath，A.et al.，Abstract，“Conformations of Somatostatn AnalogsHaving Antitumor Activity”(有抗肿瘤活性的促生长素抑制素类似物的构象)”，22nd European peptide Symposium，September 13-19，1992，Interlaken，Switzerland；
Curtis，et al.，Am.J.Physiol.Heart.Circ.Physiol，278：H 1815(2000)；
Nicolaou，et al.，“Design and synthesis of a peptidomimetic employing β-D-glucose for scaffolding(使用β-D-葡萄糖作为支架结构设计并合成肽模拟物)”Peptides，Rivier and Marshall，eds.，ESCOM(1990)，
Papageorgiou，et al.，“Design，synthesis，and binding affinity of a nonpeptide mimic of somatostatin(促生长素抑制素非肽模拟物的设计、合成及结合亲和性)”Bioorganic&Medicinal Chemistry Letters，vol.2，pp.135-140，1992；andR.Hirschmann，et al.，“De novo design and synthesis of somatostatinnonpeptide peptidomimetics utilizing beta-D-glucose as a novel scaffolding(利用β-D-葡萄糖作为新的支架结构重新设计并合成促生长素抑制素非-肽的肽模拟物)”J.Am.Chem.Soc.，vol.115，pp.12550-12568，1993。
PCT申请WO 91/09056(1991)；
欧洲申请EP 0 363 589 A2(1990)；
欧洲申请EP P5 164 EU(发明人：G.Keri)；
美国专利US 6,262,229；
美国专利US 6,197,963；
美国专利US 6,159,941；
美国专利US 6,127,343；
美国专利US 6,083,960；
美国专利US 6,020,349；
美国专利US 5,552,534；
美国专利US 5,817,879；
美国专利US 5,811,512；
美国专利US 4,904,642(1990)；
美国专利US 4,871,717(1989)；
美国专利US 4,853,371(1989)；
美国专利US 4,725,577(1988)；
美国专利US 4,684,620(1987)；
美国专利US 4,650,787(1987)；
美国专利US 4,603,120(1986)；
美国专利US 4,585,755(1986)；
欧洲申请EP 0 203 031 A2(1986)；
美国专利US 4,522,813(1985)；
美国专利US 4,486,415(1984)；
美国专利US 4,485,101(1984)；
美国专利US 4,435,385(1984)；
美国专利US 4,395,403(1983)；
美国专利US 4,369,179(1983)；
美国专利US 4,360,516(1982)；
美国专利US 4,358,439(1982)；
美国专利US 4,328,214(1982)；
美国专利US 4,316,890(1982)；
美国专利US 4,310,518(1982)；
美国专利US 4,291,022(1981)；
美国专利US 4,238,481(1980)；
美国专利US 4,235,886(1980)；
美国专利US 4,224,199(1980)；
美国专利US 4,211,693(1980)；
美国专利US 4,190,648(1980)；
美国专利US 4,146,612(1979)；
美国专利US 4,133,782(1979)；
美国专利US 5,506,339(1996)；
美国专利US 4,261,885(1981)；
美国专利US 4,728,638(1988)；
美国专利US 4,282,143(1981)；
美国专利US 4,215,039(1980)；
美国专利US 4,209,426(1980)；
美国专利US 4,190,575(1980)；
欧洲专利EP 0 389 180(1990)；
欧洲申请EP 0 505 680(1982)；
欧洲申请EP 0 083 305(1982)；
欧洲申请EP 0 030 920(1980)；
PCT申请WO 88/05052(1988)；
PCT申请WO 90/12811(1990)；
PCT申请WO 97/01579(1997)；
PCT申请WO 91/18016(1991)；
PCT申请WO 00/75186(2000)；
英国申请GB 2,095,261(1981)；和
法国申请FR 2,522,655(1983)。
SSTR-1选择性促生长素抑制素激动剂的例子包括，但不受限于，下列促生长素抑制素类似物，其在上述引证的参考文献中已公开：
H-Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys-NH2；
