CN1482906A - 新的临床疗法 - Google Patents
新的临床疗法 Download PDFInfo
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- CN1482906A CN1482906A CNA018215076A CN01821507A CN1482906A CN 1482906 A CN1482906 A CN 1482906A CN A018215076 A CNA018215076 A CN A018215076A CN 01821507 A CN01821507 A CN 01821507A CN 1482906 A CN1482906 A CN 1482906A
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Abstract
本发明涉及有效剂量的N-乙酰L-半胱氨酸或其二聚体形式的制药用途,所制造的药物可以使哺乳动物上皮来源的瘤形成细胞回复到正常分化,从而使该瘤形成细胞的异常增殖回复到正常途径。
Description
本发明涉及N-乙酰-L-半胱氨酸或其二聚体形式的用途,用于临床治疗哺乳动物上皮来源的瘤形成细胞。
肿瘤或赘生物包含新生组织,其中的细胞增殖失控并且是进行性的。并非所有的异常生长类型都是恶性的;非恶性即认为是良性肿瘤。与恶性生长相反,良性肿瘤由有序生长的细胞组成,往往与其正常对应物相同或非常相近。
但是,癌症的特征在于增殖失控,以及受侵袭的细胞生长紊乱。根据显微镜观察,伴随其无限制生长的能力,癌细胞及其组成的组织丧失正常形态,并呈现功能异常。癌细胞是侵袭性的,侵袭周围组织,波及远处部位,最后杀死宿主。1994年,癌症导致美国全部死亡的近四分之一。
肿瘤,不论恶性或良性,都是基于其组成细胞的结构和功能特性及其生物学行为。恶性肿瘤的细胞和组织与其起源的组织不同。它们生长更为迅速,并呈现结构和功能的变化。恶性肿瘤细胞的特性适于加强和支持其增殖,并扩张到全身组织和器官。相反,良性肿瘤的细胞和组织倾向于生长较为缓慢,一般非常类似于其起源的正常组织。如果良性肿瘤细胞的结构与功能与正常细胞在形态和功能上难以区别,那么生长为肿瘤团是表现其致瘤本质的唯一特征。
本领域公认,可以描述连续增殖细胞的生长和复制周期开始于一个新的小细胞,它经过第一个生长期(G1)。G1期之后是DNA合成期,每个染色体获得一份拷贝(S期)。然后继之以第二个生长期,合成所有蛋白质、膜、细胞器等的拷贝,这是为了从母细胞获得两个细胞所必需的(G2期)。在G2期,细胞的大小增加。有丝分裂期(M期)完成实际的细胞分裂,得到两个新细胞,细胞周期再次开始。
化疗能够治愈某些形式的癌症,已经使用了在有丝分裂期间(即G2期之后)干扰细胞周期的化疗剂。这种外源性物质干扰细胞骨架蛋白质(例如微管蛋白纤维)的聚集和解聚动力学。这种物质以长春花生物碱(例如紫杉醇)为例。
然而,大多数癌症药物的使用受到限制。难题之一在于,任一时刻只有某一比例的细胞在分裂,而大多数癌症药物只能破坏进行分裂的那部分细胞群体。另一难题在于,除了损害癌细胞,癌症药物也损害正常细胞和组织。为了克服这些困难,在各种治疗程序中,同时或依次使用以不同方式作用于细胞的化疗剂组合。
已经假定细胞总的氧化还原状态与增殖调节有关。据若干观察报道,如果转为氧化,则诱导细胞增殖,如果补充还原剂,则细胞倾向于分化。处于各种来源氧化应激(即UV辐射、电离辐射和化学剂)之下的细胞,常常表现出增殖反应。自由基和过氧化氢残基产生氧化应激,在大多数情况下,利用抗氧化剂和自由基清除剂进行预处理,可以减低或完全消除增殖反应。
