CN105688185A - 一种用于治疗骨髓增生、骨癌的药物组合物及其用途 - Google Patents
一种用于治疗骨髓增生、骨癌的药物组合物及其用途 Download PDFInfo
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Abstract
本发明公开了药物组合物在制备治疗骨癌及骨髓增生异常的药物中的应用,所述药物组合物含有GATA多肽,也可以与硼替佐米联合给药联合给药。其有效治疗量为0.1~20mg/Kg体重,给药时,可以为口服给药、静脉注射给药、皮下注射给药、肌肉注射给药。实验证明:本发明的多肽可抑制肿瘤细胞生长,对骨癌及骨髓增生异常有良好的抑制作用,具有广泛的用途。
Description
技术领域
本发明涉及制备治疗骨髓增生、骨癌的药物及其应用。
背景技术
骨肿瘤的病因至今未明,以往认为损伤特别是慢性轻微损伤、慢性感染均可引起骨肿瘤。骨肿瘤发病年龄男性为15~24岁,女性为5~14岁,可能与不同性别骨的生长与内分泌发育的早晚和时间长短有关。多发性骨髓瘤是浆细胞异常增生的恶性肿瘤,一种进行性的肿瘤性疾病。其特征为骨髓浆细胞瘤和单克隆免疫球蛋白(IgG,IgA,IgD或IgE)或BenceJones蛋白质(游离的单克隆性κ或Y轻链)过度增生,多发性骨髓瘤常伴有多发性溶骨性损害、高钙血症、贫血、肾脏损害,而且对细菌性感染的易感性增高,正常免疫球蛋白的生成受抑,发病率估计为2-3/10万,男女比例为1.6:1,大多患者年龄>40岁。目前尚无根治疗法,仍以化疗为主,大剂量化疗已解后,可考虑自身或同种异体骨髓存移植。
骨髓增生异常综合症(myelodysplasticsyndrome,MDS)造血干细胞增殖分化异常所致的造血功能障碍。主要表现为外周血全血细胞减少,骨髓细胞增生,成熟和幼稚细胞有形态异常即病态造血。临床表现为造血细胞在质和量上出现不同程度的异常变化。其具体临床表现为贫血,可伴有感染或出血,部分病人可无症状。部分患者可有肝,脾,淋巴结轻度肿大,少数患者可有胸骨压痛,肋骨或四肢关节痛。血象可呈全血细胞减少,或任何一系及二系血细胞减少。1982年由FAB协作组建议确立病名,并将MDS分为五型:难治性贫血;难治性贫血伴环状铁粒幼细胞增多;难治性贫血伴原始细胞增多,转变中的难治性贫血伴原始细胞增多;慢性粒_单核细胞白血病。
矮碱茅为多年生的高山植物,具有耐寒、耐旱的植物,发明人通过生物库批量筛选,发现矮碱茅具有较强的抗氧化的能力,其中可能存在着抑制癌症的物质。
目前治疗骨髓增生异常的药物主要集中在中药组合物以及T-2毒素,但是这些方法都不可避免的对人体产生一定的副作用,并且治疗效果并不是非常的理想。因此,开发一种高效的、对人体无害的药物显得迫在眉睫。
发明内容
针对上述现有技术,本发明提供了一种新的药物组合物用于治疗骨癌及骨髓增生异常。
本发明的一个技术方案为一种用于治疗骨髓瘤的药物组合物,其由GATA多肽以及药学上可以接受的载体构成。所述多肽的序列如GATA-1~29任一所示,其序列分别对应于SEQIDNO:1-29所示。
