CN106573036A - 用于改善化学治疗所造成的不良副作用的组合疗法 - Google Patents
用于改善化学治疗所造成的不良副作用的组合疗法 Download PDFInfo
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- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
本发明大致上关于同时地、同期地或依序地用于治疗疾病、尤其是用于治疗增生性疾病、更尤其是用于治疗一或多种癌症的免疫调节蛋白与化学治疗用药剂。本发明还关于由真菌免疫调节蛋白(FIP)与化学治疗用药剂所构成的组合,以及关于其医药与生技用途,特别是在治疗疾病、尤其是在治疗增生性疾病,更尤其是在治疗一或多种癌症的领域上的医药与生技用途。
Description
优选权请求
本申请要求于2014年3月13日递交的申请号为61/952,311的美国专利申请的优先权,其全文通过引用的方式并入本文。
技术领域
本发明关于同时地、同期地或依序地用于治疗疾病、尤其是用于治疗增生性疾病、更尤其是用于治疗一或多种癌症的真菌免疫调节蛋白(FIP)与化学治疗用药剂。本发明还关于由FIP与化学治疗用药剂所构成的组合,以及关于其医药与生技用途,特别是在治疗疾病、尤其是在治疗增生性疾病,更尤其是在治疗一或多种癌症的领域上的医药与生技用途。本发明另关于保护一个体免于疾病、尤其是增生性疾病、更尤其是一或多种癌症的化学治疗所造成的不良副作用的方法与组成物。
背景技术
灵芝属植物(Ganoderma)是稀有且珍贵的中药材,在中国泛称为“灵芝”超过5000年。各种各样的灵芝属植物包括:赤芝(G.lucidum;红色)、树舌灵芝(G.applanatum;棕色)、松杉灵芝(G.tsugae;红褐色)、甜芝(G.sinense;黑色)及俄勒冈灵芝(G.oregonense;深棕色)。
已经知道灵芝有抗过敏(Chen H.Y et al.,J.Med.Mycol.1992;33:505-512)、保肝(Lin J.M.et al.,Am J Chin Med.1993;21(1):59-69)、抗癌(Wasser SP,Crit RevImmunol 1999.19:65-96)与增加免疫力等功能(Kino,J Biol.Chem.1989.264(1):472-8)。然而,灵芝在利用上,都是以粗萃物(Homer W.E.et al.,Allergy 1993;48:110-116)或是小分子萃出物(Kawagishi H.,et al.,Phytochemistry 1993;32:239-241)的形式呈现。
数种源自于例如赤芝(Ganoderma lucidum)、草菇(Volvariella volvacea)、金针菇(Flammulina velutipes)等可食性菌类的蛋白质具有相似的胺基酸序列和免疫调节功能。这些蛋白质被命名为真菌免疫调节蛋白(FIPs,Ko J.L.,Eur.J.Biochem.1995;228:224-249)。
1989年,Kino等人由赤芝中发现命名为Ling Zhi-8(LZ-8)的蛋白(Kino K.etal.,J.Biol.Chem.1989;264(1):472-8)。LZ-8对全身性过敏反应(Anaphylaxis)有疗效,可以用于治疗肝癌,与预防糖尿病。LZ-8以及从金针菇(Flammulina velutipes)中发现的真菌免疫调节蛋白FIP-fve具有与免疫球蛋白重链相似的胺基酸序列与二级结构;再者,实验显示,增强LZ-8的表现对于患有全身系统性过敏反应的病人有很好的疗效(Ko J.L.,Eur.J.Biochem.1995;228:224-249)。进一步研究指出,FIP可以活化人类外围血液单核淋巴球(HPBMCs,human peripheral blood mononuclear cells),并且促进HPBMCs与老鼠脾细胞的增生(van der Hem,et al.,Transplantation,1995;60,438-443)。利用氚标定胸腺嘧啶核苷(3H-thymidine)分析FIP-gts对细胞增生的效应时进一步发现,5μg/ml的FIP-gts或是100μg/ml的FIP-fve相较于植物凝集素(PHA,phytoagglutinin)足以让人类淋巴球达到最大增生速率(Hsu,C.,同上)。于非-B与非-T两群细胞,研究发现FIP-gts只能促进非-B细胞的增生。
与植物凝集素和其它凝集素类细胞分裂激素(lectin mitogen)相似,LZ-8会促进细胞分裂。LZ-8主要是在单核球细胞的帮助下使T-细胞增生。一种新的真菌免疫调节蛋白(FIPs)家族最近已经被鉴定出来(Ko JL et al.Eur J Biochem 1995;228(2):244-249)。从赤芝(Ganoderma lucidum)、金针菇(Flammulina veltipes)、草菇(Volvariellavolvacea)、松杉灵芝(Ganoderma tsugae)、紫芝(Ganoderma japoncium)、小孢子灵芝(Ganoderma microsporum)、甜芝(Ganoderma sinense)、红球丛赤壳菌(Nectriahaematococca)、银耳(Tremella fuciformis)、樟芝(Antrodia camphorate)中已经鉴定并单离出至少10种FIPs,而且分别命名为LZ-8(也被称为FIP-glu)、FIP-fve、FIP-vvo、FIP-gts、FIP-gja(GenBank:AY987805)、FIP-gmi、FIP-gsi、FIP-nha、FIP-tfu(GenBank:EF152774)和FIP-aca(Hsu H C,et al.,Biochem J 1997;323(Pt 2):557-565;Kong etal.,Int.J.Mol.Sci.2013;14:2230-2241;Han et al.,J Appl Microbiol 2010,109:1838-44;美国专利第7,531,627号;以及中国专利第102241751B号)。FIPs于活体外对于人类周边血液淋巴细胞(hPBLs)和老鼠脾细胞来说是促进有丝分裂物质。他们所引起的钟形剂量反应曲线与凝集素类细胞分裂激素类似。hPBLs受到FIPs所活化导致了IL-2、IFN-γ及肿瘤坏死因子-α等分子的产量增加,并且与ICAM-1的表现相关(Wang P H,et al.,J AgricFood Chem 2004;52(9):2721-2725.)。FIPs也能作为免疫抑制剂。于活体内,这些蛋白质能防止全身的过敏反应,并且在老鼠的阿都司氏(Arthus)反应期间能显著地减少足垫水肿。这些观察显示FIPs能够促进健康而且具有疗效。