H-D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2；
H-Cys-Phe-Phe-D-Trp-Lys-Ser-Phe-Cys-NH2；
H-Cys-Phe-Tyr-D-Trp-Lys-Thr-Phe-Cys-NH2；
H-Cys-Phe-Tyr(1)-D-Trp-Lys-Thr-Phe-Cys-NH2；
；
和
Caeg-c(D-Cys-Pal-D-Trp-Lys-D-Cys)-Thr(Bzl)-Tyr-NH2，其中“Caeg”的结构是
应当注意，对于此处所述的所有促生长素抑制素激动剂而言，每个氨基酸残基代表的是-NH-C(R)H-CO-结构，其中R是侧链(例如，Ala中的CH3)。氨基酸残基之间的短线代表连接氨基酸的肽键。并且，其中的氨基酸残基是有旋光活性的，除非清楚地说明是D-形，否则它是指L-形的构型。二硫键(例如，二硫桥键)存在于Cys残基的两个游离巯基之间；但没有标出。
促生长素抑制素激动剂的合成
合成促生长素抑制素激动剂的方法已经有详细的记载，而且能被本领域普通技术人员实施。例如，上述H-D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2可按照欧洲专利申请EP 0 395 417 A1实施例1中提出的方案获得。具有取代N-末端的促生长素抑制素激动剂的合成可通过WO 88/02756，欧洲专利申请EP 0 329 295，和PCT公开WO 94/04752中提出的方案获得。
促生长素抑制素受体结合测定法
人SSTR-1，SSTR-2，SSTR-3，SSTR-4，和SSTR-5的cDNA克隆已经被描述过(SSTR-1和SSTR-2在Yamada，Y.等，Proc.Natl.Acad.Sci.USA.，89：251-255(1992)中描述；SSTR-3在Yamada等，Mol.Endocrinol.6：2136-2142(1993)中描述；SSTR-4和SSTR-5在Yamada等，Biochem.Biophys.Res.Commun.195：844-852(1993)中描述)，并可从American Type CultureCollection(ATCC，Rockville，MD)(ATCC Nos.79044(SSTR-1)，79046(SSTR-2)，和79048(SSTR-3))得到。以限制性内切核酸酶图谱为基础，可通过适当的限制性内切核酸酶的消化将每个SSTR cDNA的整个编码区切下来(Maniatis，T.，et al.，Molecular Cloning-A Laboratory Manual，CSHL，1982)。限制性内切核酸酶可从New England Biolabs(Beverly，MA)得到。使用标准分子生物学技术(见，例如，Maniatis，T.，et al.，Molecular Cloning-ALaboratory Manual，Cold Spring Harbor Laboratory，1982)将此eDNA片段插入到哺乳动物表达载体pCMV(Russell，D.等，J.Biol.Chem.，264：8222-8229(1989))中，从而产生表达质粒pCMV-人SSTR-1到pCMV-人SSTR-5。其它的哺乳动物表达载体包括pcDNA1/Amp(Invitrogen，Sandlesy，CA)。将表达质粒引入到适宜的细菌宿主，大肠埃希氏菌HB101(E.Coli HB101)(Stratagene，La Jolla，CA)中，通过氯化铯梯度离心法制备用于转染的质粒DNA。
CHO-K1(中国仓鼠卵巢)细胞是从ATCC(ATCC No.CCL 61)获得的。所述细胞在标准组织培养条件下，在补充有10％胎牛血清的Ham’s F12培养基(Gibco BRL，Grand Island，NY)中生长并维持。为了进行转染，以1×106/60-cm平板(Baxter Scientific Products，McGraw Park，IL.)的密度接种所述细胞。DNA-介导的转染是使用磷酸钙共-沉淀方法进行的(Ausubel，F.M.等，Current Protocols in Molecular Biology，John Wiley & Sons，1987)。质粒pRSV-neo(ATCC；ATCC No.37198)可以以表达载体1/10的浓度，作为一种选择性标记物被包括在内。选择已经稳定遗传了转染DNA的CHO-K1克隆细胞系在含有10％胎牛血清和0.5mg/ml的G418(Sigma)的Ham’s F12培养基中生长。所述细胞是环状-克隆的，并在相同的培养基中展开以便进行分析。
人SSTR-1到SSTR-5受体在CHO-K1细胞中的表达是通过RNA印迹分析细胞制备的总RNA(Sambrook，J.E.等，Molecular Cloning-A LaboratoryManual，Ed.2.，Cold Spring Harbor Laboratory，Cold Spring Harbor，NY，1989)，并使用(125I-Tyr11)促生长素抑制素-14作为配体进行受体结合而检测的。表达人SSTR受体的转染细胞系在培养基中克隆展开，并用于下列SSTR结合方案。