N-乙酰-L-半胱氨酸(NAC)是包含巯基的化合物,可以防止或减低氧化作用。它因而具有若干药学和实验用途。尽管未经最后证明,其特性与巯基残基(-SH)相当有关。由于其抗氧化剂特性,也有报道NAC对抗炎症的副产物-自由基的作用,而用作抗炎药物。
WO 97/29759将NAC用于阿霉素的药物组合物中,以抑制癌瘤形成。在这种情况下,NAC的抗氧化剂活性抵消了阿霉素的心脏毒性。
在细胞增殖(Cell Proliferation)(1998),31(5/6),217-229中,评价了表现抗氧化剂特性的含巯基化合物,用于细胞保护和化学预防。将N-乙酰-L-半胱氨酸(L-NAC)及其非代谢的活性立体异构体N-乙酰-D-半胱氨酸(D-NAC)与药物巯甲丙脯酸和二硫赤藓糖醇(DTT)一起进行研究,评价其对细胞周期进展的影响。拓扑异构酶IIa的活性下降与G2期积聚的细胞相对数目增加6倍有关。
NAC的其它药学和临床用途包括常见的粘液溶解作用,以及治疗经扑热息痛和相关化合物治疗之后的暴发性肝衰竭。临床使用时,即使大剂量NAC,例如10g/天,未产生明显副作用。这与其它有害的含巯基化合物(例如巯基乙醇和二硫苏糖醇)相反。此外,NAC的清除相对迅速。
由于N-乙酰-L-半胱氨酸(NAC)具有体外对抗骨髓瘤型肿瘤细胞的抗癌活性,JP08040888将其用作抗癌剂,治疗骨髓瘤型肿瘤,获得了肿瘤增殖抑制活性。
与骨髓瘤型肿瘤相反,上皮来源的大多数实体组织的细胞生长和细胞更新可以描述为,一个干细胞复制成一个末期细胞和一个具有持续生长潜能的细胞。该末期细胞然后进入分化途径,执行各种组织功能,其寿命有限。
进入分化途径的细胞表现出细胞-细胞接触显著增强,该过程通常也表示为接触抑制。若干证据表明,细胞进入分化终点的信号来自细胞-细胞接触的自身成分。细胞-细胞粘附也负责在细胞之间传播信号。
可以认为癌细胞是丧失接触抑制并连续增殖的分化细胞。因此,癌细胞丧失了响应分化信号的能力。在这点上,癌细胞是永生的,而不具有分化细胞的有限寿命。
本发明的目的在于制备药物,用作上皮组织分化功能失常相关疾病的治疗剂。
为达此目的,已经赋予了本发明方法如权利要求1所述的特征。
人们惊奇发现,N-乙酰-L-半胱氨酸(NAC)及其二硫化物二聚体N,N’-二乙酰-L-胱氨酸(di-NAC)是回复性物质,可使上皮来源的瘤形成细胞的异常增殖回复到正常途径,包括阻断增殖、分化以及有限的细胞寿命,而没有毒性作用。N-乙酰-L-半胱氨酸的其它二聚体形式以及类似结构,例如4,4’-(异亚丙基-二硫)双[2,6-二-叔丁基酚],也表现出这些作用。
在这方面,瘤形成细胞是指形成赘生物的细胞,即在不会引起或停止正常细胞增殖的条件下进行性增殖的细胞。这种良性或恶性的细胞过度增殖包括组织转化(metaplasia),即组织中的细胞类型改变为该组织的非正常形式;退行性变化(anaplasia),即丧失细胞分化及彼此的定位;进行性分化(prosoplasia),即组织分化异常;以及退行性化生(retroplasia),即组织或细胞退化为更原始的类型。
NAC或di-NAC的回复作用涉及细胞的常规分化,公认的形态不均一性分化发生于细胞周期G1-G0期之后,而非G2期。
根据本发明,当一个细胞进行分化-而不再进一步分裂时,通过使用N-乙酰-L-半胱氨酸或其二聚体形式,该细胞显示其最终的正常形态。上皮来源的细胞和组织的肿瘤性增殖行为,在新DNA合成之前,即S期之前开始回复。然后细胞从G1期进入G0期(零生长),从此开始分化期(D期)。该期合成并组装表征组织中最终分化及功能性活性细胞所需的全部成分,形成适当的形态。
本发明利用NAC或di-NAC处理瘤形成细胞,增加了细胞-细胞粘附结构,获得了良好分化细胞典型的、每种细胞类型各不相同的若干其它结构和功能(如下实施例所述),以及停止了增殖,证明其分化正常。其它的生物化学分化标志为早期转录因子。