Lin等人由松杉灵芝(Ganoderma tsugae)菌丝体中纯化出一种免疫调节蛋白,命名为FIP-gts(Lin,W.H.,et al.,JBiol.Chem.1997.272,20044-20048.)。只有从松杉灵芝菌丝体中纯化的FIP-gts有免疫调节的功效,而松杉灵芝子实体纯化的FIP-gts则无效果。选殖FIP-gts基因后,发现其脱氧核糖核酸序列与赤芝中发现的LZ-8一样。二分子皆具有免疫调节功效,显示它们是相同的蛋白质。
以Gamier分析法预测FIP-gts的二级结构发现,此蛋白有两个α-螺旋、七个β-折片与一个β-转折。以SDS-PAGE分析,FIP-gts的分子量为13kDa。以20μM戊二醛进行胺基酸结合分析,发现FIP-gts为两个相同次单元所组成的双聚体(homodimer),分子量为26kDa。
此外,以芽细胞形成刺激活性分析法(Blast-formation stimulatory activityassay,BFSA)发现三个真菌蛋白。除了由赤芝所发现的蛋白以外,由金针菇(Flammulinavelutipes)与草菇(Volvariella volvacea)中发现的凝血蛋白都具有部分免疫调节功能。这些蛋白的分子量都差不多是13kDa,而且它们皆不含组胺酸、半胱胺酸或甲硫胺酸。它们属于与碳水化合物相连结的凝集素类型。
虽然FIPs的免疫调节活性已被广泛研究,但其抗癌功能直到近年来才受到探讨。转让给本申请人的美国专利第8,163,519号教示了在先前的研究中发现LZ-8可供用于治疗肝癌。转让给本申请人的美国专利第8,629,096号揭露LZ-8能够于活体外和于活体内抑制癌细胞的增生和侵犯,从而指出FIPs具有做为广效抗癌剂的潜力。美国专利公开案第2011/009597号提供了进一步的实验数据,其显示由嗜甲醇酵母表现出来的重组型LZ-8蛋白能够于活体外引起血癌细胞的程序化细胞死亡,而且能够于活体内抑制肝癌细胞的生长。
化学治疗法乃是运用一或多种化学治疗用药剂做为治疗癌症的一部分标准疗程,这些化学治疗用药剂通常是抗肿瘤剂。化学治疗的给予可以治愈为目的,或是着眼于延长生命或减轻症状。化学治疗经常与例如放射治疗、外科手术及/或高温疗法等其它癌症疗法搭配使用。某些化学治疗用药剂也在其它病况的治疗上扮演一定角色,包括强直性脊柱炎(ankylosing spondylitis)、多发性硬化症(multiple sclerosis)、克隆氏症(Crohn′sdisease)、干癣症(psoriasis)、干癣性关节炎(psoriatic arthritis)、全身性红斑狼疮(systemic lupus erythematosus)类风湿性关节炎(rheumatoid arthritis)和硬皮症(scleroderma)。
化学治疗已知会伴随着许多副作用-从恶心、掉发至极度疲惫。常用的化学治疗用药剂大多是主要影响体内的快速生长细胞,诸如血液细胞,以及口腔、胃部和肠道的内衬细胞。副作用可能在化学治疗后立即发生,也可能于数小时、数日内发生,甚至慢性发生持续数周至数年。
因此,需要新的医疗组合和方法,保护病人免于化学治疗所造成的不良副作用。
发明内容
在第一方面中,本申请所提供的是一种用于保护一个体免于化学治疗所造成的不良副作用的方法,所述方法包含将一足以改善所述不良副作用的有效量的真菌免疫调节蛋白(FIP)给予所述个体。
在第二方面中,本申请所提供的是一种用于保护一个体免于化学治疗所造成的不良副作用的药学组成物,所述组成物包含一足以改善所述不良副作用的有效量的真菌免疫调节蛋白(FIP)。
在第三方面中,本申请所提供的是一种真菌免疫调节蛋白在制造一医药品上的用途,所述医药品用于保护一个体免于化学治疗用药剂所造成的不良副作用。
在第四方面中,本申请所提供的是一种真菌免疫调节蛋白,其用于保护一个体免于化学治疗所造成的不良副作用,其中所述FIP呈现一足以改善所述不良副作用的有效量。
在第五方面中,本申请所提供的是一种包含化学治疗用药剂与真菌免疫调节蛋白(FIP)的组合,尤其是一种包含化学治疗用药剂与足以改善所述化学治疗用药剂所造成的不良副作用的一有效量的FIP的组合,所述组合供同时地、同期地或依序地用于治疗一个体的增生性疾病。
在第六方面中,本申请所提供的是一种用于治疗一需要接受治疗的个体内的增生性疾病的方法,所述方法包含将一化学治疗用药剂合并真菌免疫调节蛋白(FIP),尤其是一化学治疗用药剂合并足以改善所述化学治疗用药剂所造成的不良副作用的一有效量的FIP,给予所述个体。
在第七方面中,本申请所提供的是一种将一组合用于制造一医药品上的用途,所述医药品用于治疗一需要接受治疗的个体内的增生性疾病,其中所述组合包含一化学治疗用药剂,以及足以改善所述化学治疗用药剂所造成的不良副作用的一有效量的FIP。
附图说明
本发明的上述与其他目的、特征与效应在参照下列较佳实施例的说明连同说明书附图将变得显明,其中:
图1显示以PBS、FIP-fve或FIP-gts预处理,接着以欧洲紫杉醇(Docetaxel)共同处理的小鼠模型所使用的实验流程;
图2A显示通过苏木素和伊红染色的绒毛组织学影像,显示给予PBS、FIP-fve或FIP-gts后再接着共同给予欧洲紫杉醇所得到的小鼠绒毛形态;