粗膜是利用POLYTRON匀浆器(设置，6，15秒)，通过在20ml冰冷却的50mM Tris-HCl中均化转染细胞制备的。加入缓冲液，得到40ml的最终体积，并于0-4℃时，将匀浆在Sorval SS-34转子中，以39,000g离心10分钟。倾出所得的上清液并弃去。将颗粒状沉淀在冰冷却的缓冲液中如前述方法再次均化，稀释，并离心。所得颗粒状沉淀在10mM Tris HCl中再次混悬，并在冰上保存，以便进行受体结合测定。
30℃时，用50mM HEPES(pH7.4)中的0.05nM(125I-Tyr11)促生长素抑制素-14(2000Ci/mmol；Amersham Corp.，Arlington Heights，IL)培养膜制品的等分试样30分钟，其中所述HEPES含有各种浓度(例如，10-11-10-6)的试验用促生长素抑制素激动剂，10mg/ml牛血清白蛋白(V部分)(SigmaChemical Co.，St.Louis，MO)，MgCl2(5mM)，抑肽酶特拉西罗(Trasylol)(200KIU ml)，杆菌肽(0.02mg/ml)，和苯甲基磺酰氟(0.02mg/ml)。最终的测定体积是0.3ml。培养是利用Brandel多功能过滤装置，通过GF/C过滤器(预先浸泡在0.3％聚次乙亚胺(polyethylenimine)中30分钟)迅速过滤而终止的。然后用5ml冰冷却的缓冲液的等分试样将每个管和过滤器洗涤3次。特异性结合被定义为总的(125I-Tyr11)SRIF-14的结合减去存在1000nM的结合的数值。促生长素抑制素激动剂的Ki值是使用下列公式计算的：Ki＝IC50/(1+(LC/LEC))，其中IC50是抑制50％放射性配体(125I-Tyr11)促生长素抑制素-14的特异性结合所需的试验用促生长素抑制素激动剂的浓度，LC是放射性配体的浓度(0.05nM)，LEC是放射性配体的平衡解离常数(0.16nM)。
增殖和毛细管形成的抑制
为了研究由促生长素抑制素类似物引起的对内皮细胞的抗增殖作用和对内皮细胞增殖及毛细管形成的抑制，已建立了两个不同的人体外模型。这些模型可用于研究促生长素抑制素类似物对模拟体内毛细管生长的胞外基质中的二维内皮细胞层和三维内皮细胞生长的作用。此外，这些测定法还可长期(分别为72小时和28天)治疗人组织，使可能的长期临床方法接近抗血管生成疗法。
原料和方法
原料
重组人表皮生长因子(EGF)和重组人血管内皮生长因子(VEGF)来源于PeproTechEC LTD(London，UK)。根据数据表的信息，EGF和VEGF是以100μg/mL的浓度在无菌蒸馏水中重新构成的。
细胞培养基199和没有酚红的培养基199是从Gibco BRL(Paisley，UK)购买的。这部分没有列出的，源于猪皮添加物的A型明胶和所有其它的化学品都是从Sigma Chemical Co.(St.Louis，MO，USA)获得的。用于细胞培养的塑料由Costar(Cambridge，MA，USA)提供。
将促生长素抑制素-14，BIM-23014C，BIM-23120C，BIM-23190C，BIM-23197C，BIM-23206C，BIM-23268C，BIM-23745C和BIM-23926C(来源于Biomeasure，Incorporated，Milford，MA，USA)溶解在含有0.1％无脂肪酸的牛血清白蛋白(BSA)的0.01N醋酸溶液中，-80℃下贮藏。
前述化合物对各种促生长素抑制素受体的相对亲和性概括如下：
化合物 SSTR-1 SSTR-2 SSTR-3 SSTR-4 SSTR-5
促生长素 高 高 高 高 高
抑制素-14
BIM-23014C 低 高 低 低 高
BIM-23120C 低 高 低 低 低
BIM-23190C 低 高 低 低 高
BIM-23197C 低 高 中等高 低 高
BIM-23206C 低 低 低 低 高
BIM-23268C 高 中等高 高 中等高 高
BIM-23745C 中等 低 低 低 低
BIM-23926C 高 低 低 低 低
SU5416，3-((2，4-二甲基吡咯-5-基)亚甲基)-2-吲哚酮(3-((2，4-dimethylpyrrol-5-yl)methylidenyl)2-indolinone)；来源于Sugen Inc.(San Francisco，CA，USA)。
细胞培养条件
使Ades等(Journal of Investigative Dermatology 1992，99：683-690)描述的无限增殖化人微血管内皮细胞系HMEC-1在培养基199中维持，所述培养基199补充有10％热-灭活的胎牛血清(FBS)，青霉素(50IU/mL)和氢化可的松(100μg/mL)。细胞按常规在75cm2覆盖有明胶的组织培养瓶中生长，并于37℃，在含有5％CO2的湿润大气中保存。对所有试验而言，当细胞在上述培养条件下长期生长并维持时，用0.25％胰蛋白酶-0.03％EDTA溶液收集细胞。
细胞毒性的测定
体外化学敏感性试验是在HEMC-1细胞的单-细胞混悬液上进行的，其中所述HEMC-1细胞接种(5×103细胞/孔)在96-孔覆盖有明胶的无菌塑料平板上，并粘附过夜。处理方案(图1)是：24小时后，加入10-10-10-6促生长素抑制素-14、促生长素抑制素类似物、作为阳性对照的SU5416 10-6M+VEGF 10ng/mL或赋形剂，培养平板72小时(详见图1)。对所述处理进行安排，以便每个肽都由至少9个孔表示。在实验结束时，用磷酸盐缓冲生理盐水(PBS)洗涤细胞，用胰蛋白酶/EDTA收集，并用血细胞计数器计数。结果用细胞增殖与对照组的百分比表示，它是重复了3次的，3次独立实验的平均值±S.E.。