例如,如果用高浓度NAC或di-NAC处理肿瘤,获得的细胞-细胞粘附包含位于相邻细胞之间或者细胞和基底的细胞外基质之间的若干粘附结构。显微镜下所见为紧密连接和粘附连接、以及桥粒和间隙连接,每个由蛋白质的复杂结构组成,通常由重复亚基组成。这些接触横跨细胞膜,具有细胞外、跨膜和细胞质位点。这些多蛋白质结构的细胞质位点依次连接细胞骨架蛋白质网络,而细胞外位点与邻近细胞或基底的细胞外基质相连。
例如,利用NAC或di-NAC处理原发的正常人表皮角质细胞(NHEK)以及人结肠癌细胞系(CaCo2),两种细胞类型均在3天内分化。这些细胞在局部浓度大约1mM获得最大增殖抑制(表明不生长)。较低剂量也具有抗增殖作用,但并非如此之大。由于NAC和di-NAC的抗氧化剂特性,极低剂量具有轻微的增殖作用。因此,根据本发明,获得高于最大增殖抑制(即绝对不生长)所需浓度的有效量的N-乙酰-L-半胱氨酸或其二聚体形式,使上皮来源的哺乳动物瘤形成细胞回复到正常分化,从而使该异常增殖的细胞回复到正常途径。所以,抑制增殖并不意味着回复为本来的瘤形成细胞,而只是伴随分化。
在这些较高剂量的NAC和di-NAC下,大多数细胞骨架蛋白质发生破坏。NAC和di-NAC也防止破坏的细胞骨架自然恢复。细胞骨架段裂时,获得更强的细胞-细胞接触以及更多的细胞-细胞连接,即,细胞连接之间的相互作用强度增加,这种连接的数目增多。这可能由于细胞-细胞连接与细胞骨架网络相连,可使该连接保持供细胞增殖的正确距离。一旦足够浓度的NAC或di-NAC破坏了该网络,连接将会瓦解,得到更为紧密的细胞-细胞接触。这种所谓的接触抑制导致增殖停止,并意外地开始分化,就肿瘤细胞来说,即为肿瘤回复。因此,通过增加细胞-细胞接触,获得对这些细胞的生长控制,诱导功能失调的上皮来源的哺乳动物细胞回复到正常分化。
因此,本发明提出NAC或di-NAC的用途,用于分别在高或低的浓度下,通过抑制或稳定相应疾病,临床治疗上皮来源的瘤形成细胞。本发明使用的瘤形成细胞的类型不受限制,可以是退行性变化细胞、组织转化细胞、进行性分化细胞或退行性化生细胞。
优选地,本发明的用途包含抗癌治疗,其中上皮来源肿瘤的增殖(包括良性和恶性过度增殖)回复到分化途径。NAC或di-NAC可以迫使良性肿瘤细胞回到正常分化,以表皮肿瘤细胞和类风湿细胞为例。恶性肿瘤可以是肺癌、乳腺癌、前列腺癌或人结肠癌。根据本发明,可以回复到正常途径的恶性细胞和肿瘤,其更全面的非限制性名单包括CNE2人上皮肿瘤细胞系、A431细胞系、66-kDa Shc食管癌细胞系、HepG2人肿瘤细胞系、包含人乳头瘤病毒16型的癌细胞系、Merkel细胞癌细胞系、头颈癌细胞系、食管癌细胞系、以及胶质母细胞瘤细胞、视网膜母细胞瘤、人视网膜母细胞瘤Y79细胞、肝细胞癌细胞、SH-SY5Y细胞、Ehrlich腹水肿瘤细胞、肝上皮肿瘤细胞、胸腺样分化的纺锤形上皮肿瘤(SETTLE)、绒毛膜上皮细胞间皮瘤、上皮细胞卵巢癌、外阴上皮内瘤形成、人肠系膜动脉瘤形成、间皮瘤形成、上皮内瘤形成、非小细胞肺癌、管囊肿明细胞腺癌、结肠腺癌细胞、肝色素沉着细胞腺瘤、非鳞状散在腺瘤、Barrett’s食管及相关腺癌、直肠阴道隔腺癌、前列腺癌、胰腺癌、垂体嗜酸性干细胞腺瘤、唾液腺样囊性癌、胆囊内分泌腺细胞癌、胰腺巨囊浆液性囊腺瘤、腺鳞癌或柱状细胞瘤形成、鳞状细胞癌、子宫颈鳞状细胞癌、神经母细胞瘤、播散性掌跖汗孔角化病损伤所致鳞状细胞癌、子宫颈鳞状细胞癌、胰腺实体假乳头瘤、有或无杆状特征的肾细胞癌、肝细胞癌、大细胞神经内分泌癌、小细胞癌、小细胞肺癌、小细胞乳腺癌、乳腺癌、乳腺导管癌、指环状细胞小叶癌、粘液癌、基底细胞癌细胞、甲状腺退行发