本发明另外提供一种多肽的制备方法,该方法包括:称取矮碱茅叶片2g,捣碎后配制成底物浓度为5%的PBS水溶液,调pH至8.0,加入胰蛋白酶4000U/g叶片,酶解温度为50℃,酶解90min后,将酶解液迅速升温至90℃,保持20min,进行灭酶处理。然后迅速冷却至室温,在以3000r/min离心15min,取上清液。按照100克:100ml的比例在湿大孔吸附树脂DA201-C中加入胰蛋白酶解液,25℃在恒温摇床保持180min,转速为150r/min,用75%的乙醇溶液洗脱120min,收集不同时间段的洗脱液。回收小分子量的条带,共得到78个小肽的序列。经过验证,其中有29个小肽具有抑制癌细胞增增殖并且杀死癌细胞的功能。根据色谱柱中不同的峰值分离时间,可以批量获得相应的小肽。常规的,所述的多肽通过人工合成的方法可以批量的用于工业化的应用,避免了原料不足,带来的局限性。
在其它实施方案中,协同效应允许一种或多种其它的治疗剂与本发明的多肽以批准剂量联合给予,但是具有高于预期的效能。
在典型的实施方案中,多肽以浓度足以允许以0.5mg/kg至20mg/kg静脉内给药的药物组合物存在。在某些实施方案中适合用于所述组合物和方法中的多肽浓度包括,但是并不局限于此,至少约0.5mg/kg,至少约0.75mg/kg,至少约lmg/kg,至少约2mg/kg,至少约2.5mg/kg,至少约3mg/kg,至少约4mg/kg,至少约5mg/kg,至少约6mg/kg,至少约7mg/kg,至少约8mg/kg,至少约9mg/kg,至少约10mg/kg,至少约llmg/kg,至少约12mg/kg,至少约13mg/kg,至少约14mg/kg,至少约15mg/kg,至少约16mg/kg,至少约17mg/kg,至少约18mg/kg,至少约19mg/kg,和至少约20mg/kg。
多肽可以单剂量或多剂量方案给予。通常,多肽在自约I小时至约24小时的时间段内给予,但是典型地在约I至2小时的时间段内给予。剂量可以重复约I周至约6周或更长时间,总共6剂或更多剂。典型地,剂量每周重复一次,每隔一周重复一次,或每月一次,最少6剂至最多50剂。
给药时,可以为口服给药、静脉注射给药、皮下注射给药、肌肉注射给药。本发明利用多肽对癌细胞的特异性杀伤作用治疗骨髓增生异常综合征,作用于骨髓及其他造血组织,抑制肿瘤细胞生长。对骨癌及骨髓增生异常有良好的杀伤。
具体实施方式
下面结合具体实施例对本发明作进一步说明,这些实施例仅用于说明本发明,而不限制本发明范围。
实施例1多肽的获得
称取矮碱茅叶片2g,捣碎后配制成底物浓度为5%的PBS水溶液,调pH至8.0,加入胰蛋白酶4000U/g叶片,酶解温度为50℃,酶解90min后,将酶解液迅速升温至90℃,保持20min,进行灭酶处理。然后迅速冷却至室温,在以3000r/min离心15min,取上清液。按照100克:100ml的比例在湿大孔吸附树脂DA201-C中加入胰蛋白酶解液,25℃在恒温摇床保持180min,转速为150r/min,用75%的乙醇溶液洗脱120min,收集不同时间段的洗脱液。回收小分子量的条带,共得到78个小肽的序列。经过验证,其中有29个小肽具有抑制癌细胞增增殖并且杀死癌细胞的功能。所述多肽的序列分别如GATA-1~29任一所示,其序列分别对应于SEQIDNO:1-29所示。
实施例2药物组合物的制备
取GATA-1多肽0.01份、淀粉1份、甜蜜素或/和蔗糖适量作为甜味剂、苯甲酸0.1份,混匀,过50目筛,灭菌后,包装即可。
GATA-2~29的多肽按照GATA-1多肽的制备方法也都分别制备成为相应的组合物。
实施例3药物组合物与其它制剂的混合
将GATA-1多肽与硼替佐米按照1:0.75的比例混合,然后以混合后的药物重量作为基础份数,再加入淀粉1份、甜蜜素或/和蔗糖适量作为甜味剂、苯甲酸0.1份,混匀,过50目筛,灭菌后,包装即可。
实施例4药物安全性检测
根据本领域常规的验证方法,可以得出本发明经动物试验证实安全无毒,实验结果与结论如下:
(1)急性毒性实验表明:根据急性毒性剂量分级标准,属于实际无毒性级;
(2)骨髓细胞微核试验、精子畸形试验、Ames试验结果为阴性;
(3)30天喂养试验:实验动物生长情况良好,血液学检查,生化学检查,主要脏体比及组织学检查结果与对照组相比,均未见异常,证明本发明安全无毒。
实施例5药物活性实验
(1)细胞培养
大鼠骨肉瘤细胞系UMR-106培养在100mL/L的FCS-1640完全培养液中(含HEPES25mol/L),隔日换液,及时传代。采用MTT法检测细胞生长状况,直至细胞生长到3.0*108即可。
(2)大鼠骨肉瘤模型的制备
收集培养的UMR-106,洗1次,调整细胞浓度;在右后肢外侧皮下对SD大鼠接种100ml细胞悬液0.5mL,接种后15天,取20只合格SCID小鼠随机分为两组,对照组瘤内注射2ml生理盐水,实验组将溶解于乙醇生理盐水混合液的药物之合物按照1.0mg/kg体重的剂量瘤内注射。给药后第1、2、3、4、5周用游标卡尺每周测量肿瘤长径a和短径b,并计算平均直径,即r=(a+b)/2。约5周后,肿瘤即可成长为合适的体积。取合格的注射了细胞的SCID小鼠,对照组瘤内注射2ml生理盐水,实验组将溶解于乙醇生理盐水混合液的药物组合物按照2.0mg/kg体重的剂量腹腔注射。给药后第0、10、20天测定皮下移植瘤最长径(a)及垂直径(d),计算肿瘤相对体积,结果见表1药物对多发性骨髓瘤体积的抑制作用(mm3)
从表1可以看出,本发明的药物具有较好的抑制肿瘤生长的功能,并且能够显著的缩小肿瘤的体积。特别是与硼替佐米联合给药其能够协同的抑制肿瘤的生长的功能。GATA-2~29的多肽与硼替佐米联合给药可以达到与GATA-1与硼替佐米联合给药相同的技术效果,具体数值在此不一一赘述。
序列表
〈110〉曹帅
〈120〉一种用于治疗骨髓增生、骨癌的药物组合物及其用途
〈160〉29
〈210〉1
〈211〉18
〈212〉PRT
〈213〉人工序列
〈400〉GATA-1
AQYQWGKDHRNFPTGNEY
〈210〉2
〈211〉18
〈212〉PRT
〈213〉人工序列
〈400〉GATA-2
WFLPWGVQLHCCHPHFLH
〈210〉3
〈211〉18
〈212〉PRT
〈213〉人工序列
〈400〉GATA-3
WGGGWWSSRGDHSGVRKA
〈210〉4
〈211〉18
〈212〉PRT
〈213〉人工序列
〈400〉GATA-4
VQHAWKETRIRWWQGRKN
〈210〉5
〈211〉18
〈212〉PRT
〈213〉人工序列
〈400〉GATA-5
SRSQPYRFGMMSSCERVD
〈210〉6
〈211〉18
〈212〉PRT
〈213〉人工序列
〈400〉GATA-6
ANIDTQKPARIDHTSNML
〈210〉7
〈211〉18
〈212〉PRT
〈213〉人工序列
〈400〉GATA-7
HMYNHPLTMAWMIPTFHR
〈210〉8
〈211〉18
〈212〉PRT
〈213〉人工序列
〈400〉GATA-8
ASWTAYQWDFHSHDYKFI
〈210〉9
〈211〉18
〈212〉PRT
〈213〉人工序列
〈400〉GATA-9
IHNHERVATPHHCRQQRW
〈210〉10
〈211〉18
〈212〉PRT
〈213〉人工序列
〈400〉GATA-10
RYHGRRYYKRAPLPHTPW
〈210〉11
〈211〉17
〈212〉PRT
〈213〉人工序列
〈400〉GATA-11