人胎盘血管的体外培养
下面详细描述的人胎盘外植体实验模型的使用由Ethics committee ofPisa University Hospital(Protocol n.005567)批准。
Brown等(Laboratory Investigation 1996，75：539-555)描述的实验过程如下，并在本研究中进行了改进。自然分娩之后，立即在无菌条件下采集胎盘并切除表层的血管，血管直径大约1-1.5米，长1-5厘米。将血管外植体放在含有2.5mg/mL两性霉素B(amphotericin B)和50μg/mL庆大霉素(gentamycin)的磷酸盐缓冲生理盐水(PBS)溶液中，并将其切成大约1-mm的片段。在24-孔培养平板中进行培养；将没有酚红的培养基199中的3mg/mL血纤蛋白原溶液以0.5mL/孔加入到各个孔中，随后迅速加入15μL凝血酶(在0.15M NaCl中为50NIH U/mL)。在血凝块形成之后，将血管外植体迅速放在孔中央，以0.5mL/孔的血纤蛋白原溶液覆盖，为了使它们在两个血凝块之间以相同水平混悬，同时又加入了15μL凝血酶。凝块形成之后，以1mL/孔加入无酚红的培养基199，所述培养基199中还补充有10％热-灭活的FBS，0.1％ε-氨基己酸，L-谷酰胺(2mM)，和抗生素(链霉素50μg/mL，青霉素50 IU/mL和两性霉素B 2.5mg/mL)。培养血管，每隔两天用10-10-10-6M的促生长素抑制素-14，促生长素抑制素类似物，和SU5416 10-6M或赋形剂，于37℃，在含有95％空气/5％CO2的湿润大气中处理28天(图2)。第28天时，用相衬Leitz MD IL显微镜(Leica，Heerbrugg，Switzerland)拍摄血管外植体，并进行图象分析。
图象分析
适于本研究的图象分析过程由Bocci等(Cancer ChemotherapyPharmacology 1999，43：205-212)描述。简单地说，利用彩色摄像机TK-1280E(JVC，Tokyo，Japan)和微电脑处理器，以512×512-像素模型将从胎盘片段测定法获得的图象数字化。数字化的照片在高分辨率的彩色显示屏上成像。运行准确的彩色图象分析软件包KS 300 v.1.2(Kontron Elektronik GmbH，Eching，Germany)，进行图象的交互处理，量化和数据采集。用已知大小的样品调整几何校准，进行灰度模式(agray-scale)分析，测量0-255范围内的像密度，其中0是黑的(存在血管生长)，255是白的(不存在血管生长)。在胎盘血管外植体的血纤蛋白培养物中，测量生长区域的平均灰度水平，生长指数(SI)的定义如下：
生长指数＝((生长面积/生长面积的平均灰度水平)/外植体的周长)×100
结果由生长指数+/-S.E.与对照组的百分比表示。
结果
细胞毒性的测定
所有结果在表1中给出。本研究各浓度的所有促生长素抑制素类似物对无限增殖化的人微血管内皮HMEC-1细胞都具有抗增殖活性，作用最大的浓度为10-7-10-8M。SU5416 10-6M，一种特异性VEGF-受体抑制剂的阳性对照，导致56.2％的细胞生长的阻断。
人胎盘血管的体外培养
血纤蛋白基质内的外植体生长是由胎盘片段周围众多的微血管为特征表现的。血管细胞呈放射状地组构形成微血管，其经历连续的改变(图3)。三维微血管网的最大生长出现在第3-4周内，并在移植后第27天达到稳定水平。组织学上，在血纤蛋白凝胶中，观察到(图5)一种内皮细胞的精细结构，它对于冯维勒布兰德因子(von Willebrand factor)(图4)是免疫反应性的。在绝大多数情况下，微血管显示出原始腔；其它腔是空的，仅观察到内皮细胞(图5)。
培养第一天的胎盘外植体显微照片在图6A中给出(条，2mm)；大约在培养的第六天观察到内皮细胞从胎盘培养的血管片段长出(SI＝0.055±0.004(mm/平均灰色)×100；图6D)。
表II概括了促生长素抑制素类似物作用于毛细管生长的活性的实验数据。用SMS类似物和SU5416处理的培养物在图7-16中表示，其中显示出了最大作用。BIM-23926C和BIM-23745C显示出长期治疗的有效抑制；与没有治疗过的对照组相比，它们在10-7M和10-8M浓度下，分别产生17.18±11.8％和42.84±5.6％的SI。阳性对照SU5416在10-6M浓度下产生32.92±9.7％的SI。
其它实施方案
前面的描述已经被限制到本发明的具体实施方案。然而，很显然为了获得本发明的一部分或全部有利之处，还可对本发明进行改变和改进。这种实施方案也包括在下列权利要求的范围之内。
Claims (16)
1.一种治疗患者血管增殖的方法，该方法包括给予所述患者治疗有效量的促生长素抑制素1-型受体激动剂。
2.根据权利要求1所述的方法，其中所述促生长素抑制素1-型受体激动剂对促生长素抑制素1-型受体的Ki小于5nM。
3.根据权利要求1所述的方法，其中所述促生长素抑制素1-型受体激动剂是促生长素抑制素1-型受体的选择性激动剂。
4.根据权利要求3所述的方法，其中所述促生长素抑制素1-型受体选择性激动剂对1-型促生长素抑制素受体的Ki比对促生长素抑制素2-型，3-型，4-型，和5-型受体的Ki至少小10倍。
