CN117797164A - 一种防治肿瘤的药物及其用途 - Google Patents
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Abstract
本发明公开了一种防治肿瘤的药物,特别涉及O6‑甲基‑2‑脱氧鸟苷‑5‑三磷酸(O6‑Methyl‑dGTP)在制备预防和/或治疗肿瘤的药物中的用途及含有O6‑Methyl‑dGTP的防治肿瘤的药物,属于制药领域。O6‑甲基‑2‑脱氧鸟苷‑5‑三磷酸(O6‑Methyl‑dGTP)在制备治疗、预防和/或控制肿瘤的药物中的用途。本发明意外地发现O6‑甲基‑2‑脱氧鸟苷‑5‑三磷酸(O6‑Methyl‑dGTP)对于多种肿瘤具有显著抑制增殖、促进凋亡的作用,为肿瘤的预防和治疗提供了一种全新的候选药物。动物实验显示O6‑甲基‑2‑脱氧鸟苷‑5‑三磷酸(O6‑Methyl‑dGTP)具有明显的抑制肿瘤效果,因此具备很强的工业实用性和巨大的商业价值和社会价值。
Description
技术领域
本发明涉及一种防治肿瘤的药物,特别涉及O6-甲基-2-脱氧鸟苷-5-三磷酸(O6-Methyl-dGTP)在制备治疗、预防和/或控制肿瘤的药物中的用途,及含有O6-Methyl-dGTP的防治肿瘤的药物,属于制药领域。
背景技术
当前,化疗仍是癌症治疗的主要手段。在众多化疗药物中,烷化剂是应用最早,也是目前应用广泛的抗癌药。当前认为烷化剂抗肿瘤机制为:烷化剂自发进行分解或经酶水解后生成具有活性的亲电子试剂,攻击DNA等大分子,产生大量烷基化DNA加合产物,相比于其它产物,占修饰量8%的O6-甲基鸟嘌呤(O6meG)足以导致细胞死亡,发挥抗肿瘤的细胞毒性作用。
虽然目前有关烷化剂的研究集中在DNA链上O6-MedG造成的损伤及后续的细胞毒性,但值得注意的是,与存在于DNA链中的核苷酸相比,游离核苷酸对烷基化损伤的敏感性高约190~13000倍。Helleday团队将O6-methyl-dGTP显微注射进斑马鱼胚胎中,DNA链上O6-methyl-dG的含量明显增加,在MTH1抑制剂和/或MGMT抑制剂存在情况下可对胚胎产生毒性。但O6-methyl-dGTP对肿瘤细胞的作用如何,尚无报道。
癌症已成为全球第二大死亡原因。尽管各种新型治疗手段层出不穷,例如分子靶向治疗、免疫治疗等,但是由于受到特定肿瘤类型和治疗费用的限制,化疗仍是癌症治疗的主要手段。在众多化疗药物中,烷化剂是应用最早,也是目前应用广泛的抗癌药物。烷化剂干预细胞或机体后可产生大量烷基化DNA加合产物,相比于其它产物,占修饰量8%的O6-甲基鸟嘌呤(O6meG)足以导致细胞死亡。DNA链上O6MeG可与T配对,诱导G:C到A:T的突变,当DNA错配修复(mismatch repair,MMR)切除O6MeG时,会产生无效错配修复循环,在DNA中产生单链和双链断裂,如果无法进一步修复,则会导致凋亡途径激活,导致细胞死亡。机体存在多种烷基化DNA损伤修复机制,其中甲基鸟嘌呤甲基转移酶(MGMT)可以将DNA中的甲基从鸟嘌呤的6位转移到其活性位点的半胱氨酸残基上,之后自身被降解。因此细胞或组织MGMT的表达量与烷化剂的临床治疗效果密切相关,若机体MGMT表达量较高,则会对烷化剂的治疗产生一定程度的耐药。因此探究烷化剂不同作用机制和耐药机制、探索新型化疗药物迫在眉睫。
基于我们之前的研究,虽然当前有关烷化剂的研究集中在DNA链上O6-MedG造成的损伤及后续的细胞毒性,但值得注意的是,与存在于DNA链中的核苷酸相比,游离核苷酸对烷基化损伤的敏感性高约190~13000倍。因此我们认为烷化剂可通过产生O6-Methyl-dGTP发挥作用。
