Hans Journal of Ophthalmology
Vol.04 No.03(2015), Article ID:16100,12
pages
10.12677/HJO.2015.43011
Chemotherapy for the Treatment of Adenoid Cystic Carcinoma
Tao Jiang1*, Jing Jiang2, Renping Wang3, Lihua Xiao4, Yi Wang4
1Department of Ophthalmology, The Affiliated Hospital of Qingdao University, Qingdao Shandong
2The Infectious Diseases Department, Eastern Branch of the Affiliated Hospital of Qingdao University, Qingdao Shandong
3Health Examination Center, The Affiliated Hospital of Qingdao University, Qingdao Shandong
4Institute of Orbital Disease, Armed Police General Hospital, Beijing
Email: *lanlandetian20000@163.com
Received: Aug. 27th, 2015; accepted: Sept. 17th, 2015; published: Sept. 28th, 2015
Copyright © 2015 by authors and Hans Publishers Inc.
This work is licensed under the Creative Commons Attribution International License (CC BY).
http://creativecommons.org/licenses/by/4.0/
ABSTRACT
Adenoid cystic carcinoma (ACC) is a malignant tumor, and its malignant degree is high, the characteristics of which is slow local invasive growth, easy to local recurrence and distant metastasis, with poor prognosis and high mortality, difficult to cure. In orbit it occurs in the lacrimal gland. The clinical treatment has been a difficulty. Traditional treatment methods include surgery, radiotherapy, chemotherapy, and the combination of the above methods. Most of ACC's primary cases were treated with surgical resection, followed by radiation therapy. For the treatment of recurrent cases, options are limited, and the effect of re-radiation therapy and repeat surgery is limited. In recent years, the research on the chemotherapy for ACC is gradually paid attention to. In this paper, the progress of the research is summarized.