育癌、Waldeyer’s环状区域癌、肝细胞-胆管癌、神经胶质瘤、C6神经胶质瘤细胞、少突神经胶质瘤和星形细胞瘤、神经胶质肉瘤、粘液乳头室管膜细胞瘤、胰腺癌细胞、人前列腺癌细胞、结肠直肠癌、卵巢癌细胞、肾癌细胞、非黑色素瘤皮肤癌、甲状旁腺激素相关蛋白质和皮肤癌、人喉部乳头瘤细胞、口腔腺泡细胞癌、甲状腺Hurthle细胞瘤、卵巢癌、膀胱细胞癌、结肠直肠癌、肠嗜铬样细胞、人星形细胞瘤细胞、人肾明细胞癌、转移性肾细胞癌、舌癌、头颈腺病、胰腺大腺泡细胞癌、门胆管癌、乳头状甲状腺癌、dent、人前列腺癌细胞、明细胞″糖″瘤、镰状韧带/圆韧带肌黑素细胞瘤(血管周上皮状明细胞家族成员)以及输尿管移行细胞癌。
此外,NAC或di-NAC可以有效治疗角化症皮肤,例如银屑病和棘细胞层水肿性皮炎。同样,NAC或di-NAC可以纠正表皮向性,重建与血管损伤一起形成的糖尿病损害的内皮细胞。
已经表明,di-NAC抑制WHHL兔子的动脉硬化。同样,在中度及显著的小动脉性肾硬化(40%)的肾中,肾上皮细胞瘤较之没有或最轻微的小动脉性肾硬化(8%)的肾更为常见(Budin RE,McDonnell PJ.Arch Pathol Lab Med 1984 Feb;108(2):138-40)。在高于或低于60岁的患者中均发现这种联系。肾上皮细胞瘤的形成与肾瘢痕有关;并非独立的年龄相关现象。
50%的动脉硬化细胞回复到正常途径,应该与细胞角蛋白(cytokeratin)表达有关。据认为,细胞角蛋白(CK)的表达是上皮细胞分化状态的标志。CK也存在于某些血管平滑肌细胞(VSMC)中,这意味着与较少分化的表型有关。在处于应激、有丝分裂或凋亡的上皮细胞中,显示存在CK的翻译后修饰。
最近研究了人VSMC的CK磷酸化模式(Bar H,Bea F,BlessingE,Watson L,Wende P,Kreuzer J,Kubler W,Jahn L.,BasicRes Cardiol 2001 Feb;96(1):50-8)。
利用细胞角蛋白8和18特定细胞角蛋白磷酸化位点的特异性抗体,通过免疫荧光显微术,以Ki-67抗原为增殖标志并利用切口末端标记(TUNEL)检测凋亡,评价正常外周和冠状动脉、动脉硬化损伤和脐带血管的组织样品。所有样品均包含细胞角蛋白阳性的VSMC,但其磷酸化模式各不相同。在冠状动脉损害的绝大多数表达CK的VSMC中,细胞角蛋白8的C端丝氨酸431(CK8Ser-431)磷酸化。这些细胞只有一部分显示CK18Ser-33的磷酸化,或者CK8Ser-73的磷酸化程度甚至更低。
DNA段裂主要发生于包含CK8Ser-431磷酸化结构域细胞的样品中。相反,闭塞的外周损害显示很少或没有磷酸化。脐带血管中新生的VSMC包含大量的磷酸化CK结构域,再次以CX8Ser-431为主,但也有CK18Ser-33。此外,发现只有单个细胞增殖或包含DNA段裂。因此,在动脉硬化损伤的VSMC中,CK的大量磷酸化提示对细胞应激的特异性功能性反应,并可能与凋亡有关。
根据定义,所有的化疗剂必定是抗增殖的。因此,根据本发明,为获得NAC或di-NAC的回复作用所需剂量高于仅仅抑制增殖所需的剂量。与报道的毒性强、副作用大的所有其它化学治疗剂相反,NAC可以在相应疾病的严重期和进行期,根据治疗的细胞类型,按局部浓度0.1-50mM用于治疗瘤形成细胞。
优选浓度0.2-40mM的NAC没有毒性作用。例如,为了解救扑热息痛中毒后的自杀,15分钟内静脉内注射10克剂量的NAC,随后的30分钟内注射一半剂量,根本没有报道任何副作用。
当然,完全阻断增殖所需的NAC或di-NAC的绝对最高或最低剂量,取决于所治疗的细胞类型。例如,为促进正常角质细胞分化所需最低剂量为0.5mM,而角质细胞在1mM完全分化。然而,浓度1mM的NAC或di-NAC诱导结肠癌细胞回复,5mM则结肠癌完全分化。