目前O6-Methyl-dGTP干预细胞和动物的研究较少。仅有Helleday团队将O6-Methyl-dGTP显微注射进斑马鱼胚胎中发现DNA链上O6-Methyl-dG的含量明显增加,在MTH1抑制剂和/或MGMT抑制剂存在情况下可对胚胎产生毒性。但O6-Methyl-dGTP对肿瘤细胞和实验动物的作用如何,尚无报道。因此我们制备了O6-Methyl-dGTP药物,并将其干预多种肿瘤细胞以及荷瘤裸鼠和小鼠,发现O6-Methyl-dGTP可明显降低肿瘤细胞活力,抑制细胞增殖和荷瘤裸鼠、小鼠肿瘤生长,促进凋亡且效果不受MGMT表达水平的影响。因此O6-Methyl-dGTP优于烷化剂,具备很强的药用价值和社会价值。
发明内容
本发明要解决的技术问题是:提供一种防治肿瘤的药物及其用途。
为实现上述目的,本发明采用以下技术方案。
O6-甲基-2-脱氧鸟苷-5-三磷酸(O6-Methyl-dGTP)在制备治疗、预防和/或控制肿瘤的药物中的用途。
所述治疗、预防和/或控制肿瘤是指抑制肿瘤细胞增殖、预防肿瘤的发生、或促进肿瘤细胞死亡中的一种用途或几种用途。
优选的,所述肿瘤为实体瘤和血液肿瘤。
优选的,所述肿瘤包括神经系统肿瘤、头颈癌、鼻咽癌、口腔癌、甲状腺癌、乳腺癌、宫颈癌、子宫内膜癌、卵巢癌、肺癌、食道癌、胃癌、结直肠癌,肝癌、胰腺癌、膀胱癌、肾癌、睾丸癌、前列腺癌、骨肿瘤、血液系统肿瘤、淋巴瘤;晚期恶性肿瘤、不可切除恶性肿瘤、转移性恶性肿瘤等。
一种治疗、预防和/或控制肿瘤的药物,含有O6-甲基-2-脱氧鸟苷-5-三磷酸(O6-Methyl-dGTP)。
所述药物还含有生物体可接受的辅料或载体。
所述药物为口服给药制剂、注射的胃肠外给药制剂、鼻腔粘膜给药制剂、经皮给药制剂、直肠给药制剂、或贮库制剂。
所述口服给药制剂为片剂、胶囊、扁胶囊、软胶囊、溶液或混悬液;注射的胃肠外给药制剂为快速静脉注射制剂或持续输注制剂;鼻腔粘膜给药制剂为气雾剂、喷雾剂、薄雾剂或液滴剂;所述经皮给药制剂为凝胶剂、软膏剂、缓释经皮给药制剂、脂质体制剂、透皮贴片或透皮喷雾制剂;直肠给药制剂为栓剂或滞留灌肠剂;贮库制剂为皮下或肌肉植入给药制剂或肌内注射给药制剂。
一种治疗、预防和/或控制肿瘤的方法,该方法包括给予哺乳动物治疗有效量的O6-甲基-2-脱氧鸟苷-5-三磷酸(O6-Methyl-dGTP)。
所述治疗有效剂量为5μg-2000μg/kg体重,优选200-1000μg/kg体重。
所述肿瘤包括神经系统肿瘤、头颈癌、鼻咽癌、口腔癌、甲状腺癌、乳腺癌、宫颈癌、子宫内膜癌、卵巢癌、肺癌、食道癌、胃癌、结直肠癌,肝癌、胰腺癌、膀胱癌、肾癌、睾丸癌、前列腺癌、骨肿瘤、血液系统肿瘤、淋巴瘤;晚期恶性肿瘤、不可切除恶性肿瘤、转移性恶性肿瘤等。
本发明的优点如下:
本发明意外发现O6-Methyl-dGTP可显著抑制多种移植瘤裸鼠肿瘤的生长,抑制肿瘤细胞的增殖,为肿瘤的与预防和治疗提供了一种全新的候选药物。另O6-Methyl-dGTP化学合成方式已标准化,因此具备很强的临床应用前景和社会价值。
附图说明
下面结合附图对本发明的具体实施方式作进一步详细的说明。
图1示出O6-Methyl-dGTP干预不同来源细胞后细胞活力变化
图2示出O6-Methyl-dGTP干预不同胶质瘤细胞后细胞活力变化
图3示出敲减MGMT后检测O6-Methyl-dGTP对Hela细胞活力的影响
图4示出O6-Methyl-dGTP阻滞细胞周期进展
图5示出O6-Methyl-dGTP干预肿瘤细胞后细胞凋亡增加
图6A示出O6-Methyl-dGTP抑制CT26移植瘤裸鼠瘤块生长
图6B示出O6-Methyl-dGTP和替莫唑胺抑制U251异种移植瘤裸鼠瘤块生长
图6C示出O6-Methyl-dGTP抑制Ln229异种移植瘤裸鼠瘤块生长