5.根据权利要求1所述的方法，其中所述促生长素抑制素1-型受体激动剂是：
H-Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys-NH2；
H-D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2；
H-Cys-Phe-Phe-D-Trp-Lys-Ser-Phe-Cys-NH2；
H-Cys-Phe-Tyr-D-Trp-Lys-Thr-Phe-Cys-NH2；
H-Cys-Phe-Tyr(1)-D-Trp-Lys-Thr-Phe-Cys-NH2；
Caeg-c(D-Cys-Pal-D-Trp-Lys-D-Cys)-Thr(Bzl)-Tyr-NH2；或
3-((2，4-二甲基吡咯-5-基)亚甲基)-2-吲哚酮；
或其药学上可接受的盐。
6.根据权利要求5所述的方法，该方法包括给予治疗有效量的通式化合物：
Caeg-c(D-Cys-Pal-D-Trp-Lys-D-Cys)-Thr(Bzl)-Tyr-NH2
或其药学上可接受的盐。
7.根据权利要求1所述的方法，其中所述血管增殖包括血管生成，再狭窄，内皮细胞增殖，平滑肌增殖，或新血管生长。
8.根据权利要求1所述的方法，其中所述血管增殖发生于包括自身免疫性疾病，关节炎，硬皮病，癌性肿瘤，角膜移植片新血管形成，糖尿病性视网膜病，血管瘤，肥大性瘢痕形成，或牛皮癣在内的疾病或病症中。
9.根据权利要求1所述的方法，其中所述血管增殖易发生于或由血管成形术或AV分流术所引起。
10.根据权利要求1所述的方法，其中所述血管增殖发生于包括疣，肉芽肿，卡波济氏肉瘤，过敏性水肿在内的疾病或病症中。
11.根据权利要求1所述的方法，其中所述血管增殖发生于包括子宫内膜异位，机能障碍性子宫出血，或滤泡囊肿在内的疾病或病症中。
12.根据权利要求1所述的方法，其中所述血管增殖发生于包括早熟性视网膜病，脉络膜病，黄斑变性，或与年龄有关的黄斑变性在内的疾病或病症中。
13.根据权利要求1所述的方法，其中所述血管增殖发生于包括实体瘤，瘤转移，良性瘤，听神经瘤，神经纤维瘤，沙眼，白血病，脓性肉芽肿，心肌血管生成，血小板新血管形成，动脉粥样硬化，冠状侧突，脑侧突，动静脉畸形，局部缺血性四肢血管生成，角膜移植片排斥，Osler-Webber综合征，潮红，新血管性青光眼，晶状体后纤维组织形成，糖尿病性视网膜病，糖尿病性新血管形成，骨折，血管生成，血细胞生成，排卵，月经，胎盘形成，猫抓伤，消化性溃疡，幽门螺杆菌引起的溃疡，牛皮癣，毛细管扩张性牛皮癣，类风湿性关节炎，克罗恩氏病，肠粘连，瘢痕形成，肥大性瘢痕，瘢痕瘤，毛细管扩张，血友病性关节，血管纤维瘤或伤口肉芽发生在内的疾病或病症中。
14.根据权利要求1所述的方法，其中所述促生长素抑制素1-型受体激动剂位于血管斯腾氏固定模之上或之内。
15.根据权利要求14所述的方法，其中所述促生长素抑制素1-型受体激动剂是以缓释制剂成分提供的。
16.根据权利要求14所述的方法，其中所述促生长素抑制素1-型受体激动剂是以聚合组合物成分提供的。
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| IL (1) | IL156506A0 (zh) |
| NO (1) | NO20033117L (zh) |
| NZ (1) | NZ526676A (zh) |
| PL (1) | PL361879A1 (zh) |
| RU (1) | RU2288739C2 (zh) |
| WO (1) | WO2002064160A2 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1317031C (zh) * | 2005-09-14 | 2007-05-23 | 上海第二医科大学附属新华医院 | 增强实体肿瘤细胞化疗敏感性的高效混合制剂 |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7109166B1 (en) * | 1999-08-18 | 2006-09-19 | Societe De Conseils De Recherches Et D'applications Scientifiques, Sas | Sustained release formulation of a peptide |
| ES2315365T3 (es) | 2001-06-13 | 2009-04-01 | Magnachem International Laboratories, Inc. | Formulaciones de lactona y metodo de uso. |
| US20040198653A1 (en) * | 2001-06-25 | 2004-10-07 | Culler Michael De Witt | Pharmaceutical compositions which inhibit proliferation of pituitary adenomas and method of use thereof |
| US8188145B2 (en) | 2002-06-12 | 2012-05-29 | Magnachem International Laboratories, Inc. | Synthetic lactone formulations and method of use |