此外,直接显现对结肠癌细胞和正常角质细胞获得的分化作用,也就是说,在仅仅补充一次NAC或di-NAC之后。
可以制备包含有效量NAC或di-NAC以及合适载体的药物和兽用组合物。该载体为本领域技术人员公知。NAC或di-NAC可以直接或以组合物形式给予人或动物受试者。
本发明的回复剂可以通过偶联靶向分子(例如指向作用部位附近表位的抗体),而被有意引到特定的作用部位。此外,NAC或di-NAC可以按这种方式结合指向特异性上皮组织的抗体,以使回复活性靶向上皮细胞来源的瘤形成细胞,并与其结合。
可以根据所治疗疾病的类型及其阶段,局部及全身性补充NAC或di-NAC,通过口服、静脉内、关节内等给予。例如,对于表皮肿瘤,局部应用足以。另一方面,对于类风湿性关节炎,需要关节内注射。适当的给药途径也取决于所治疗的疾病类型。例如,NAC已经有效用于局部治疗银屑病,全身以及局部治疗银屑病关节炎和类风湿性关节炎。
NAC或di-NAC的治疗可以间隔重复几次,该物质也可以连续补充。既然这种治疗并不杀死肿瘤细胞,疾病明显回复的时间间隔取决于所治疗细胞类型的特定寿命。例如对于表皮细胞寿命大约30天的表皮肿瘤,肿瘤块在该时间之后应该呈现明显减小。本发明治疗银屑病时,在治疗几天至3-4周以后,症状消失,几个月后可能必须进行重复治疗。
本发明使用的NAC或di-NAC,不仅通过恢复细胞-细胞接触,诱导功能失调细胞的生长控制,从而引起分化(就肿瘤细胞而言,即肿瘤回复)。在这些浓度下,NAC和di-NAC也显示较低浓度下获得的接触抑制,导致细胞停止增殖。此外,本发明使用的NAC和di-NAC也具有抗氧化剂作用。
实施例
现将参照以下实施例,进一步描述和说明本发明。然而应当指出,这些实施例不应理解为以任何方式限制本发明。
实施例1.NAC和di-NAC对人结肠癌细胞的作用。
使用建立的人结肠癌细胞系(CaCo2)。CaCo2是增殖的人结肠癌细胞系,形态不规则,形成缺乏微绒毛结构以及细胞间隙较大的多细胞层。
长期培养大约14天以后,细胞逐渐获得典型的分化细胞形态,
i)基侧极性增加,
ii)在细胞上表面出现凸出的绒毛状结构(刷状缘),
iii)细胞上部和基部的肌动蛋白细胞骨架纤维(连接到与相邻细胞新建立的紧密连接)局部化。
iv)细胞核重定位到基膜附近。
利用2-10mM各种毫摩尔浓度的NAC处理CaCo2细胞。细胞接种后24小时,将NAC加入培养基中。在NAC存在下培养3天后,分析细胞的下列标志参数:
-细胞骨架结构:观察到肌动蛋白纤维结构破坏,出现应力纤维。细胞上部的肌动蛋白纤维重定位,维持刷状缘微绒毛,以及细胞基部的细胞角蛋白纤维重定位。细胞角蛋白纤维也稀疏地出现段裂。
-表面形态:观察到细胞表面适当数量的微绒毛状结构,具有终端分化细胞的形态。
-细胞-细胞粘附:观察到各种细胞粘附结构的数目增加。细胞内空间也显著减少。
-微管蛋白表达和聚合:NAC处理使微管蛋白的表达出现大大下降。有丝分裂中期的细胞常常缺少有丝分裂纺锤体。
-增殖:细胞增殖以剂量依赖方式下降,2mM NAC作用最强。
-毒性:细胞生活力不受加入的各种剂量NAC处理的影响。未观察到凋亡和坏死。
利用di-NAC处理CaCo2细胞,同样诱导细胞的形态和生物化学变化。例如获得细胞厚度、顶端基侧的极性增加、E-钙粘蛋白(E-cadherin)表达提高、刷状缘和紧密连接形成,以及增殖降低。di-NAC处理有时比NAC处理更为有效。
总之,利用NAC或di-NAC处理,诱导CaCo2细胞回复到分化途径,而没有任何可检测的毒副作用。由于分化,CaCo2细胞的增殖也降低了。
实施例2.NAC或di-NAC对人表皮角质细胞的作用。