图7示出不同浓度8-oxodGTP和O6-Methyl-dGTP干预U251细胞24h后细胞活力变化
具体实施方式
实施例1:含有O6-Methyl-dGTP的药物
一、实验材料
1、活性成分:O6-甲基-2-脱氧鸟苷-5-三磷酸(O6-Methyl-dGTP),委托天津药明康德新药开发有限公司合成。
2、药物载体:Engreen Biosystem Co,Ltd.公司(英格恩生物公司)的EntransterTM-in Vivo试剂,Cat.No.18668-11,Size:1ml,购于北京英格恩生物科技有限公司;Thermo Fisher Scientific公司的LipofectamineTM 3000转染试剂,Cat.L3000001,Size:1.5mL,购于北京华生健生物技术有限公司。
二、制法
按两种药物载体的使用手册操作,将活性成分与药物载体配置成转染复合物,其中活性成分O6-甲基-2-脱氧鸟苷-5-三磷酸(O6-Methyl-dGTP)的浓度为0.5μg/μl,即得本发明药物。
实施例2:肿瘤防治细胞实验
一、实验材料
1、实验试剂:
(1)O6-Methyl-dGTP注射剂:实施例1得到的药物
(2)空白载体试剂:Thermo Fisher Scientific公司的LipofectamineTM 3000转染试剂,按实施例1方法配制,并以Opti-M取代O6-甲基-2-脱氧鸟苷-5-三磷酸(O6-Methyl-dGTP),即为不含活性成分的载体溶液。
(3)细胞活力检测试剂:Promege公司的CellTiter-Luminescent CellViability Assay试剂,Cat.G7571,Size:10×10ml,购于北京照生莱博商贸有限公司;按照说明书将试剂混合均匀即得到细胞活力检测试剂。
(4)细胞凋亡检测试剂:碧云天生物技术公司的Annexin V-FITC细胞凋亡检测试剂盒,Cat:C1062M,购于北京百诺威生物科技有限公司。
(5)细胞周期检测试剂:碧云天生物技术公司的细胞周期与细胞凋亡检测试剂盒,Cat:C1052,购于北京百诺威生物科技有限公司。
2、实验细胞:
A549、HCT116购于ATCC;MCF7、SW480、HepG2、U251购于北京协和细胞资源中心、LN229和U87MG购于北京欣生科科技有限公司。
二、实验方法
1、检测O6-Methyl-dGTP对肿瘤细胞活力的影响
取5×103细胞铺于96孔板,贴壁生长24小时后,使用LipofectamineTM 3000转染不同浓度O6-Methyl-dGTP至肿瘤细胞内,继续培养48小时。将细胞培养板在室温放置30分钟,100μl细胞培养基中加入100μl细胞活力检测试剂,在定轨振荡器上将内容物混合2分钟以诱导细胞裂解,而后将培养板在室温孵育10分钟,以稳定发光信号,上机检测,记录信号值。
2、流式细胞术检测O6-Methyl-dGTP对肿瘤细胞周期的作用
将1×105细胞铺于24孔板,贴壁生长24小时后,使用LipofectamineTM 3000转染不同浓度O6-Methyl-dGTP至肿瘤细胞内,继续培养48小时。收集细胞,加入约1毫升冰浴预冷的PBS,重悬细胞,并转移到1.5毫升离心管内。再次离心沉淀细胞,小心吸除上清,加入1毫升冰浴预冷70%乙醇,轻轻吹打混匀,4℃固定2小时后,进行碘化丙啶染色,最后使用流式细胞仪上机检测。
3、流式细胞术检测O6-Methyl-dGTP对肿瘤细胞凋亡的影响