| WO2004024877A2 (en) * | 2002-09-13 | 2004-03-25 | Attenuon, Llc | Human kininogen d3 domain polypeptide as an anti-angiogenic and anti-tumor agent |
| KR20050059319A (ko) * | 2002-10-31 | 2005-06-17 | 센주 세이야꾸 가부시키가이샤 | 각막 장해 치료제 |
| WO2004041217A2 (en) | 2002-11-05 | 2004-05-21 | Magnachem International Laboratories, Inc. | Synthetic lactone formulations and method of use |
| EP1692099A1 (en) * | 2003-12-12 | 2006-08-23 | Oy Juvantia Pharma Ltd | Somatostatine receptor subtype 1 (sstr1) active compounds and their use in therapy |
| WO2009112741A2 (fr) | 2008-02-21 | 2009-09-17 | Hexacath | Dispositif medical implantable avec une couche de protection/retention d'un agent actif ou medicament, notamment hydrosoluble |
| US8969450B2 (en) | 2009-12-01 | 2015-03-03 | Bridgestone Corporation | Modified rubber compositions and methods of preparation |
| FR3052075B1 (fr) | 2016-06-01 | 2022-01-07 | Hexacath | Dispositif formant catheter d'infusion pour traiter au moins une obstruction partielle ou totale dans un conduit, tel que conduit corporel |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5595760A (en) * | 1994-09-02 | 1997-01-21 | Delab | Sustained release of peptides from pharmaceutical compositions |
| TW334434B (en) * | 1995-05-16 | 1998-06-21 | Kanebo Ltd | Novel quinazoline compound and anti-tumor agent |
| US5750499A (en) * | 1995-10-18 | 1998-05-12 | The Salk Institute For Biological Studies | Receptor-selective somatostatin analogs |
| US6355613B1 (en) * | 1996-07-31 | 2002-03-12 | Peptor Limited | Conformationally constrained backbone cyclized somatostatin analogs |
| EP0960123A4 (en) * | 1996-11-07 | 2004-05-19 | Univ Leland Stanford Junior | BRANCHED PROTEIN AND CODING SEQUENCE |
| US6124256A (en) | 1998-03-27 | 2000-09-26 | Haeyry; Pekka | Method for the prevention of a patient's fibroproliferative vasculopathy |
| US5968903A (en) | 1998-05-07 | 1999-10-19 | Biomeasure, Incorporated | Inhibition of H. pylori proliferation |
| AU5687199A (en) * | 1998-08-24 | 2000-03-14 | Global Vascular Concepts, Inc. | Use of anti-angiogenic agents for inhibiting vessel wall injury |
| CA2246791A1 (en) * | 1998-09-01 | 2000-03-01 | Alison Buchan | Treatment of endothelium with somatostatin analogues |