Keywords:Adenoid Cystic Carcinoma (ACC), Chemotherapy
腺样囊性癌的化学治疗
姜涛1*,姜靖2,王仁萍3,肖利华4,王毅4
1青岛大学附属医院眼科,山东 青岛
2青岛大学附属医院东区感染科,山东 青岛
3青岛大学附属医院健康查体中心,山东 青岛
4北京武警总医院眼眶病研究所,北京
Email: *lanlandetian20000@163.com
收稿日期:2015年8月27日;录用日期:2015年9月17日;发布日期:2015年9月28日
摘 要
腺样囊性癌(adenoid cystic carcinoma, ACC)恶性程度高,其特征为缓慢地局部浸润性生长,易局部复发与远处转移,预后差,难根治,死亡率较高,于眼眶部好发于泪腺,其临床治疗一直以来就是一个难点。传统的治疗方法包括手术切除、放射治疗、化学治疗及上述方式的联合应用等综合治疗方法。大部分ACC的初发病例采用手术切除治疗,然后行放射治疗,对于复发病例,治疗选择有限,再次放疗与重复手术切除的治疗效果有限。近年来,ACC的化学治疗研究逐渐为人们所重视,本文将其研究的进展情况进行综述。
关键词 :腺样囊性癌,化学治疗
1. 概述
腺样囊性癌(adenoid cystic carcinoma, ACC)是一种恶性肿瘤,但却有类似良性的组织学表现,其特征为缓慢地局部浸润性生长,且很容易局部复发与远处转移[1] 。ACC恶性程度比较高,属上皮性肿瘤,可发生于全身各处,常见的有涎腺[2] -[11] (颌下腺[4] [7] 、舌下腺[8] [9] 、腮腺[10] [11] )、肺[12] -[16] 、气管[17] [18] 、乳腺[19] [20] 、皮肤[21] [22] 等,于眼眶部则好发于泪腺[23] -[27] ,其中以发生于上颌面部的涎腺处[19] [27] 最为常见,眼眶泪腺处[27] 次之。
泪腺ACC的平均发病年龄为40岁左右,女性稍多见,其发病率在泪腺上皮性肿瘤中仅次于多形性腺瘤而居于第2位,是泪腺恶性上皮性肿瘤中最为常见并且恶性程度最高的肿瘤,占所有眼眶肿瘤的1.6% [28] ,其患病率占所有原发眼眶肿瘤的4.8%,占泪腺上皮性肿瘤的29% [29] ,是一种浸润性极强预后很差的肿瘤,很难根治,多数会局部复发,死亡率较高,其15年存活率不到20% [30] 。最新的一项研究表明,2286名接受了手术切除的头颈部ACC患者,其5年、10年、15年、20年、25年的存活率分别为77.3%、59.6%、44.9%、35.0%、25.5% [31] 。
ACC具有嗜神经特性[32] ,其生物学特点为沿神经周侵袭和远处转移,可有自发痛与触痛,沿神经周侵袭与远处转移明显与患者的预后相关,其中最重要的影响存活率的因素是远处转移[33] 。ACC可沿神经侵袭、可蔓延侵犯骨质而转移至颅内[34] [35] ,如泪腺ACC通过神经侵袭而蔓延至颅内者占15% [36] 。ACC的远处转移主要发生在肺部[37] ,有研究表明,196名ACC患者中,有74名发生了远处转移,占38%,这其中有50名发生了单纯的肺部转移,有17名发生了包括肺部在内的多处转移,即一共有67名患者发生了肺部转移,占90.5% [38] 。
ACC按组织学特征,有三种病理分型:筛状型、管状型和实性型[1] 。其中,实性型易于发生远处转移[39] ,预后最差。用同样的治疗方法,筛状型和管状型的远处转移率和存活率无差异;筛状型易于局部复发,而实性型因易于转移而远期存活率低,管状型和筛状型预后较好[40] -[42] 。根据实性型所占比例,将ACC分为三级:I级:筛状型或管状型,不含实性型成分;II级:单纯筛状型或混合小于30%的实性型;III级:主要为实性型,比例超过30%。通过分级,可对预后作出判断,如III级肿瘤较大,频繁复发,患者一般于4年内死亡;I级肿瘤较小,可行手术切除[41] 。