将1×105细胞铺于24孔板,贴壁生长24小时后,使用LipofectamineTM3000转染不同浓度O6-Methyl-dGTP至肿瘤细胞内,继续培养48小时。收集细胞,用PBS轻轻重悬细胞并计数,取5-10万重悬的细胞,1000g离心5分钟,弃上清,加入195μl AnnexinV-FITC结合液轻轻重悬细胞,加入5μl Annexin V-FITC后加入10μl碘化丙啶染色液,轻轻混匀。室温避光孵育10-20分钟,立即上机检测。
三、实验结果
1、O6-Methyl-dGTP抑制肿瘤细胞生长
如图1和图2所示,不同浓度O6-Methyl-dGTP干预不同类型肿瘤细胞48小时后,细胞活力显著下降,且具有剂量依赖性,效果最明显者在200μM O6-Methyl-dGTP干预后可达到近90%的抑制率。
2、O6-Methyl-dGTP对肿瘤细胞的作用与MGMT表达量无关
如图3所示,MGMT表达量的高低几乎不改变O6-Methyl-dGTP对肿瘤细胞活力的影响。
3、O6-Methyl-dGTP阻滞肿瘤细胞周期进展
如图4所示,不同浓度O6-Methyl-dGTP干预U251细胞48小时后,细胞周期阻滞在S期,其中0.2mM O6-Methyl-dGTP干预后S期细胞所占比例比对照组增加近一倍。
4、O6-Methyl-dGTP诱导肿瘤细胞凋亡
如图5所示,不同浓度O6-Methyl-dGTP干预U251细胞48小时后,细胞凋亡增加,0.2mM O6-Methyl-dGTP组相比于对照组凋亡细胞增加2倍多,2mM O6-Methyl-dGTP组凋亡细胞所占比例为对照组的6倍多,由此可见O6-Methyl-dGTP可诱导肿瘤细胞凋亡。
实施例3:肿瘤防治动物实验
一、实验材料
1、实验试剂:
(1)O6-Methyl-dGTP注射剂:实施例1得到的药物
(2)空白载体试剂:Engreen Biosystem Co,Ltd.公司(英格恩生物公司)的EntransterTM-in Vivo试剂,按实施例1方法配制,并以纯水取代O6-甲基-2-脱氧鸟苷-5-三磷酸(O6-Methyl-dGTP),即为不含活性成分的载体溶液。
2、实验动物:
Balb/c雄性裸鼠和小鼠,17-19g,6weeks,购于北京维通利华实验动物技术有限公司。
实验涉及的所有小鼠均按照无特定病原(SPF)级动物饲养标准饲养室内温度控制在20-26℃,湿度50%-60%,照明采取12h昼夜交替的方式。小鼠的饲料为灭菌后的标准饮食,自由摄食和饮水。
3、实验细胞:
CT26细胞、LN229细胞购于ATCC,U251细胞购于北京协和细胞资源中心。
二、实验方法
裸鼠肿瘤接种,注射给药及解剖
1.将1x106 CT26细胞(200μl)细胞接种至小鼠腋背部皮下,在瘤块长到一定大小后,将瘤块二次接种至21只小鼠皮下,随机分为正常饲养组,空白载体对照组,O6-Methyl-dGTP组,在二次接种后第二天对小鼠进行尾静脉给药。O6-Methyl-dGTP组的给药剂量为2.5mg/kg/次,载体对照组注射等体积的空白载体试剂。在D0、1、2、4、6、8、10、12注射,共注射8次,注射完毕后取瘤块、称瘤重,计算抑制率(抑制率=(1-T实验组/C对照组)×100%)
2.将1x107 U251细胞(200μl)细胞接种到裸鼠腋背部皮下,在瘤块长到一定大小后,将瘤块二次接种,待生长至一定大小后,再一次接种,再生长到一定大小后,将瘤块接种至18只裸鼠侧腹皮下,待肿瘤大小大于3×2mm后,随机分为空白载体对照组,O6-Methyl-dGTP组和TMZ组,并开始隔两天经尾静脉给药,O6-Methyl-dGTP和TMZ组的给药剂量为2.5mg/kg/次,载体对照组注射等体积的空白载体试剂。在D0、3、6、9、12、15注射,共注射6次,注射完毕后取瘤块、称重,计算抑制率(抑制率=(1-T实验组/C对照组)×100%)