原发的正常人表皮角质细胞(normal human epidermalkeratinocytes,NHEK)得自Clonetics Inc.(San Diego,CA,USA),在厂商提供的培养基中培养。该细胞的培养寿命有限,大约15天,经历表皮角质细胞的正常分化过程,最后去核并脱落。接种后,细胞获得细胞-细胞粘附的多角形形态。细胞骨架形态组织很好,主要位于细胞边缘。
利用1-10mM各种毫摩尔浓度的NAC或di-NAC处理NHEK细胞。接种后24小时,将这些物质加入培养基中。在2mM NAC或di-NAC存在下培养3天后,分析细胞的下列标志参数:
-细胞骨架结构:观察到肌动蛋白纤维结构破坏,分散出现于细胞质中,并出现若干应力纤维。细胞角蛋白纤维显著段裂。利用电泳也观察到细胞骨架段裂。处理后得到若干条带,而未处理的细胞只看见一条宽带。
-表面形态:细胞表面丧失代表增殖角质细胞的细小微绒毛结构而显得平滑。伴随初期角化包膜的出现,观察到很多去核细胞。
-细胞-细胞连接:观察到连接数增加,细胞内空间显著减少。E-钙粘蛋白的浓度也增加了。
-微管蛋白表达和聚合:该处理似乎降低了微管蛋白的表达。观察到有丝分裂中期细胞形成有丝分裂纺锤体的百分比略微减少。
-分化:通过western印迹确定,角质细胞增殖状态的标志消失。
-增殖:细胞增殖以剂量依赖方式下降,2mM NAC或di-NAC完全抑制细胞增殖。
-毒性:细胞生活力不受各种剂量NAC处理(即,直至10mM)的影响。未观察到凋亡和坏死。
应当指出,分离的角质细胞是在绝对没有淋巴细胞的情况下进行NAC处理。
总之,利用NAC或di-NAC处理NHEK细胞,可诱导回复以及分化加快3-4倍,而没有毒副作用。诱导的分化还导致NHEK增殖停止。
实施例3.NAC或di-NAC对银屑病的作用。
银屑病是慢性皮肤病,以细胞良性过度增殖、产生细胞因子、积聚炎症细胞、角质化异常以及血管化增强而著称。
利用包含10-20重量百分比的NAC或di-NAC的膏剂,对表现局部银屑病斑的五位有知识的自愿者进行局部治疗。每晚施用膏剂,进行不同时间(几周-几个月),上或不上封闭的绷带。每日治疗之间正常清洗患者的皮肤。不同时使用其它药物。
治疗1-2次以后,已经观察到迅速改善,鳞屑减少,皮肤平滑。延长治疗引起所有症状完全缓解。根据个体反应以及疾病的严重性,完全缓解所需治疗时间有所不同。最经常报道的副作用与局部连结有关,移动封闭的绷带即可消失。一个病例还报告有膨胀。
治疗中止以后,只有一名患者在4个月后出现新的小银屑病斑,进一步治疗几天后消失。
因此,消除了银屑病角质细胞的异常增殖及缺乏分化。
实施例4.NAC对大肠肿瘤的作用。
利用1,2-二甲基肼(DMH)处理雄性Sprague-Dawley大鼠,诱导肠肿瘤,研究每日或间断的NAC治疗对肠肿瘤的作用。
与相应的对照组相比,NAC间断治疗组大鼠的大肠肿瘤负担显著降低(分别为11和1个肿瘤/处理组,p=0.001)。NAC治疗组的大肠肿瘤块指数同样显著低于对照组(分别为1.93和0.04,p<0.001)。每日NAC治疗的大鼠结肠中没有腺癌存在。
结论为,NAC减少DMH诱导的雄性Sprague-Dawley大鼠的大肠肿瘤,就显著抑制大鼠结肠内肿瘤来看,NAC具有保护作用。
实施例5. NAC对结肠腺癌的作用。
在此实验模型中,将BD-IX大鼠分成4组:G1和G2组定为″肿瘤组″,用于研究NAC对结肠癌进展的作用,G3和G4组定为″毒性组″,用于研究该处理对代谢过程和实质(parenchyma)的作用。G1和G2组动物的胸部皮下注射DHD/K12-PROb细胞。接种后1-13周,G2和G4组的动物每周接受NAC注射。G1和G3组动物不经处理。