图2B显示在静脉注射欧洲紫杉醇后,经FIP-fve与FIP-gts处理的小鼠绒毛长度定量分析,其中符号***代表P<0.001(相对于对照组),而符号###代表P<0.001(相较于仅以欧洲紫杉醇处理组),数据以平均值±标准差来表示;
图3A-3C显示得自于对照组、欧洲紫杉醇、欧洲紫杉醇+FIP-fve与欧洲紫杉醇+FIP-gts组的胫骨样本的显微-CT三维影像;
图4A显示欧洲紫杉醇对活体内骨髓脂肪生成的效应,和FIP-fve与FIP-gts对于防止脂肪生成的效应;以及
图4B显示在解剖显微镜下计数的脂肪细胞数目,其中符号***代表P<0.001(相对于对照组),而符号##代表P<0.01(相较于仅以欧洲紫杉醇处理组),数据以平均值±标准差来表示。
具体实施方式
除非内容另有清楚表明,单数形式“一”与“所述”在本申请中也包括复数指涉物。举例来说,提到一组成物含有“一化学治疗用药剂”可能意指所述组成物包括二或多个化学治疗用药剂的混合物。也应注意到用语“或”在意义上一般也包括“及/或”,除非内容另有清楚表明。
本申请所使用的用语“真菌免疫调节蛋白”或缩写成“FIP””指的是属于首先定义于Ko et al.,Eur.J.Biochem.1995;228:244-249的蛋白家族的蛋白,其是基于胺基酸序列与免疫反应效应的相似性。经报导,FIP家族的免疫调节蛋白共享至少57%的序列同源性。尤其,FIP-gts、FIP-fve、FIP-vvo与LZ-8的一级结构展现60-70%的序列同源性(Kong etal.,Int.J.Mol.Sci.2013,14,2230-2241;中国专利第CN102241751B号;Wang XF et al.,Curr.Topics Nutraceutical Res.2012,10(1):1-12;以及Li OZ et al.,Crit.Rev.Biotech.2011,31(4):365-375)。因此,本申请所使用的用语“真菌免疫调节蛋白”意欲涵盖与SEQ ID NO:1所示FIP-gts的胺基酸序列具有至少57%、较佳为至少60%、至少70%、至少80%、至少90%或至少95%胺基酸同源性并具有引发、增强或延伸个体免疫反应的能力的任何多肽。在一较佳实施例中,所述真菌免疫调节蛋白具有选自于由下列所组成的群组的胺基酸序列:SEQ ID NO:1(FIP-gts)、SEQ ID NO:2(FIP-fve)、SEQ ID NO:3(FIP-vvo)、SEQ ID NO:4(LZ-8)、SEQ ID NO:5(FIP-gja)、SEQ ID NO:6(FIP-gmi)、SEQ IDNO:7(FIP-gsi)与SEQ ID NO:8(FIP-nha),及其作为免疫调节剂的功能性变异体。在另一较佳实施例中,所述FIP源自于灵芝属或草菇,尤其是具有选自于由下列所组成的群组中的胺基酸序列:SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ IDNO:6与SEQ ID NO:7。最佳者包含SEQ ID NO:1的胺基酸序列、基本上由SEQ ID NO:1的胺基酸序列所组成、或由SEQ ID NO:1的胺基酸序列所组成。
本申请所使用的FIP可得自于天然来源、真菌培养物,抑或是于诸如细菌或酵母菌宿主等原核或真核微生物宿主中重组表现。依此获得的FIP可为粗制物形式,或是通过任何适宜技术所分离、分馏、或部分或实质上纯化自于真菌物质的精制调配物。较佳为所述蛋白在使用前经过至少部分地纯化。可供用于制备FIP的一种方法揭示于WO2005040375A1,所述方法涉及培养包涵带有FIP基因的表现载体的酵母转形株,并从酵母培养物收集重组型FIP蛋白。其他有供运用的方法可见于,举例来说,Kong et al.(同前)与CN101205553A;以及Wang XF et al.,Curr.Topics Nutraceutical Res.2012;10(1):1-12。
在所使用的FIP为LZ-8或FIP-gts的情况下,所述FIP可以直接单离自于赤芝或松杉灵芝,或在宿主细胞系统中由重组蛋白技术制备出来。宿主细胞可为酵母菌或细菌系统。较佳为宿主细胞系统选自于由下列所组成的群组:啤酒酵母(Saccharomycescerevisiae)、嗜甲醇酵母(Pichia pastoris)、汉逊氏酵母(Hansenula polymorpha)、产朊假丝酵母(Candida utilis)、博伊假丝酵母(Candida boidinii)、麦芽糖假丝酵母(Candida maltose)、乳糖克鲁维酵母(Kluyveromyces lactis)、解脂耶罗威亚酵母(Yarrowia lipolytica)、西方许旺酵母(Schwanniomyces occidentalis)、粟酒裂殖酵母(Schizosaccaromyces pombe)、球拟酵母属(Torulopsis sp.)、陆地酵母(Arxulaadeninivorans)、曲霉属(Aspergillus sp.)(例如构巢曲霉(A.nidulans)、黑曲霉(A.niger)、泡盛曲霉(A.awamori)和米曲霉(A.oryzae)),以及木霉属(Tricoderma sp.)(例如瑞氏木霉(T.reesei))。
本申请所使用的用语“化学治疗用药剂”以最广义意义而言包括带有抗细胞增生活性的任何化学化合物或药物,其可抑制或遏止癌性细胞或未成熟癌前细胞的生长、杀死癌性细胞或未成熟癌前细胞、增加癌性或癌前细胞对其他化学治疗用药剂的易感性、及/或抑制癌性细胞转移。举例来说,一化学治疗用药剂可包括但不限于任何干扰细胞分裂、扰乱微管(microtubules)的正常功能、抑制代谢产物的利用、置换核苷酸类似物进入细胞DNA、或抑制DNA复制所需酶的药剂。