基于ACC的上述特点,其临床治疗一直以来就是一个难点:虽然生长缓慢,但恶性程度高,局部浸润生长侵袭性强;手术治疗难以治愈,多数会局部复发,甚至是多年以后复发;局部淋巴结转移少见,但很容易发生远处转移;5年存活率较高,但10~20年的存活率却很低[42] 。传统的治疗方法包括手术切除、放射治疗、化学治疗及上述方式的联合应用等综合治疗方法。大部分ACC的初发病例采用手术切除治疗,然后行放射治疗,对于复发病例,治疗选择有限,因为再次放疗与重复手术切除的治疗效果有限。报道的资料显示,化学治疗的反应率不高,有针对性的靶向治疗可能是一种选择[43] 。近年来,ACC的化疗研究逐渐为人们所重视,现将其研究的进展情况综述如下。
2. ACC治疗及化疗方法的演进
与大部分恶性肿瘤的治疗方法类似,ACC的治疗方法演进也是从传统的手术、放疗、化疗到后来的综合疗法。对于原发性局部肿瘤,一般采用手术切除的方式,针对病理情况及类型可考虑术后再行辅助放疗或辅助化疗。对于有远处转移或复发的恶性肿瘤,放化疗就成为主要的治疗方法,尤其以化疗方式为主。
对于涎腺的ACC、粘液表皮样癌、高度恶性腺癌这些手术和/或放疗等局部治疗无法治愈的中晚期病例,只能考虑全身化疗这种保守疗法,且在治疗中更强调靶向药物的潜力[44] 。
目前,对于像ACC这样的涎腺恶性肿瘤并没有其标准化疗方案,但以顺铂(cisplatin)为基础的治疗方案是经常使用的[45] 。1987年,有人用CAP法,即环磷酰胺(cyclophosphamide)、阿霉素(adriamycin)和顺铂的三联化疗法治疗中晚期大小涎腺原发性恶性肿瘤(主要为ACC,还有部分腺癌)。当时用的方法是在28天为一疗程的第一天行静脉注射,剂量为环磷酰胺500 mg/m2、阿霉素50 mg/m2、顺铂50 mg/m2,平均每个患者行4.7个疗程的治疗,结果发现CAP法对治疗涎腺恶性肿瘤有效,可作为诱导治疗或辅助治疗的方法[46] 。
也有人用CEF法[47] 治疗复发的涎腺恶性肿瘤(主要为ACC),即顺铂、表柔比星(epirubicin)、5-氟尿嘧啶(5-fluorouracil)联合化疗方案,具体方法是在21天为一疗程的第一天行静脉注射,剂量为顺铂60 mg/m2、表柔比星50 mg/m2、5-氟尿嘧啶600 mg/m2,结果显示对部分病例有一定效果。
非顺铂类的用药方案有CVF法[48] ,即环磷酰胺、长春新碱(vincristine)和5-氟尿嘧啶联合化疗方案治疗头颈部ACC。方法为每4周静脉推注一次环磷酰胺、长春新碱,并连续5天静脉输注5-氟尿嘧啶,得出的结论是CVF法是治疗头颈部ACC的耐受性良好的联合化疗方案,但在预防复发病例中效果不大。
近年最新的治疗方法的报道比较零散,有报道用奥沙利铂(oxaliplatin)联合西妥昔单抗(cetuximab)治疗食管小涎腺ACC有效[49] ;还有多个新的药物组合化学治疗方法,比如:顺铂或卡铂(carboplatin) + 吉西他滨(gemcitabine) [45] ,在进行治疗涎腺恶性肿瘤的临床Ⅱ期实验,结果有待进一步观察。