3.将5×106Ln229(200μl)细胞接种至裸鼠腋背部皮下,在瘤块长到一定大小后,将瘤块二次接种至12只裸鼠皮下,待肿瘤大小大于3×2mm后,随机分为空白载体对照组,O6-Methyl-dGTP组,对裸鼠进行尾静脉给药。O6-Methyl-dGTP组的给药剂量为2.5mg/kg/次,载体对照组注射等体积的空白载体试剂。在D0、2、4、6、8注射,共注射5次,注射完毕后取瘤块、称瘤重,计算抑制率(抑制率=(1-T实验组/C对照组)×100%)
三、实验结果
O6-Methyl-dGTP抑制裸鼠和小鼠瘤块生长
如表1、2、3与图6A、图6B、图6C所示,相比于载体对照组,O6-Methyl-dGTP对CT26、U251、Ln229源异种移植瘤抑制率分别为41.32%、68.77%、50.15%。
表1.CT26小鼠瘤重及抑制率
表2.U251裸鼠瘤重及抑制率
组别 | 瘤重(mg) | 抑制率 |
载体对照组 | 214±140.43 | 0% |
O6-Methyl-dGTP组 | 66.83±36.01 | 68.77% |
TMZ | 80.83±24.90 | 62.22% |
表3.Ln229裸鼠瘤重及抑制率
组别 | 瘤重(mg) | 抑制率 |
载体对照组 | 284.5±93.61 | 0% |
O6-Methyl-dGTP组 | 141.83±80.05 | 50.15% |
四、实验结论
细胞实验和动物实验结果显示,给与O6-Methyl-dGTP干预肿瘤后,细胞生长受到抑制,凋亡增加,裸鼠和小鼠肿瘤生长减慢,这表明O6-Methyl-dGTP有抑制肿瘤增殖和促进肿瘤细胞凋亡的作用。
实施例4.对比实验
8-oxodGTP和O6methyl-dGTP是不同的两种小分子,最主要的不同点是碱基修饰位点不同,导致的突变类型不同,涉及的核酸损伤修复酶和修复机制不同,作为肿瘤抑制药物作用效果不同。
1.碱基修饰位点不同
8-oxodGTP由鸟嘌呤C8位氧化生成,而O6methyl-dGTP由鸟嘌呤O6位甲基化生成。
(1)8-oxodGTP结构式如下:
(2)O6methyl-dGTP结构式如下:
2.导致的突变类型不同
8-oxodGTP可由DNA聚合酶λ掺入与模板上的腺苷dA配对,其掺入至dA与dC对面的效率相同,导致A:T到C:G和G:C到T:A的突变,而O6methyl-dGTP可掺入到DNA链上与dT配对,导致G:C到A:T的突变,且配对dT的偏好性是配对dC的20倍。
3.涉及的核酸损伤修复酶和修复机制不同
8-oxodGTP掺入DNA链后与腺嘌呤A和胞嘧啶C碱基配对,人类8-羟基鸟嘌呤DNA糖苷酶1(human 8-oxoguanine DNA glycosylase1,OGG1)优先识别并切除与C配对的8-oxoG,启动碱基切除修复(BER)。哺乳动物MutY同源物(MUTYH)切除与8-oxoG错配的A,而之后若C掺入8-oxoG对侧,OGG1可继续去除与C配对的8-oxoG,从而产生无效碱基切除修复,导致链断裂。
而O6methyl-dGTP掺入DNA链后可被O6-甲基鸟嘌呤DNA甲基转移酶(MGMT)切除,若未被修复,O6meG:T可被错配修复系统识别,将T从新生链中移除,在下一个周期中,若O6meG再次与T配对,可产生无效错配修复循环,导致DNA链断裂。
4.作用效果不同
分别使用0.05、0.1、0.2、2mM 8-oxodGTP和O6methyl-dGTP干预U251细胞24h后,使用CellTiter-Luminescent Cell Viability Assay(Promega,G7571)试剂盒检测细胞活力变化。
实验方法如下:
将5×103细胞铺于96孔板,贴壁生长24小时后,使用LipofectamineTM 3000转染不同浓度8-oxodGTP和O6-Methyl-dGTP至U251细胞内,继续培养24小时。将CellTiter-Luminescent Cell Viability Assay(CTG)试剂A与B混合,取出96孔板置于室温下平衡30分钟后每孔加入100uL CTG试剂,置于振荡器上震荡2分钟,避光平衡10分钟后上机检测。(CTG试剂购于Promega,货号G7571)
结果见图7所示。可发现相同浓度干预相同时间后,O6methyl-dGTP对U251细胞的抑制效果明显优于8-oxodGTP。
上文所列出的一系列的详细说明仅仅是针对本发明的可行性实施方式的具体说明,它们并非用以限制本发明的保护范围,本领域技术人员可以设计出很多其他的修改和实施方式,这些修改和实施方式将落在本申请公开的原则范围和精神之内。更具体地说,在本申请公开、附图和权利要求的范围内,可以对主题组合布局的组成部件和/或布局进行多种变型和改进。除了对组成部件和/或布局进行的变型和改进外,对于本领域技术人员来说,其他的用途也将是明显的。
Claims (11)
1.O6-甲基-2-脱氧鸟苷-5-三磷酸(O6-Methyl-dGTP)在制备治疗、预防和/或控制肿瘤的药物中的用途。
2.根据权利要求1所述的用途,其特征在于:所述治疗、预防和/或控制肿瘤是指抑制肿瘤细胞增殖、预防肿瘤的发生、或促进肿瘤细胞死亡中的一种用途或几种用途。
3.根据权利要求1或2所述的用途,其特征在于:所述肿瘤为实体瘤和血液肿瘤。
4.根据权利要求3所述的用途,其特征在于:所述肿瘤包括神经系统肿瘤、头颈癌、鼻咽癌、口腔癌、甲状腺癌、乳腺癌、宫颈癌、子宫内膜癌、卵巢癌、肺癌、食道癌、胃癌、结直肠癌,肝癌、胰腺癌、膀胱癌、肾癌、睾丸癌、前列腺癌、骨肿瘤、血液系统肿瘤、淋巴瘤;晚期恶性肿瘤、不可切除恶性肿瘤、转移性恶性肿瘤等。
5.一种治疗、预防和/或控制肿瘤的药物,其特征在于:含有O6-甲基-2-脱氧鸟苷-5-三磷酸(O6-Methyl-dGTP)。
6.根据权利要求5所述的治疗、预防和/或控制肿瘤的药物,其特征在于:所述药物还含有生物体可接受的辅料或载体。
7.根据权利要求5或6所述的治疗、预防和/或控制肿瘤的药物,其特征在于:所述药物为口服给药制剂、注射的胃肠外给药制剂、鼻腔粘膜给药制剂、经皮给药制剂、直肠给药制剂、或贮库制剂。
8.根据权利要求7所述的治疗、预防和/或控制肿瘤的药物,其特征在于:所述口服给药制剂为片剂、胶囊、扁胶囊、软胶囊、溶液或混悬液;注射的胃肠外给药制剂为快速静脉注射制剂或持续输注制剂;鼻腔粘膜给药制剂为气雾剂、喷雾剂、薄雾剂或液滴剂;所述经皮给药制剂为凝胶剂、软膏剂、缓释经皮给药制剂、脂质体制剂、透皮贴片或透皮喷雾制剂;直肠给药制剂为栓剂或滞留灌肠剂;贮库制剂为皮下或肌肉植入给药制剂或肌内注射给药制剂。
9.一种治疗、预防和/或控制肿瘤的方法,该方法包括给予哺乳动物治疗有效量的O6-甲基-2-脱氧鸟苷-5-三磷酸(O6-Methyl-dGTP)。
10.根据权利要求9所述的治疗、预防和/或控制肿瘤的方法,其特征在于:所述治疗有效剂量为5μg-2000μg/kg体重,优选200-1000μg/kg体重。
11.根据权利要求9或10所述的治疗、预防和/或控制肿瘤的方法,其特征在于:所述肿瘤包括神经系统肿瘤、头颈癌、鼻咽癌、口腔癌、甲状腺癌、乳腺癌、宫颈癌、子宫内膜癌、卵巢癌、肺癌、食道癌、胃癌、结直肠癌,肝癌、胰腺癌、膀胱癌、肾癌、睾丸癌、前列腺癌、骨肿瘤、血液系统肿瘤、淋巴瘤;晚期恶性肿瘤、不可切除恶性肿瘤、转移性恶性肿瘤等。
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