在一些较佳实施例中,化学治疗用药剂可供用于治疗增生性疾病,包括实体肿瘤疾病,例如乳癌、结肠及大致上胃肠道的癌症,包括胃癌、肝癌;肺癌,特别是小细胞肺癌与非小细胞肺癌;肾癌、间皮瘤、神经胶质瘤;皮肤的鳞状细胞癌;头颈癌;泌尿生殖癌症,例如子宫颈、子宫、卵巢、睾丸、前列腺或膀胱的癌症;何杰生氏症(Hodgkin′s disease)、类癌瘤症候群、卡波西氏瘤(Kaposi′s sarcoma)、佩吉特氏病(Paget′s disease of bone)、肿瘤诱发型高钙血症、骨转移和多发性骨髓瘤;以及液体肿瘤,例如白血病。化学治疗用药剂也适用于治疗或预防肿瘤的转移扩散以及微小转移(micrometastases)的增长或发展。
适宜种类的化学治疗用药剂包括(a)烷基化剂,例如氮芥类(例如双氯乙基甲胺(mechlorethamine)、癌德星(cylophosphamide)、好克癌(ifosfamide)、威克瘤(melphalan)、瘤克宁(chlorambucil)、伸乙亚胺类和甲基三聚氰胺类(例如六甲基三聚氰胺、噻替哌(thiotepa))、烷基磺酸酯(例如补束克(busulfan)、亚硝基脲类(例如卡氮芥(carmustine)、罗氮芥(lomustine)、氯脲霉素(chlorozoticin)、链脲霉素(streptozocin))和三口井类(例如达卡巴仁(dicarbazine);(b)抗代谢物,例如叶酸类似物(例如灭杀除癌(methotrexate))、嘧啶类似物(例如5-氟尿嘧啶(5-fluorouracil)、氟尿苷(floxuridine)、阿糖胞苷(cytarabine)、氮尿甙(azauridine)和嘌呤类似物及相关物质(例如6-巯基嘌呤、6-硫代鸟嘌呤、喷司他丁(pentostatin));(c)天然产物,例如长春花属生物碱(例如长春花碱(vinblastine)、长春新碱(vincristine))、表鬼臼毒素(epipodophyllotoxins)(例如依托泊苷(etoposide)、替尼泊苷(teniposide))、抗生素(例如更生霉素(dactinomycin)、柔红霉素(daunorubicin)、多柔比星(doxorubicin)、博莱霉素(bleomycin)、普卡霉素(plicamycin)与米托蒽醌(mitoxanthrone))、酶(例如L-天门冬酰胺酶(L-asparaginase))和生物反应修饰剂(例如干扰素-α(Interferon-α));以及(d)无归类药剂,例如铂配位错合物(例如顺铂(cisplatin)、卡铂(carboplatin))、经取代脲类(例如羟基脲(hydroxyurea))、甲基肼衍生物(例如procarbazine)、以及肾上腺皮质抑制剂(例如米托坦(mitotane)),以及有丝分裂抑制剂(例如紫杉烷类(taxanes))。
在较佳实施例中,化学治疗用药剂为有丝分裂抑制剂,例如微管稳定剂、微管去稳定剂与微管聚合抑制剂。所述等药剂包括但不限于紫杉烷类,例如太平洋紫杉醇(Paclitaxel)与欧洲紫杉醇;长春花属生物碱,例如长春花碱,尤其长春花碱硫酸盐,长春新碱,尤其是长春新碱硫酸盐;以及长春瑞滨(vinorelbine)和海绵内酯(discodermolide)、秋水仙碱类(colchicines)和埃坡霉素类(epothilones)及其衍生物,例如埃坡霉素B或其衍生物。在这些药剂当中,紫杉烷类特别适用于本发明的目的。
本申请所使用的用语“紫杉烷(taxane)”指的是紫杉烷类、紫杉碱类(taxines)和类紫杉烷类(taxoids),还有它们的衍生物或类似物。在一些实施例中,紫杉烷包括,举例来说,太平洋紫杉醇(商品名:由必治妥施贵宝公司出品)、欧洲紫杉醇(商品名:由安万特药品公司出品);蛇鞭菊种素(spicatin);紫杉-2,13-二酮、5β,9β,10β-三羟基-,环状9,10-缩丙酮乙酸酯;紫杉-2,13-二酮、5β,9β,10β-三羟基-,环状9,10-缩丙酮;紫杉-2β,5β,9β,10β-四醇、环状9,10-缩丙酮;紫杉烷;三尖杉宁-7-木糖甙(cephalomannine-7-xyloside);7-表-10-去乙酰基三尖杉宁;三尖杉宁;紫杉醇B;13-(2′,3′-二羟基-3苯丙酰基)浆果赤霉素III;云南红豆杉醇(yunnanxol);7-(4-叠氮苯甲酰基)浆果赤霉素III;N-去苯甲酰基紫杉醇A;O-乙酰基浆果赤霉素IV;7-(三乙硅基)浆果赤霉素III;7,10-二-O-[(2,2,2,-三氯乙氧基)羰基]浆果赤霉素III;浆果赤霉素III 13-O-乙酸酯;浆果赤霉素二乙酸酯;浆果赤霉素;浆果赤霉素VII;浆果赤霉素VI;浆果赤霉素IV;7-表-浆果赤霉素III;浆果赤霉素V;浆果赤霉素I;浆果赤霉素III;浆果赤霉素A;10-去乙酰基-7-表紫杉醇;表紫杉醇;10-去乙酰基紫杉醇C;7-木糖基-10-去乙酰基紫杉醇;10-去乙酰基紫杉醇-7-木糖甙;7-表-10-去乙酰基紫杉醇;10-去乙酰基紫杉醇;或10-去乙酰基紫杉醇B。
在一更佳实施例中,所述紫杉烷类选自于由太平洋紫杉醇或欧洲紫杉醇所组成的群组。最佳者为欧洲紫杉醇。本申请所使用的用语“欧洲紫杉醇”指的是(2R,3S)N-羧基-3-苯基异丝胺酸,N-三级丁酯,13-酯和5,20-环氧基-1,2,4,7,10,13-六羟基紫杉-11-烯-9-酮4-乙酸酯2-苄酸酯,三水合物(CAS号:114977-28-5),可以其学名药名或以商品药名取得。本申请发明所使用的用语“太平洋紫杉醇”指的是以学名药或市购的药物并具有以下IUPAC名称:(2α,4α,5β,7β,10β,13α)-4,10-双(乙酰氧基)-13-{[(2R,3S)-3-(苄酰基胺基)-2-羟基-3-苯基丙酰基]氧基}-1,7-二羟基-9-酮基-5,20-环氧基紫杉-11-烯-2-基苄酸酯。用语“欧洲紫杉醇”与“太平洋紫杉醇”也包括具抗肿瘤特性的天然衍生及相关形式与化学合成物或其衍生物。
欧洲紫杉醇与太平洋紫杉醇是乳癌、前列腺癌、卵巢癌、胃癌、头颈癌和非小细胞肺癌患者的常见治疗处方用药。这两种药物都有做为有丝分裂抑制剂的类似药理作用机制,其中欧洲紫杉醇主要致使S-期细胞周期停滞,而太平洋紫杉醇基本上作用在细胞周期的G2-M期。