1998年,Meldrum等人[50] 首次报道了治疗晚期泪腺ACC的经颈动脉新辅助化疗方法,引起了重视。他们为两例广泛蔓延的泪腺ACC患者在术前行经颈动脉顺铂治疗与经静脉阿霉素治疗,发现其中一名患者原先有颅内蔓延的肿物已缩小至眶内,可行手术治疗,对两名患者施行了眶内容剜除术后,在切下来的标本中都发现了肿瘤的坏死。术后患者又接受了55到60 Gy的眶部放疗,再加上经静脉的顺铂与阿霉素的化疗,两名患者分别获得了9年半与7年半的存活期。Goldberg [51] 也在同期发表文章认可这种经动脉化疗治疗泪腺ACC的新方法。具体方法如下:治疗前,先行细针穿刺活检,证实诊断后,根据泪腺动脉与颈外动脉有交通支的解剖特点,经颈外动脉插管,给予顺铂100 mg/m2,溶入500 ml盐水,1小时内滴完。滴完后即给予静脉内滴注阿霉素,每日剂量25 mg/m2,连续给3天。21天为一疗程,至少给予2疗程,如影像学证实治疗有效,可给予第3疗程。在最后一个疗程后3~4周,血象正常的情况下,施行眶内容剜除术。术后4至6周,放疗55~60 Gy。每周放疗前,给予放射增敏剂顺铂20 mg/m2静脉内滴注,30分钟内滴完。放化疗结合治疗后2至4周,给予静脉内顺铂滴注,剂量100 mg/m2。阿霉素的剂量减少到20 mg/m2,给予3天。
经颈动脉内给药化学治疗方法的主要优势在于:1) 在手术破坏肿瘤的供血动脉前,将最大浓度、没有经过血液稀释的化疗药物直接作用于肿瘤区的血管系统,药物可直接输送到肿瘤床,可明显提高对肿瘤细胞的杀伤力,取得较佳的治疗效果;根据不同靶器官肿瘤细胞清除率的不同,经动脉给药的次数可多于经典的经静脉给药次数,同时该系统的毒副作用不会增加,减少了心肾损害;2) 可使肿瘤体积缩小,利于手术;3) 可以诱导肿瘤细胞坏死,杀灭边界外的亚临床病变,减少局部复发,降低手术造成潜在瘤细胞播散的机会,利于手术完整切除肿瘤[51] [52] 。
越来越多的学者逐渐认同并实施了经动脉化疗法来治疗ACC。有人用顺铂联合多西紫杉醇(docetaxel)经动脉化疗同时放疗治疗涎腺恶性肿瘤[53] ,取得了较好的效果。他们对一例舌下腺复发性ACC患者与一例腮腺原发性腺癌患者行经股动脉化疗,应用足量顺铂和多西紫杉醇,同时行外部放射治疗,顺铂与多西紫杉醇的剂量分别为80~100 mg/m2与10~15 mg/m2,先行输注多西紫杉醇,接着输注顺铂。得出的结论是对于复发的或无法手术切除的涎腺恶性肿瘤,经动脉顺铂与多西紫杉醇化疗联合放疗是一可行的选择。
到目前为止,原发性泪腺ACC还没有得到进一步的分级,但可以被划分为低度与高度恶性。新辅助经动脉“减瘤”化疗方法治疗ACC是治疗这种侵袭性肿瘤的最重要的进展之一[54] 。
3. 化疗药物及应用方案
3.1. 抗肿瘤药物的分类
根据各期肿瘤细胞对药物的敏感性不同,将抗肿瘤药物分为两大类。
1) 细胞周期非特异性药(cell cycle nonspecific agent, CCNSA):CCNSA可以杀灭各期增殖细胞,包括:① 烷化剂:典型药物包括氮芥类、环磷酰胺类、亚硝脲类,常用药物有环磷酰胺、卡氮芥、环己亚硝脲等。此类药物的常见不良反应为血液毒性、肝肾功能损害、消化道反应等,剂量限制性毒性多为骨髓抑制。② 抗癌抗生素:常用的有放线菌素、平阳霉素、丝裂霉素、阿霉素等。常见不良反应为肝肾功能损害、黏膜毒性等,平阳霉素主要表现为发热和肺纤维化。阿霉素则具心肌毒性,其改进产品表柔比星毒性大为降低。③ 铂类:常用药物为顺铂、卡铂。常见不良反应为肾毒性、血液毒性和消化道反应。
2) 细胞周期特异性药物(cell cycle specific agent, CCSA):CCSA仅杀灭某一期增殖细胞,包括:① 抗代谢类药物(叶酸抗代谢药物、嘌呤抗代谢药物和嘧啶抗代谢药物),常用药物有:甲氨蝶呤、6-巯基嘌呤和5-氟尿嘧啶。此类药物主要作用于S期。② 植物类抗癌药(长春碱类、鬼臼碱类、三尖杉酯碱类、美登素、榄香烯乳等)。其中长春碱类主要作用于M中期,通过阻止聚合及诱导微管蛋白解聚使有丝分裂停止。不良反应为周围神经毒性或骨髓抑制。
根据其作用机制,抗肿瘤药物又可分为五类:干扰核酸合成的药物,如氟尿嘧啶;破坏DNA结构和功能的药物;嵌入DNA干扰转录RNA的药物;干扰蛋白质合成的药物;影响激素合成,抑制肿瘤的药物[55] 。
3.2. ACC化疗药物及应用方案