另外,使用动物和人结肠腺癌细胞系(DHD/K12-PROb和HT-29)进行体外分析,以检查NAC的细胞毒性。
在此实验研究中发现,利用NAC长期治疗大鼠结肠腺癌导致寿命延长。此外,经NAC治疗的雌性及雄性大鼠的肿瘤生长显著减慢。
实施例6.NAC对结肠癌的作用,化学预防机制。
既然NAG抗结肠癌的功效显著,在氧化偶氮甲烷(AOM)诱导的大鼠结肠癌模型中,研究结肠粘膜和肿瘤组织中的蛋白激酶C(PKC)、酪氨酸蛋白激酶(TPK)和二酰甘油激酶(DGK)的活性以及8-异前列腺素的水平,以探索抑制结肠癌发生的机制。
7周龄时,相应组大鼠s.c.注射氧化偶氮甲烷(AOM;15mg/kg体重,每周一次,进行两周),继续各种实验,直到第二次AOM处理后38周为止。然后处死大鼠,评价结肠粘膜以及肿瘤样品的PKC、TPK、DGK和8-异前列腺素水平。
给予NAC显著抑制了结肠粘膜和肿瘤的Ca2+依赖性和非依赖性PKC活性(P<0.01)。给予NAC也显著抑制结肠粘膜和肿瘤的TPK活性(P<0.01)。相反,接受NAC的大鼠显示DGK活性显著提高(P<0.01)。另外,NAC处理大鼠的结肠肿瘤比对照的8-异前列腺素水平低。
这些发现提示,NAC化学预防结肠癌的机制涉及通过诱导PKC和TPK活性下调以及DGK活性上调,调节蛋白激酶C、酪氨酸蛋白激酶和二酰甘油激酶的活性。因此,这些事件可能在某种程度上导致抗结肠癌发生的化学预防活性。此外,这些结果暗示,NAC增强结肠中PKC、TPK和DGK活性的调节。
实施例7. NAC或di-NAC对口部角化细胞肿瘤及其转移性传播的作用。
将4NQO诱导的大鼠恶性口部角质细胞克隆群原位移植到无胸腺小鼠,检测NAC或di-NAC对其转移能力的作用。多角形细胞和纺锤形细胞在所有动物的接种部位(口腔底部)分别形成分化良好的鳞状细胞癌(角蛋白阳性及波形蛋白(vimentin)阴性)和未分化的纺锤状细胞肿瘤(角蛋白阴性及波形蛋白阳性)。
以高细胞密度移植5×106任一细胞类型的细胞,引起大约50%的动物形成肺转移。
未分化的纺锤形细胞系表达转化生长因子β1(TGF-β1),原位移植以后根据本发明进行处理,尽管几乎所有的移植动物均形成原发性肿瘤,但形成肺转移的动物较少。
此结果提示,NAC或di-NAC诱导的TGF-β1可以作为该细胞类型的肿瘤抑制剂。外源性NAC显著抑制多角形细胞克隆,也抑制纺锤形细胞。此结果还提示,经过NAC或di-NAC处理,分化的大鼠恶性口部角质细胞的侵袭性较小,较之未处理的对应物其转移潜能下降。在未分化的纺锤形细胞对应物中观察到类似发现。TGF-β及其受体特征的作用可以部分解释以下发现,即NAC或其二聚体形式减少了恶性口部角质细胞肿瘤及其转移性传播。
实施例8.组织靶向。
流感病毒颗粒(重组的流感病毒包膜)可以靶向卵巢癌细胞(OVCAR-3),而保存融合活性。这通过将聚(乙二醇)(PEG)衍生的脂质引入病毒核蛋白颗粒的膜中而实现。(Mastro-battista E,SchoenP,Wilsohut J,Crommelin DJ,Storm G.FEBS Lett 2001 Nov30;509(1):7176)。
将单克隆抗体(mAb)323/A3(抗上皮细胞糖蛋白-2)的Fab’片段偶联到PEG脂质的远端。该PEG层作为遮蔽,防止病毒血凝素与无所不在的唾液酸残基的相互作用,并作为抗体附着的空间锚位。从而获得特异性结合病毒颗粒的OVCAR-3细胞。抗体重定向的病毒颗粒以pH依赖性方式,与OVCAR-3细胞的膜融合。
利用这种方法,(Mastrobattista E,Schoen P,Wilschut J,Crommelin DJ,Storm G.,FEES Lett 2001 Nov 30;509(1):71-76)可以将NAC和di-NAC偶联mAb 323/A3的Fab’片段,附着于病毒颗粒。