就本发明目的而言,用语“化学治疗(chemotherapeutic treatment)”或“化疗(chemotherapy)”指的是运用上文所定义的化学治疗用药剂来治疗一个体,例如增生性疾病的化学治疗法,例如癌症的化学治疗法。就此而言,用语“不良副作用」或“化学治疗用药剂所造成的不良副作用”指的是除了化学治疗用药剂预期的所欲效应以外的任何非所欲结果,包括摄取化学治疗用药剂所可能造成的任何异常、缺陷、突变、病变、退化或损伤。
通常,化学治疗用药剂是通过杀死快速分裂的细胞来发生作用,快速分裂是大部分癌症细胞的一个主要特性。就此而言,化学治疗还会损害在正常情况下快速分裂的健康细胞,包括在骨髓、消化道和毛囊的细胞,于是导致不良副作用。因此,“不良副作用”意图涵盖骨髓抑制(血细胞生产减少,因此也有免疫抑制和贫血)、黏膜炎(消化道内膜发炎,造成恶心、呕吐、嘴巴酸痛、厌食和吞咽困难)、骨质疏松、疲惫、生活质量下降、掉发(脱发)与疼痛。在一实施例中,“不良副作用”包括但不限于血液疾病,例如全血细胞低下症(pancytopenia)、嗜中性白血球低下症(neutropenia)、白血球低下症(leucopenia)、无颗粒白血球增多症(agranulocytosis)、贫血、发热性嗜中性白血球低下症与血小板低下症(thrombocytopenia);消化道疾患,例如口部与胃肠道黏膜炎、恶心、呕吐、腹泻、厌食、嘴巴酸痛和吞咽困难;骨质疏松;生活质量下降、衰弱及癌因性疲惫症;神经系统疾患,例如感觉神经功能障碍和运动神经功能障碍;掉发;皮疹或发痒;过敏反应;体液滞留;以及对感染的抵抗力下降。在更佳实施例中,“不良副作用”选自由下列所组成的群组:白血球低下症、贫血、血小板低下症、胃肠道黏膜炎、化学治疗引起的骨质疏松、生活质量下降与癌因性疲惫症。
为评估化学治疗所造成的不良副作用,发明人建立了一个小鼠模型,其中不良副作用是通过给予代表性化学治疗用药剂来引发。根据本申请提供的揭示内容,欧洲紫杉醇被选用做为代表性化学治疗用药剂,因为由其所引发的潜在不良副作用出现于所有化学治疗,当中许多已有文件记载。欧洲紫杉醇为主要用于治疗乳癌、卵巢癌、前列腺癌和非小细胞肺癌的细胞周期专用药剂,其通过结合至细胞β-微管蛋白,增加其聚合并促进微管组合来发生作用。药物与微管蛋白的结合抑制了微管蛋白的去聚合作用,造成细胞停滞在细胞周期的S-期。因此,它对体内所有分裂中细胞皆有细胞毒性。如下文实施例1-4所示,在小鼠模型中是通过给予欧洲紫杉醇来引发典型的不良副作用,包括骨髓抑制、黏膜炎与骨质疏松。
FIP-gts与FIP-fve被选用来代表上文所定义FIP。发明人意外地发现到,在小鼠模型中,通过预先给予与共同给予FIP,能够有利地改善化学治疗一较佳使用代表性化学治疗用药剂欧洲紫杉醇-所造成的不良副作用。
本申请所使用的用语“保护一个体免于不良副作用”可涵盖预防不良副作用发生在所述个体及/或治疗已出现在所述个体的不良副作用。在此方面,用语“预防”包括减轻不良副作用的严重性/强度,或减少不良副作用的发生。用语“治疗”包括在不良副作用出现后予以缓解。但是,用语“保护”在意义上不应被理解成对于不良副作用总是有100%的保护力。因此,用语“改善不良副作用”指的是实质上减少或消除已发生或可能发生在个体的不良副作用。
用语“预先给予(pre-administration)”指的是在给予化学治疗用药剂前将FIP投至个体。在某些实施例中,在给予化学治疗用药剂前,所述个体事先被给予FIP一段充足时间,例如数日、数周或数月,以容许FIP发挥预防不良副作用的效应。用语“共同给予(co-administration)”指的是将两物质一起供给或在某段所欲时间内供给一个体。
在一实施例中,以欧洲紫杉醇为主的化学治疗所引发的不良副作用为骨髓抑制,其特征在于血细胞生产减少。较佳地,骨髓抑制的程度是通过进行标准全血细胞计数(CBC)以获得全血资料来评估。如下文实施例2所示,欧洲紫杉醇所引发的骨髓抑制-例如白血球低下症、贫血与血小板低下症-可以被FIP-gts与FIP-fve此两者所改善,尤其是从白血球细胞、血小板和血红蛋白的回复位准的角度。
在另一实施例中,化学治疗所引发的不良副作用为黏膜炎,其特征在于黏膜损伤,例如可在显微镜下观察到的绒毛高度降低。如下文实施例3所示,欧洲紫杉醇所引发的黏膜炎-例如胃肠道黏膜炎-可以被FIP-gts与FIP-fve此两者所改善,尤其是从小鼠模型中的肠绒毛的回复结构完整性的角度。
在再另一实施例中,化学治疗所引发的不良副作用为骨质疏松,其特征在于骨质减少(osteopenia),例如骨密度降低与小梁骨的损耗。就本发明目的而言,骨质疏松的程度进一步由小梁骨的结构完整性与脂肪生成来评估。如下文实施例4所示,欧洲紫杉醇所引发的骨质疏松可以被FIP-gts与FIP-fve此两者所改善,尤其是从小鼠模型中的小梁骨的结构完整性与脂肪生成程度的角度。
本申请的发明人另执行化学治疗所造成的生活质量下降(QOL)与癌因性疲惫症(CRF)的临床研究。经选定的人类病患的QOL与CRF是以美国东岸肿瘤学合作组织(ECOG)性能状态量表(0至5级)进行评估(Oken M.M.,et al,.Am.J.Clin.Oncol.;1982,5(6):649-55),其中各级别代表:
0-无症状(活动自如,能够不受限地进行所有疾病前活动,无任何限制);
1-有症状,但能自由走动(限制身体剧烈活动但能自由走动,并能够进行轻度或久坐性质的工作。举例来说,轻度家务、办公室工作);
2-有症状,日间<50%在床上(自由走动并能够完全自理,但无法进行任何工作活动。清醒时间不少于50%);
3-有症状,>50%在上床,但未瘫倒在床(仅能有限自理,清醒时间中有50%或以上侷限在床或椅子上);
4-瘫倒在床(完全失能。完全不能自理。全部侷限在床或椅子上);以及
5-死亡。
已知经历化学治疗的癌症病患,例如因肺癌接受欧洲紫杉醇及/或顺铂的癌症病患,会面临到各种各样的生理和情绪问题,可能很快地导致CRF与QOL下降。其结果导致,ECOG级数会随着化学治疗的进行而倾向于上升。然而,发明人意外地发现到ECOG级数在共同给予FIP与化学治疗用药剂的所有研究案例中皆维持不变,如下文实施例5所示。