1) 顺铂(顺式二氨基二氯络铂,顺氯氨铂,顺式铂,顺式二氨二氯铂) (cisplatin, DDP),1965年由美国科学家Rosenborg等人首次发现的[56] ,第一个具有抗癌活性的金属配合物。他在1965年意外发现“惰性的铂电极”能引起细菌的菌丝生长这一事实,从而展开了顺式二氨基二氯络铂的抗癌特性。顺铂具有抗癌谱广、作用强、与多种抗肿瘤药有协同作用、且无交叉耐药等特点,为当前联合化疗中最常用的药物之一。用法用量:口服无效。静脉注射或静脉滴注:每次20~30 mg,或20 mg/m2,溶于生理盐水20~30 ml中静脉注射,或溶于5%葡萄糖注射液250~500 ml中静脉滴注。大剂量:80~120 mg/m2,每3周1次,同时注意水化,使患者尿量保持在2000~3000 ml,也可加用甘露醇利尿,以降低肾脏毒性。动脉注射:每次20~30 ml,由插管推注,间隔3周可重复。动脉灌注主要用于头颈部肿瘤。ACC的化学治疗中,顺铂是主要的静脉化疗及动脉化疗药物。近年来,又作为放射增敏剂,在放化疗应用中发挥着重要作用[56] 。
2) 环磷酰胺(环磷氮芥、癌得散、癌得星、安道生、CPM) (cyclophosphamide, cytoxan, endoxan, CTX):为氮芥与磷酰胺基结合而成的化合物,是一种烷化剂,具有细胞毒性和免疫抑制性。在体外无抗肿瘤活性,通过其体内代谢产物而发挥生物学抗肿瘤活性,主要通过肝脏微粒体功能氧化酶所产生的酰胺氮芥发挥作用[57] 。酰胺氮芥对肿瘤细胞有细胞毒作用。骨髓抑制、出血性膀胱炎、脱发和性腺的损害是环磷酰胺主要的毒性作用。环磷酰胺是双功能烷化剂及细胞周期非特异性药物,可干扰DNA及RNA功能,尤以对前者的影响更大,它与DNA发生交叉联结,抑制DNA合成,对S期作用最明显。环磷酰胺现被广泛应用于癌症化疗[57] 。在治疗ACC的化疗方案中,环磷酰胺也是经常用到的药物,如CAP法[46] 、CVF法[48] 等。
3) 阿霉素(羟柔红霉素、羟正定霉素、多柔比星、ADR) (adriamycin, doxorubicin, ADM):是一种抗肿瘤抗生素,可抑制RNA和DNA的合成,对RNA的抑制作用最强,抗瘤谱较广,对多种肿瘤均有作用,属周期非特异性药物,对各种生长周期的肿瘤细胞都有杀灭作用。主要适用于急性白血病,对急性淋巴细胞白血病及粒细胞白血病均有效,一般作为第二线药物,即在首选药物耐药时可考虑应用此药。恶性淋巴瘤,可作为交替使用的首先药物。乳腺癌、肉瘤、肺癌、膀胱癌等其他各种癌症都有一定疗效,多与其他抗癌药联合使用。主要的毒性反应有,白细胞和血小板减少,约60%~80%的病人可发生;100%的病人有不同程度的毛发脱落,停药后可以恢复生长;心脏毒性,表现为心律失常,ST-T改变,多出现在停药后的1~6个月,及早应用维生素B6和辅酶Q10可减低其对心脏的毒性;恶心、食欲减退;药物溢出血管外可引起组织溃疡及坏死。另外,用药后尿液可出现红色。
本品为广谱抗肿瘤药,对机体可产生广泛的生物化学效应,具有强烈的细胞毒性作用。其作用机理主要是本品嵌入DNA而抑制核酸的合成。临床上用于治疗急性淋巴细胞白血病、急性粒细胞性白血病、何杰金和非何杰金淋巴瘤、乳腺癌、肺癌、卵巢癌、软组织肉瘤、成骨肉瘤、横纹肌肉瘤、肾母细胞瘤、神经母细胞瘤、膀胱瘤、甲状腺瘤、绒毛膜上皮癌、前列腺癌、睾丸癌、胃癌、肝癌等。在治疗ACC的化疗方案中,经常用到阿霉素这种药物,如CAP法[46] 、经动脉化疗法[50] [51] 等。