RVTQLGCQVSQPSWPNP
〈210〉12
〈211〉16
〈212〉PRT
〈213〉人工序列
〈400〉GATA-12
VLLREWSTSRRNWCGK
〈210〉13
〈211〉17
〈212〉PRT
〈213〉人工序列
〈400〉GATA-13
VWRLRSDPNDHCMTCNY
〈210〉14
〈211〉16
〈212〉PRT
〈213〉人工序列
〈400〉GATA-14
WQIPFSMWYVWWRCDA
〈210〉15
〈211〉17
〈212〉PRT
〈213〉人工序列
〈400〉GATA-15
ISRHSVFKVQKYQFLEP
〈210〉16
〈211〉16
〈212〉PRT
〈213〉人工序列
〈400〉GATA-16
LQAVKQSIPSTNRKVR
〈210〉17
〈211〉17
〈212〉PRT
〈213〉人工序列
〈400〉GATA-17
GPIGFGYCQQQSYRVGN
〈210〉18
〈211〉16
〈212〉PRT
〈213〉人工序列
〈400〉GATA-18
QDHQQWEQWSHSSKPD
〈210〉19
〈211〉17
〈212〉PRT
〈213〉人工序列
〈400〉GATA-19
QEHEHSWRGTRKGDKDS
〈210〉20
〈211〉16
〈212〉PRT
〈213〉人工序列
〈400〉GATA-20
KHQLRPRSAVGQWGFA
〈210〉21
〈211〉17
〈212〉PRT
〈213〉人工序列
〈400〉GATA-21
YGSAWKMKDKTRMRNDG
〈210〉22
〈211〉16
〈212〉PRT
〈213〉人工序列
〈400〉GATA-22
HSRHIWAMSFAAEYTG
〈210〉23
〈211〉17
〈212〉PRT
〈213〉人工序列
〈400〉GATA-23
TFILGQFIGQGQECGVK
〈210〉24
〈211〉16
〈212〉PRT
〈213〉人工序列
〈400〉GATA-24
RYLSSRRECGRRQFPC
〈210〉25
〈211〉17
〈212〉PRT
〈213〉人工序列
〈400〉GATA-25
GFMTRTTTHQRYCSQWF
〈210〉26
〈211〉16
〈212〉PRT
〈213〉人工序列
〈400〉GATA-26
PQSAHWLQVNNCLSAF
〈210〉27
〈211〉17
〈212〉PRT
〈213〉人工序列
〈400〉GATA-27
VVVCAVLDQVTETCDKV
〈210〉28
〈211〉16
〈212〉PRT
〈213〉人工序列
〈400〉GATA-28
INRTLACQLGLLQWGW
〈210〉29
〈211〉17
〈212〉PRT
〈213〉人工序列
〈400〉GATA-29
WNGWARRGSASWGMSIN
Claims (5)
1.一种用于治疗骨髓增生、骨癌的药物组合物,其特征是,取多肽0.01份、淀粉1份、甜蜜素或/和蔗糖适量作为甜味剂、苯甲酸0.1份,混匀,过50目筛,灭菌后,包装即可。
2.如权利要求1所述的药物组合物,其特征在于:所述多肽为GATA-1~29任一多肽,其序列分别为SEQIDNO:1~29所示。
3.根据权利要求1-2所述的组合物,其特征是,还可以添加硼替佐米。
4.权利要求1-3所述的药物组合物在制备用于特异性治疗骨髓增生、骨癌的药物的应用。
5.一种多肽,其特征是,为SEQIDNO:1~29任一所示的序列。
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