根据本申请提供的揭示内容,用语“个体”意欲涵盖需要化学治疗的人类或非人类脊椎动物,例如非人类哺乳动物。非人类哺乳动物包括家畜动物、陪伴动物、实验室动物、和非人灵长类。非人类个体也包括而不限于马、牛、猪、山羊、狗、猫、小鼠、大鼠、天竺鼠、沙鼠、仓鼠、水貂、兔和鱼。应该理解,较佳的个体为人类,尤其患有增生性疾病或处于增生性疾病风险的人类病患,例如罹患乳癌、前列腺癌的人类病患。
就研究目的而言,用语“个体”可指本申请所定义的生物样本,包括但不限于细胞、组织或器官。据此,本申请所揭示的发明意欲在活体内还有活体外施用。
根据本申请所提供的揭示内容,用语“给予一个体”包括以适宜药学调配物将FIP或化学治疗用药剂通过用于递送FIP或化学治疗用药剂至所述个体所欲位置的任何适宜途径而分配、递送或施用至一个体,以使FIP或化学治疗用药剂接触目标细胞或组织。
FIP可通过任何适宜途径投至所述个体,例如局部、直肠、肠内或非经肠途径,举例来说,口服、静脉内、皮下、肿瘤内、肌肉内、腹膜内、穿皮、脊鞘内、或脑内途径。投药可以是快速的,例如通过注射,或历经一段时间,例如通过缓慢输注或给予缓释调配物。
在一较佳实施例中,FIP是欲以口服给予并制备成可口服给予调配物形式。此类调配物较佳以适宜载剂、赋形剂、润滑剂、乳化剂、悬浮剂、甜味剂、加味剂、防腐剂调配,并打成锭剂或囊封成固体胶囊或软胶囊。还设想得到此类调配物可设计成下列剂型:口服溶液、或口服小包、或口服丸剂。或者除了口服给予,还可设想得到此类调配物可设计成灌肠剂、或栓剂、或植入物、或贴片、或乳霜、或软膏剂型。适宜载剂、赋形剂、与稀释剂的若干例子包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、明胶、糖浆、甲基纤维素、甲基-丙基-羟基苄酸盐、滑石、硬脂酸镁、水、矿物油等等。调配物还可额外包括润滑剂、湿润剂、乳化剂与悬浮剂、防腐剂、甜味剂或加味剂。FIP组成物可调配成能够在运用本领域习知流程给予病患后快速、持续或延迟释放活性成分。调配物还可含有减少蛋白水解、核酸和其他降解作用的物质及/或促进吸收的物质,例如,举例来说,表面活性剂。所述组成物可和聚乙二醇(即PEG化)、白蛋白或类似物错合,以帮助促进在血流中的稳定性。
在一些较佳实施例中,FIP被调配成可口服给予剂型。
另一较佳的FIP制剂是利用生理盐水溶液载体;可设想到其他药学上可接受的载剂,例如还可使用无毒盐或化合物的生理浓度、5%葡萄糖水溶液、无菌水或等等。可能也会希望组成物内存在有适宜的缓冲液。若有需要,此类溶液可冻干储存在无菌安瓿里,待加入无菌水复溶即可用于注射。主要溶剂可为水性或者非水性。
所述载剂还可含有其他药学上可接受的赋形剂,以调整或维持调配物的pH、渗透压、黏度、澄清度、颜色、无菌性、稳定性、溶解速率或气味。类似地,载剂可另含有其他药学上可接受的赋形剂,以调整或维持调配物的释放或吸收或渗透穿过血脑屏障。此类赋形剂为惯用于调配供单位剂量或多剂量形式的非经肠给予或供通过连续或周期性输注来直接输注的药剂的物质。
FIP可通过已知的生药技术适宜地调配成上述单位剂型。此类技术包括使FIP与生理上可接受的载剂、稀释剂、佐剂及/或赋形剂结合在一起的步骤。一般而言,调配物是通过使FIP和液体载剂或细微化固体载剂或此两者均匀且紧密地结合在一起来进行制备,随后视必要性塑形成各种产品。
FIP是以足以改善化学治疗用药剂所造成的不良副作用的一治疗有效量给予个体。实际剂量可依据所选定的特定投药途径来计算。为决定适当投药剂量所必要的进一步精细计算由具本领域通常知识者以常规方式进行。因此,在给予一人类个体时,FIP较佳地每日、每周或一周两次给予一介于0.01毫克/公斤体重/日至100毫克/公斤体重/日的间,且更佳为0.1毫克/公斤/日至10毫克/公斤/日的份量。视药剂调配物的药动学参数与使用的投药途径而定,可重复多剂投药。
化学治疗用药剂可经由各种方式给予,包括以专业人士所处方的份量以非经肠与经肠途径全身性给予。
FIP与化学治疗用药剂可以在形体上充分区隔,以供可同期地或依序地给予。或者,当意欲同时使用FIP与化学治疗用药剂时,它们可以在形体上充分区别,抑或呈紧密接触或结合。在后者情况中,它们可以,举例来说,混合在一起、及/或直接或间接地彼此错合、及/或直接或间接地彼此联结(例如通过共价联结)。举例来说,它们可被调配成本申请施用所涵盖的混合物、错合物或联结产物。
因此,本申请所使用的用语“组合”指的是数种药剂的集合体,其通过同时、同期或依序给予使用于治疗。同时给予指的是给予FIP与化学治疗用药剂的混掺物(无论是真实混合物、悬浮液、乳剂或其他物理组合)。在此情况中,所述组合可为FIP与化学治疗用药剂的混掺物,抑或是置于不同容器在投药不久前才合并的FIP与化学治疗用药剂。同期给予指的是在相同时间,或是足够接近而观察到相对于任一单独药剂活性有增强或协乘活性的时间内,分开地给予FIP与化学治疗用药剂。在此情况中,所述组合包含置于不同容器的FIP与化学治疗用药剂。
下列实施例仅供用于例示目的,而非意图限制本发明的范畴。
实施例1:小鼠模型
雄性BALB/cByJNarl小鼠(6-8周龄)购自中国台湾的实验动物中心(NLAC)并随机分成四组:欧洲紫杉醇+PBS组、欧洲紫杉醇+FIP-fve组,以及欧洲紫杉醇+FIP-gts组,每组各五只小鼠,而对照组四只。小鼠以12-小时日/12-小时夜的周期被饲养在无病原体条件下,并喂食高压灭菌饮食,可自由取用标准囓齿动物饲料(Laboratory Rodent Diet 5001,LabDiet,St.Louis,Mo.,USA)。给予欧洲紫杉醇的三天前(亦即第-3日),欧洲紫杉醇+PBS组的小鼠开始被喂食磷酸盐缓冲盐水(PBS),每日每只动物100微升,整段实验期间持续PBS的每日喂食。在第1、8与15日,小鼠以30毫克/公斤体重的剂量被静脉内注射(Aventis Pharma Ltd.,Dagenham,UK)至尾静脉。欧洲紫杉醇+FIP-fve组与欧洲紫杉醇+FIP-gts组在上述相同日数被给予上述相同剂量的此外,从第-3日开始直到实验结束(第18日)的整段实验期间,两处理组每日接受100微升添加有200微克FIP-fve或400微克FIP-gts的PBS。本实施例及其他实施例中所使用的FIP-gts蛋白根据WO2005040375A1揭示方法制造。本发明所使用的FIP-fve蛋白是通过揭示在Ko J.L.,Eur.J.Biochem.1995;228:244-249中的方法由金针菇纯化出来。对照组小鼠仅被给予每日每只动物100微升PBS,并无注射抗癌剂。第4、11与18日从小鼠眼窦采血,以供后续分析。第18日让动物通过CO2窒息牺牲。实验流程绘示于图1。