4) 5-氟尿嘧啶(5-fluorouracil, 5-FU):5-FU是第一个根据一定设想而合成的抗代谢抗肿瘤药,为嘧啶类的氟化物,是目前在临床上应用最广的抗嘧啶类药物,对消化道癌及其他实体瘤有良好疗效,在肿瘤内科治疗中占有重要地位。本品需经过酶转化为5-氟脱氧尿嘧啶核苷酸而具有抗肿瘤活性。5-FU通过抑制胸腺嘧啶核苷酸合成酶而抑制DNA的合成[58] -[61] 。此酶的作用可能把甲酰四氢叶酸的一碳单位转移给脱氧尿嘧啶核苷-磷酸合成胸腺嘧啶核苷一酸。5-FU通过抑制该酶,从而阻断脱氧嘧啶核苷酸转换成胸腺嘧啶核苷核。5-FU对RNA的合成也有一定抑制作用。5-FU可以静脉及腔内注射。膀胱癌病人以恒定速率连续滴用5-氟尿嘧啶后发现,药物浓度最低在10时,而在22时~3时之间药物浓度最高。在不用恒速滴药时,将流速峰值定在凌晨4时,则允许极大地提高剂量而毒性极低,疗效因之增强。本品必须在体内经核糖基化和磷酰化等生物转化作用后,才具有细胞毒性。5-FU可经不同途径生成F-dUMP和FUMP。前者可与胸苷酸合成酶的活性中心共价结合,抑制此酶的活性,使脱氧核苷酸缺乏,DNA合成障碍。此外,5-FU的代谢物也可以伪代谢物形式掺入到RNA和DNA中,影响细胞功能,产生细胞毒性。5-FU是一种不典型的细胞周期特异性药,它除了主要作用于S期外,对其他期的细胞亦有作用。
临床用于结肠癌、直肠癌、胃癌、乳腺癌、卵巢癌、绒毛膜上皮癌、恶性葡萄胎、头颈部鳞癌、皮肤癌、肝癌、膀胱癌等。应用5-FU治疗ACC的用药方案有CEF法[47] 、CVF法[48] 等。
5) 长春新碱(vincristine, oncovin, VCR):长春新碱为夹竹桃科植物长春花中提取的有效成分。抗肿瘤作用靶点是微管,主要抑制微管蛋白的聚合而影响纺锤体微管的形成。使有丝分裂停止于中期。还可干扰蛋白质代谢及抑制RNA多聚酶的活力,并抑制细胞膜类脂质的合成和氨基酸在细胞膜上的转运。长春新碱对移植性肿瘤的抑制作用大于长春花碱且抗瘤谱广。除对长春花碱敏感的瘤株有效外,对小鼠Ridgeway成骨肉瘤、Mecca淋巴肉瘤、X-5563骨髓瘤等也有作用。长春新碱、长春花碱和长春地辛三者间无交叉耐药现象,长春新碱神经毒性在三者中最强。长春新碱对培养的人肝癌细胞株(SMMC-7721)有明显的抗癌作用,长春新碱的浓度为100 ng/ml和50 ng/ml时,可使大部分癌细胞变圆。包膜变厚,且脱落成悬浮态。浓度为100 ng/ml和50 ng/ml时可使大部分瘤细胞变圆,胞膜变厚,且脱落呈悬浮状态。长春新碱100 ng/ml浓度作用于细胞于第二天和50 ng/ml于6天起,细胞增殖抑制率就十分明显(抑制率 ≥ 50%),长春新碱100 ng/ml浓度于作用后第8天起,增殖抑制率达99.64%。同时随着VCR浓度的增加,蛋白质含量抑制率增至75.21%。≥25 ng/ml时,其对癌细胞的杀伤率亦随着增加。长春新碱对人视网膜母细胞瘤细胞系HOX-Rb44有较强的抑制作用,半数抑制浓度IC50为0.31 μg/ml,长春新碱浓度达0.01 μg/ml时,可显著诱导K562细胞的凋亡。治疗头颈部ACC用CVF法[48] ,即环磷酰胺、长春新碱和5-氟尿嘧啶联合化疗方案。
药代动力学研究[62] 显示:长春新碱(85 ± 69小时)比长春地辛(24 ± 10小时)或长春花碱(25 ± 7小时)有更长、更可变的终端半衰期。中央室体积也不相同。最重要的发现是观察到它们都有不同的血浆清除率(长春新碱0.106升/公斤/小时,长春地辛0.252升/公斤/小时,长春花碱0.740升/公斤/小时)。
6) 表柔比星(表阿霉素) (epirubicin):表阿霉素属于抗生素类抗肿瘤药。为阿霉素的同分异构体,作用机制是直接嵌入DNA核碱对之间,干扰转录过程,阻止mRNA的形成,从而抑制DNA和RNA的合成,其抗肿瘤作用在细胞周期S期最为活跃。表阿霉素通过静脉注射而起效,经肝脏代谢,主要随胆汁清除,约有10%的药物随尿液排出。消除半衰期是30至40小时。此外,表阿霉素对拓朴异构酶II也有抑制作用。为一细胞周期非特异性药物,对多种移植性肿瘤均有效。临床研究表明,对活性乳腺癌,非霍奇金淋巴瘤,卵巢癌,软组织肉瘤,胰癌有效,对胃癌,小细胞肺癌,急性白血病也有效。单一应用表阿霉素对头颈部肿瘤或非小细胞肺癌效果有限,但与其他药物联合应用或许有益,需要更多的研究来确定其联合化疗的作用。表阿霉素的急性剂量限制性毒性是骨髓抑制,另外,恶心,呕吐和脱发也很常见。与阿霉素相比,疗效相等或略高,但对心脏的毒性较小[63] 。治疗复发的涎腺恶性肿瘤(主要为ACC)可用CEF法[47] ,即顺铂、表柔比星、5-氟尿嘧啶联合化疗方案。