| US6903074B1 (en) * | 1999-06-04 | 2005-06-07 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. | Neuromedin b and somatostatin receptor agonists |
| US20020103526A1 (en) * | 2000-12-15 | 2002-08-01 | Tom Steinke | Protective coating for stent |
-
2002
- 2002-01-14 CN CNA02803564XA patent/CN1531441A/zh active Pending
- 2002-01-14 AU AU2002243552A patent/AU2002243552C1/en not_active Ceased
- 2002-01-14 CZ CZ20031695A patent/CZ20031695A3/cs unknown
- 2002-01-14 HU HU0302732A patent/HUP0302732A2/hu unknown
- 2002-01-14 CA CA002433785A patent/CA2433785C/en not_active Expired - Fee Related
- 2002-01-14 IL IL15650602A patent/IL156506A0/xx unknown
- 2002-01-14 NZ NZ526676A patent/NZ526676A/en unknown
- 2002-01-14 RU RU2003124748/14A patent/RU2288739C2/ru not_active IP Right Cessation
- 2002-01-14 JP JP2002563953A patent/JP4099065B2/ja not_active Expired - Fee Related
- 2002-01-14 PL PL36187902A patent/PL361879A1/xx not_active Application Discontinuation
- 2002-01-14 WO PCT/US2002/001125 patent/WO2002064160A2/en active IP Right Grant
- 2002-01-14 KR KR10-2003-7009238A patent/KR20030068585A/ko active Search and Examination
- 2002-01-14 US US10/466,152 patent/US7084117B2/en not_active Expired - Fee Related
- 2002-01-14 EP EP02709045A patent/EP1409007A2/en not_active Withdrawn
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2003
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1317031C (zh) * | 2005-09-14 | 2007-05-23 | 上海第二医科大学附属新华医院 | 增强实体肿瘤细胞化疗敏感性的高效混合制剂 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20030068585A (ko) | 2003-08-21 |
| WO2002064160A8 (en) | 2003-01-30 |
| JP2004527483A (ja) | 2004-09-09 |
| CA2433785A1 (en) | 2002-08-22 |
| PL361879A1 (en) | 2004-10-04 |
| JP4099065B2 (ja) | 2008-06-11 |
| RU2288739C2 (ru) | 2006-12-10 |
| US20040082517A1 (en) | 2004-04-29 |
| NZ526676A (en) | 2005-03-24 |
| US7084117B2 (en) | 2006-08-01 |
| AU2002243552C1 (en) | 2006-08-31 |
| IL156506A0 (en) | 2004-01-04 |
| WO2002064160A2 (en) | 2002-08-22 |
| AU2002243552B2 (en) | 2005-03-10 |
| NO20033117D0 (no) | 2003-07-08 |
| RU2003124748A (ru) | 2005-01-10 |
| HUP0302732A2 (hu) | 2003-12-29 |
| WO2002064160A3 (en) | 2004-02-19 |
| CA2433785C (en) | 2009-08-04 |
| NO20033117L (no) | 2003-09-04 |
| CZ20031695A3 (en) | 2004-03-17 |
| EP1409007A2 (en) | 2004-04-21 |
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