实施例2:血液分析
牺牲后,获自实施例1的全血样本收集自小鼠下腔静脉,以供全血计数(CBC)。结果显示于下表I。
表I.全血计数分析
如预测般,相较于对照组位准,单独以欧洲紫杉醇投药导致欧洲紫杉醇+PBS组小鼠的白血球细胞(WBC)、红血球细胞(RBC)、血红蛋白(HGB)、血细胞比容(HCT)与血小板(PLT)位准显著下降。然而,未经预期地发现到给予FIP-fve减少了欧洲紫杉醇所造成的HGB与PLT两者的位准下降幅度,而FIP-gts和欧洲紫杉醇的共同治疗明显地使WBC位准回复至其对照组数值。
实施例3:绒毛结构完整性
得自牺牲小鼠空肠的肠样本以10%福尔马林固定并包埋于石蜡。去石蜡切片是使用莱卡自动染色机XL ST5010(Leica Microsystems Nussloch GmbH)以苏木素和伊红染色,随后在显微镜下观察。肠道样本的绒毛组织学影像显示于图2A,通过NIS-Elements D 3.2型影像分析系统(Nikon,Japan)测量的绒毛长度显示于图2B。这些结果显示欧洲紫杉醇+PBS组的绒毛严重损伤、端部钝化,证实化学治疗用药剂对胃肠黏膜的毒性。相对地,欧洲紫杉醇+FIP-fve组与欧洲紫杉醇+FIP-gts组样本的绒毛结构完整性维持不变,这指出FIPs避免了肠道黏膜因欧洲紫杉醇投药所造成的损伤,甚至可能主导或促进肠道黏膜从损伤中恢复。
实施例4:骨质分析
自小鼠的右后肢分离出胫骨并去除血肉。随后,将个别胫骨置入15毫升锥形离心管(Becton,Dickinson and Company,Franklin Lakes,NJ,USA)并覆盖70%乙醇。将胫骨样本送至中国台湾科学委员会(NSC)的生技医药科技计划(NRPB)成立的台湾小鼠诊所,在所述诊所,样本于高分辨率低剂量X-光扫描机(SkyScan 1076,Aartselaar,Belgium)应用三维显微电脑断层扫描(即显微CT)进行扫描,并评估小梁骨的微架构。为了进行组织学分析,使若干胫骨样本泡在10%EDTA两周以脱去矿质,以渐升浓度的系列乙醇溶液加以脱水,并使用莱卡ASP300S型组织处理机(Leica Microsystems Nussloch GmbH)包埋于石蜡。去石蜡切片以苏木素和伊红染色(H&E染色),随后在显微镜下观察。
显微CT扫描的结果显示于图3A,其指出得自欧洲紫杉醇+PBS组的胫骨样本相较于对照组多了许多骨质孔洞。相对地,相较于对照组,欧洲紫杉醇+FIP-fve以及欧洲紫杉醇+FIP-gts这两组的胫骨结构完整性大致上维持不变。在膝盖样本剖面图(图3B)以及股骨远端和胫骨近端样本纵向剖面图(图3C)观察到类似结果,其中显示了经FIP-fve与FIP-gts治疗的小鼠组的样本比起单独以欧洲紫杉醇注射的小鼠组的样本显著地孔洞较少。
下表II的定量资料显示,相较于对照组,欧洲紫杉醇+PBS组小鼠验证了小梁骨数目(Tb.N)与骨体积百分比大幅下降,以及小梁骨分离(Tb.Sp)增加,验证了欧洲紫杉醇治疗会引发骨质疏松。然而,在得自于欧洲紫杉醇+FIP-fve组与欧洲紫杉醇+FIP-gts组的胫骨样本中观察到,小梁骨数目与骨体积百分比皆增加,且小梁骨分离显著下降,这表明通过给予FIPs,缓解了欧洲紫杉醇所引发的骨质疏松的症状或阻止了欧洲紫杉醇所引发的骨质疏松的进展。再者,还发现到欧洲紫杉醇+FIP-gts组的小梁骨厚度比起其他组高了许多。
表II.小梁骨的量化
图4A的显微镜影像,特别是下排的高倍率影像,还有图4B展示的脂肪细胞计数,显示了相较于对照组,欧洲紫杉醇+PBS组发生了骨髓脂肪组织增加伴随着骨体积减少,而欧洲紫杉醇+FIP-fve组与欧洲紫杉醇+FIP-gts组均证明胫骨骨髓中的相对温和的脂肪生成情形,指出骨质疏松的严重性较低。
实施例5:临床研究
五位患有第III或IV期肺癌的人类病患被纳入本研究。在研究期间,各病患被给予低剂量20-30mg/m2或高剂量60-69mg/m2的连同在医生所处方指定日的顺铂/卡铂,并接受每日两锭FIP-gts(每锭3毫克)。病患被要求在指定日到医院回诊并采集血液样本。根据上述ECOG性能状态系统评估病患的生活质量与疲惫情形。五位病患的医疗记录,还有病患投药方案绘示于下表III.A-III.E。
表III.A患者病例1
姓名:李某
出生年份:1954性别:M
诊断:肺癌,右肺中叶,中度分化腺癌,cT2N2M1a,第IV期,胸膜转移和恶性胸腔积液
表III.A(续)
表III.A(续)
表III.B患者病例2
姓名:卢某
出生年份:1952性别:M
诊断:肺腺癌(EGFR突变WT),中度分化,左肺上叶,T3,4脊柱转移,cT4N3M1b,第IV期
表III.B(续)
表III.C患者病例3
姓名:蔡某
出生年份:1949性别:M
诊断:肺鳞状细胞癌,左肺上叶,cT2bN3M0,第IIIB期
表III.D患者病例4
姓名:张某
出生年份:1966性别:M
诊断:肺腺癌(EGFR野生型),左肺上叶并侵入纵隔,T4N3M0,第IIB期,疾病进展至骨转移
表III.E患者病例5
姓名:郑某
出生年份:1944性别:M
诊断:RUL腺癌,s/p楔形切除并于2011-7-28胸膜穿刺活检。
病理:腺癌(EGFR WT)与胸膜转移,pT2aNxM1a,接受CCRT和欧洲紫杉醇与顺铂。
如表III.A-III.E所示,在整个疗程期间,所有病患的ECOG级别保持不变,验证了FIP对于维持QOL及预防CRF的效应。