7) 奥沙利铂(oxaliplatin):奥沙利铂在多种肿瘤模型系统,包括在人结直肠癌模型中,都表现出广谱的体外细胞毒性及体内抗肿瘤活性作用。体内、体外试验也证实在顺铂耐药的肿瘤模型中,它仍然有效。在体内和体外研究中,均可观察到奥沙利铂与5-氟尿嘧啶联合应用的协同细胞毒作用。关于奥沙利铂的作用机制,虽然尚未完全清楚,但已有研究表明,奥沙利铂通过产生水化衍生物作用于DNA,形成链内和链间交联,从而抑制DNA的合成,产生细胞毒作用和抗肿瘤活性。近年有用奥沙利铂治疗ACC的报道[49] 。
8) 西妥昔单抗(英文商品名:ERBITUX,中文参考商品译名:爱必妥) (cetuximab):本品可与表达于正常细胞和多种癌细胞表面的EGF受体特异性结合,并竞争性阻断EGF和其他配体,如α转化生长因子(TGF-α)的结合。本品是针对EGF受体的IgG1单克隆抗体,两者特异性结合后,通过对与EGF受体结合的酪氨酸激酶(TK)的抑制作用,阻断细胞内信号转导途径,从而抑制癌细胞的增殖,诱导癌细胞的凋亡,减少基质金属蛋白酶和血管内皮生长因子的产生。有报道用奥沙利铂联合西妥昔单抗治疗食管小涎腺ACC有效[49] 。
9) 卡铂(碳铂,卡波铂,铂尔定) (carboplatin, CBP):1980年由Clear等发现,1986年首先在英国上市,美国FDA 1989年批准上市,应用逐渐推广。我国1990年批准生产卡铂粉、针剂。
本品为第二代铂类化合物,其生化特征与顺铂相似,但肾毒性、耳毒性、神经毒性尤其是胃肠道反应明显低于DDP,是近年来广泛受到重视的新药,与DDP一样同属细胞周期非特异性药物。它主要作用DNA的鸟嘌呤的N7和O6原子上,引起DNA链间及链内交联,破坏DNA分子,阻止其螺旋解链,干扰DNA合成,而产生细胞毒作用。
本品口服无效,静脉注射后血浆中总铂以及可超虑的游离铂浓度与课题量之间均存在线性关系,可超滤的非结合型铂和母体药物的终末消除半衰期分别为6小时和1.5小时。在初始相,大多数可超滤的游离铂以原形存在,血浆总铂的终末半衰期是24小时,约87%的血浆铂在给药24小时排出。主要从尿中排出,24小时内经肾小球过滤排泄。
卡铂的药动学和顺铂有三点不同:一是血清蛋白结合率,卡铂仅24%,而顺铂在90%以上;二是可超滤的非结合型铂半衰期,卡铂为6小时,而顺铂很短,血中浓度迅速降低,三是尿排泄量,一日中尿排泄量,卡铂为6.5%,而顺铂为16%~35%,因此二者的肾脏毒性有明显差异。
本药为广谱抗肿瘤药,与其他抗肿瘤药无交叉耐药性,与DDP有交叉耐药性,该药易于溶解,不需水化、利水化、利尿,使用方便。(1) 主要用于小细胞肺癌、卵巢癌、睾丸肿瘤、头颈部鳞癌等。小细胞肺癌,单用本品缓解率为60%;与Vp-16、IFO合用治疗的总缓解率为78%;卵巢上皮癌、头颈部鳞癌单用缓解率分别为65%、29%。(2) 可用于非小细胞肺癌、膀胱癌、子宫颈癌、胸膜间皮瘤、黑色素瘤及子宫内膜癌等。(3) 也可用于消化系统肿瘤、肝癌等及放射增效治疗。在治疗涎腺恶性肿瘤的临床Ⅱ期实验中,有报道用顺铂或卡铂+吉西他滨[45] 进行治疗,结果有待进一步观察。