这些实验证明,NAC和DiNAC可用于组织靶向。
实施例9.通过NAC处理抑制PPAR合成。
过氧化物酶体增殖因子活化受体(PPARs)是属于核受体家族的配基活化的转录因子(Chinetti G.,Fruchart J.-C.,Staels B.,Inflammation Research Abstract Volume 49 Issue 10(2000),pp497-505)。这些受体行使脂质和脂蛋白代谢以及葡萄糖稳态的调节剂功能,并影响细胞增殖、分化和凋亡。PPAR-α在诸如肝、肌肉、肾和心组织中高表达,促进脂肪酸的β-氧化降解。PPAR-δ主要在肠和脂肪组织中表达。PPAR-γ引起脂肪细胞分化,并促进脂质贮存。降脂肪药氯贝特和抗糖尿病药格列酮分别是PPAR-α和PPAR-γ的合成配基。此外,脂肪酸和类二十烷酸是天然的PPAR配基:PPAR-α由白三烯B4活化,而前列腺素J2是PPAR-γ的配基。
此外,PPAR-α缺陷的小鼠显示对炎症刺激物的反应延长。PPAR活化剂也显示通过负干扰NF-κ、STAT和AP-1信号途径,抑制炎症反应基因(例如IL-2、IL-6、IL-8、TNF-α和金属蛋白酶)的活化。PPAR活化剂在表达PPARs的不同免疫学和血管壁细胞类型中(例如单核细胞/巨噬细胞、内皮细胞、上皮细胞和平滑肌细胞)发挥这些抗炎活性。
因此,有效浓度的NAC(参见上述)通过抑制PPARs,表现出不仅控制代谢,而且控制炎症。
可能的治疗应用为炎症相关疾病,例如动脉粥样硬化和炎症性肠部疾病。
Claims (19)
1.有效剂量的N-乙酰L-半胱氨酸或其二聚体形式用于制备药物的用途,所说的药物可使哺乳动物上皮来源的瘤形成细胞回复到正常分化,从而使该瘤形成细胞的异常增殖回复到正常途径。
2.权利要求1的用途,其特征在于该瘤形成细胞是退行性变化的细胞。
3.权利要求2的用途,其特征在于该退行性变化的细胞是良性肿瘤细胞。
4.权利要求3的用途,其特征在于该良性肿瘤细胞是表皮肿瘤细胞。
5.权利要求4的用途,其特征在于该表皮肿瘤细胞是银屑病细胞。
6.权利要求5的用途,其特征在于该良性肿瘤细胞是类风湿细胞。
7.权利要求2的用途,其特征在于该退行性变化的细胞是恶性肿瘤细胞。
8.权利要求7的用途,其特征在于该恶性肿瘤细胞是肺癌、乳腺癌、前列腺癌或人结肠癌。
9.权利要求1的用途,其特征在于该瘤形成细胞是组织转化细胞。
10.权利要求9的用途,其特征在于该组织转化细胞是角化病细胞。
11.权利要求10的用途,其特征在于该角化病细胞是银屑病细胞。
12.权利要求9的用途,其特征在于该组织转化细胞是表现糖尿病损伤的细胞。
13.权利要求1的用途,其特征在于该瘤形成细胞是进行性分化细胞。
14.权利要求1的用途,其特征在于该瘤形成细胞是退行性化生细胞。
15.权利要求1-14中任一项的用途,其特征在于N-乙酰-L-半胱氨酸或其二聚体形式的有效剂量为局部0.1-50mM。
16.权利要求15中任一项的用途,其特征在于N-乙酰-L-半胱氨酸或其二聚体形式的有效剂量为局部0.25-40mM。
17.可使哺乳动物上皮来源的瘤形成细胞回复到正常分化,从而使该瘤形成细胞的异常增殖回复到正常途径的组合物,其特征在于治疗有效量的N-乙酰-L-半胱氨酸、或其二聚体形式、以及药学可接受的载体。
18.权利要求17的组合物,其特征在于组织靶向分子附加到N-乙酰-L-半胱氨酸或其二聚体形式上。
19.权利要求18的组合物,其特征在于该组织靶向分子是
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