尽管本发明已参照以上较佳实施例说明,应认知到较佳实施例仅为例示目的给予而非意图限制本发明的范畴,可进行对本领域技术人员而言极为明显的各种更动与改变,而仍属于本发明精神与范畴。
本申请提到的所有论文、刊物、文献、专利、专利申请案、网址、及其他印刷或电子文件-包括但不限于下文所列参考文献-以参照方式整体并入。若有冲突,将以本说明-包括定义-为准。
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<120> 改善化学治疗所造成的不良副作用的组合疗法
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Ile Asp Pro Asp Thr Gly Ala Asp Phe Ile Ile Ala Gln Trp Asn
100 105 110
<210> 8
<211> 114
<212> PRT
<213> 红球丛赤壳菌(Nectria haematococca)
<220>
<221> 肽
<222> (1)…(114)
<400> 8
Met Ala Thr Thr Asn Asp Ser Ala Val Leu Phe Tyr Ile Val Ala Ser
1 5 10 15
Gln Lys Lys Leu Ser Phe Asp Tyr Thr Pro Asn Trp Gly Arg Gly Ser
20 25 30
Pro Asn Ser Tyr Ile Asp Asn Leu Thr Phe Pro Arg Val Leu Thr Asn
35 40 45
Lys Pro Tyr Lys Tyr Arg Val Val Lys Ala Gly Gln Asp Leu Gly Val
50 55 60
Arg Asp Ser Tyr Ser Val Gln Ser Asp Gly Ser Gln Lys Val Asn Phe
65 70 75 80
Leu Glu Tyr Asn Ala Gly Arg Gly Ile Ala Asp Thr Gln Thr Ile Gln
85 90 95
Val Tyr Val Val Asp Pro Asp Asn Gly Asn Gln Tyr Leu Val Ala Gln
100 105 110
Trp Lys
Claims (23)
1.一种真菌免疫调节蛋白(FIP)在制造一医药品上的用途,所述医药品用于保护一个体免于化学治疗用药剂所造成的不良副作用。
2.一种将一组合用于制造一医药品上的用途,所述医药品用于治疗一需要接受治疗的个体内的增生性疾病,其中所述组合包含一化学治疗用药剂,以及足以改善所述化学治疗用药剂所造成的不良副作用的一有效量的FIP。
3. 如权利要求1或2所述的用途,其中所述FIP与SEQ ID NO:1的胺基酸序列具有至少57%的胺基酸同源性。
4.如权利要求3所述的用途,其中所述FIP具有一选自于由下列所组成的群组中的胺基酸序列:SEQ ID NO:1、SEQ ID NO: 2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ IDNO:6、SEQ ID NO:7与SEQ ID NO:8。
5.如权利要求4所述的用途,其中所述FIP具有SEQ ID NO:1的胺基酸序列。
6.如权利要求1或2所述的用途,其中所述化学治疗用药剂具有抗细胞增生活性。
7.如权利要求6所述的用途,其中所述化学治疗用药剂为紫杉烷类。
8.如权利要求7所述的用途,其中所述紫杉烷类选自于由太平洋紫杉醇(Paclitaxel)与欧洲紫杉醇(Docetaxel)所组成的群组。
9.如权利要求1或2所述的用途,其中所述不良副作用选自于由下列所组成的群组:骨髓抑制、黏膜炎、骨质疏松、疲惫、生活质量下降、掉发与疼痛。
10.如权利要求9所述的用途,其中所述不良副作用选自于由下列所组成的群组:白血球低下症、贫血、血小板低下症、胃肠道黏膜炎、化学治疗引致的骨质疏松、生活质量下降与癌因性疲惫症。
11.如权利要求1或2所述的用途,其中所述FIP呈口服给予形式。
12.如权利要求1或2所述的用途,其中所述个体选自于由人类和非人类脊椎动物所组成的群组。
13.一种组合,所述组合包含一化学治疗用药剂,以及足以改善所述化学治疗用药剂所造成的不良副作用的一有效量的真菌免疫调节蛋白(FIP),所述组合供同时地、同期地或依序地用于治疗一个体的增生性疾病。
14. 如权利要求13所述的组合,其中所述FIP与SEQ ID NO:1的胺基酸序列具有至少57%的胺基酸同源性。
15. 如权利要求14所述的组合,其中所述FIP具有一选自于由下列所组成的群组中的胺基酸序列:SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ IDNO:6、SEQ ID NO:7与SEQ ID NO:8。
16. 如权利要求15所述的组合,其中所述FIP具有SEQ ID NO:1的胺基酸序列。
17.如权利要求13所述的组合,其中所述化学治疗用药剂具有抗细胞增生活性。
18.如权利要求17所述的组合,其中所述化学治疗用药剂为紫杉烷类。
19.如权利要求18所述的组合,其中所述紫杉烷类选自于由太平洋紫杉醇(Paclitaxel)与欧洲紫杉醇(Docetaxel)所组成的群组。
20.如权利要求13所述的组合,其中所述不良副作用选自于由下列所组成的群组:骨髓抑制、黏膜炎、骨质疏松、疲惫、生活质量下降、掉发与疼痛。
21.如权利要求20所述的组合,其中所述不良副作用选自于由下列所组成的群组:白血球低下症、贫血、血小板低下症、胃肠道黏膜炎、化学治疗引致的骨质疏松、生活质量下降与癌因性疲惫症。
22.如权利要求13所述的组合,其中所述FIP呈口服给予形式。
23.如权利要求13所述的组合,其中所述个体选自于由人类和非人类脊椎动物所组成的群组。
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