10) 吉西他滨(2,2-二氟脱氧胞嘧啶核苷,商品名称:泽菲、誉捷等) (gemcitabine, 2',2'-difluoro 2'-deoxycytidine, dFdC):是一种重要的细胞毒性胞苷类似物,属细胞周期特异性抗肿瘤药。主要杀伤处于S期(DNA合成)的细胞,同时也阻断细胞增殖由G1向S期过渡的进程。尽管结构和药理与阿糖胞苷类似,但吉西他滨在细胞药理、代谢和作用机制方面,自有特色。在细胞内由核苷激酶代谢成有活性的二磷酸核苷(nucleotides gemcitabine diphosphate, dFdCDP)和三磷酸核苷(nucleotides gemcitabine triphosphate, dFdCTP)。其细胞毒活性就来源于这两种核苷抑制DNA合成的联合作用。dFdCDP是一种核糖核苷酸还原酶的抑制剂,从而抑制该酶催化DNA合成过程中生成三磷酸脱氧核苷的化学反应,进而导致脱氧核苷酸的浓度降低,影响DNA合成。吉西他滨现被广泛应用于对恶性肿瘤的治疗[64] [65] 。在ACC的化学治疗研究中,吉西他滨的研究报道还不多。有学者用顺铂或卡铂(carboplatin) + 吉西他滨[45] ,在进行治疗涎腺恶性肿瘤的临床Ⅱ期实验,结果有待观察。但2008年,有学者[66] 报道吉西他滨对ACC治疗不敏感。
11) 多西紫杉醇(泰索帝) (docetaxel, taxotere):是一种强力抗肿瘤剂,可促进微管聚合,抑制微管蛋白解聚,导致细胞无法复制。多西紫杉醇呈现出体外和体内广泛的抗肿瘤活性。II期临床试验表明对晚期乳腺癌,包括对抗蒽环类药物的肿瘤有较高的抗肿瘤活性,对晚期非小细胞肺癌、卵巢癌、头颈部肿瘤、胰癌具有明显抗肿瘤活性,对其他肿瘤具有潜在抗肿瘤活性。推荐的给药方案为100 mg/m2,静脉注射超过一小时,每三周为一疗程,重复治疗方案。最常见的血液学副作用是中性粒细胞减少。大多数非血液学副作用一般是轻微到中度。皮肤科副作用发生频繁,常发生液体潴留。术前用皮质类固醇可预防明显的高敏反应,并可明显改善皮肤反应和液体潴留。多西紫杉醇作为单一化疗药物及作为联合化疗药物中的一种,正在进行II/III期临床试验方案的集中评估,应证明其对相当数量的肿瘤都有临床有效性。对ACC的治疗也在尝试其有效性[53] [67] 。
12) 三氧化二砷(砒霜、无水砷酸、砒、白砒、亚砷酸酐) (arsenic trioxide, As2O3):是最具商业价值的砷化合物及主要的砷化学开始物料。它也是最古老的毒物之一,无臭无味,外观为白色霜状粉末,故称砒霜。这是经某几种指定的矿物处理过程所产生的高毒性副产品,例如采金矿、高温蒸馏砷黄铁矿(毒砂)并冷凝其白烟等。
主要用途:用于提炼元素砷,是冶炼砷合金和制造半导体的原料。玻璃工业用作澄清剂和脱色剂,以增强玻璃制品透光性。皮革工业用以制亚砷酸钠作皮革保藏剂。农业上用作防治病虫害的杀虫剂,消毒剂和除锈剂,也用作其他含砷杀虫农药的原料。也用于涂料和颜料工业。可作化学试剂。还用于气体脱硫、木材防腐、锅炉防垢以及玻璃和搪瓷等方面。医学方面,三氧化二砷作为抗肿瘤药物,在治疗急性早幼粒细胞白血病方面[68] -[72] 已较为成熟,尤其对于复发病例[68] -[70] 。另外,还可用于肝癌[73] 、肺癌[74] 、胰腺癌[75] 、结肠癌[76] 、乳腺癌[77] 、宫颈癌[78] 、淋巴瘤[79] [80] 等的治疗。放化疗时应用有增加放疗敏感性提高化疗疗效作用。可用于介入治疗及术中动脉灌注。对于ACC的治疗目前仅限于实验室的研究中[81] 。
基金项目
山东省自然科学基金资助项目(No. ZR2012HM062)。
文章引用
姜 涛,姜 靖,王仁萍,肖利华,王 毅. 腺样囊性癌的化学治疗
Chemotherapy for the Treatment of Adenoid Cystic Carcinoma[J]. 眼科学, 2015, 04(03): 57-68. http://dx.doi.org/10.12677/HJO.2015.43011
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