CN101485654B - T-2毒素在制备治疗实体瘤药物中的应用 - Google Patents
T-2毒素在制备治疗实体瘤药物中的应用 Download PDFInfo
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Abstract
本发明公开了T-2毒素的一种新用途，即T-2毒素在制备治疗实体瘤药物中的应用，其效治疗量为0.1～20mg/kg体重，优选0.5～8mg/kg体重，给药时，可以为植入给药、口服给药、静脉注射给药、皮下注射给药、肌肉注射给药，优选瘤内注射。本申请的发明人建立了各种实体瘤模型，然后将T-2毒素通过瘤内注射或与细胞共培养的方式考察T-2毒素对肿瘤或肿瘤细胞的抑制作用。实验表明，通过瘤内注射对肿瘤尤其是难以切除的实体瘤有确切的疗效，且通过瘤内注射方式给药，可以进一步降低T-2毒素的副作用范围和程度，减小其副作用而提高对肿瘤组织的抑制和杀伤作用。
Description
技术领域
本发明涉及T-2毒素在制备治疗实体瘤药物中的应用。
背景技术
肿瘤是威胁人类健康的常见疾病之一，仅次于心血管疾病，关于肿瘤的研究已取得较大进展，已发展了多种治疗肿瘤的各种放疗、化疗等方法，但各种药物及疗法均存在局限性，很难达到根治的效果，且易出现耐药性和副作用。肿瘤死亡率仍居于各种疾病之首。具数据显示，2006年我国有300万人死于癌症，而且肿瘤发病率仍处于上升趋势，并有年轻化趋势。据资料统计在不到20年的时间里，我国肿瘤发病率上升了69％，死亡率上升了29.4％。因此，研究新的有效的肿瘤治疗药物仍是目前肿瘤治疗的主要方向。对实体瘤一般采用手术切除的方法，但是手术切除对患者的损伤较大，并且很难保证切除干净，肿瘤组织出现浸润粘连后，边界不清切除难度更高，而某些脑组织实体瘤切除风险很高。放疗在肿瘤治疗中也是常用方法之一，但是，其对人体损伤较为严重，往往造成患者体制下降，预后不良，对于部分患者很难承受化疗的副作用，并且放疗效果也并不理想，且费用问题也是制约其应用的原因之一。因此对肿瘤的药物治疗仍是最普遍使用的方法。
T-2毒素，分子量为466.122，分子式为C24H34O9，结构式为4β，15-二乙酰氧基-8α-(3-甲氧基酰氧基)-3α-羟基-12，13-环氧单端孢霉-9-烯，其中的氧环和双键是其活性部位，氧环打开或双键还原均可使其毒性下降。T-2毒素为白色针状结晶，熔点为151℃-152℃，难溶于水，易溶于极性有机溶剂，它在室温条件下相当稳定，放置6-7年或加热至100-120℃1小时毒性不减。T-2毒素带有酯基，用碱处理后水解成相应的醇。
T-2毒素是镰刀菌所产生的单端胞霉烯族毒素中毒性最强的一种，主要作用于细胞分裂旺盛的组织器官，如胸腺、骨髓、肝、脾、淋巴结、生殖腺及胃肠粘膜等，抑制这些器官细胞蛋白质和DNA合成。此外，还发现该毒素可引起淋巴细胞中DNA单链的断裂。T-2毒素还可作用于氧化磷酸化的多个部位而引起线粒体呼吸抑制。而肿瘤组织即具有细胞过度分裂的特点，因此，对肿瘤组织存在广泛的毒性作用。
目前对T-2毒素的研究主要集中于其对动物的毒性研究和致病性研究，对T-2毒素用于实体瘤治疗药物的研究尚未发现有报道。
发明内容
针对上述现有技术，本发明提供了T-2毒素的一种新用途。
本发明实质上是T-2毒素在制备治疗实体瘤药物中的应用。
所述实体瘤包括胰腺瘤、肺瘤、肝瘤、肾细胞瘤、脑肿瘤、前列腺瘤。
所述T-2毒素的有效治疗量为0.1～20mg/Kg体重，优选0.5～8mg/Kg体重。
所述应用是将T-2毒素制成瘤内注射制剂
给药时，可以为植入给药、口服给药、静脉注射给药、皮下注射给药、肌肉注射给药，优选瘤内注射。
本申请的发明人建立了各种实体瘤，主要是胰腺癌、肺癌、肝癌、肾细胞癌、脑肿瘤、前列腺癌的动物模型或细胞模型，然后将T-2毒素通过瘤内注射或与细胞共培养的方式考察T-2毒素对肿瘤或肿瘤细胞的抑制作用。实验表明，通过瘤内注射对肿瘤尤其是难以切除的实体瘤有确切的疗效，且通过瘤内注射方式给药，可以进一步降低T-2毒素的副作用范围和程度，减小其副作用而提高对肿瘤组织的抑制和杀伤作用。
具体实施方式
下面结合试验对本发明作进一步的说明：
实施例1：T-2毒素对胰腺癌治疗作用的实验研究
将直径2-3mm的人胰腺癌组织碎片皮下移植到小鼠体内，待肿瘤长到6-7mm后，将溶解于乙醇生理盐水混合液的T-2毒素按照2.5mg/kg体重的剂量瘤内注射，对照组注射生理盐水。于注射后第1、5、9、14、19、24天用游标卡尺或标准模板测量肿瘤的大小，测量持续24天。经24天治疗后，T-2毒素组动物的肿瘤体积仅为对照组的52.19％。
实施例2：T-2毒素对肺癌治疗作用的实验研究
将小鼠Lewis肺癌细胞置于含10％胎牛血清及DMEM的完全培养液中，在37℃、5％CO2养箱中培养，2-3d更换一次培养液。细胞呈单层贴壁生长，0.5％胰蛋白酶消化传代。细胞总数达到要求后，台盼蓝拒染法测定活细胞数大于95％，调节细胞浓度为5×106/ml，细胞悬液备用C57BL/6纯系小鼠，雄性，20只，6～8周龄，体重(18±1)g。腋部皮下接种。每只接种0.2ml，细胞计数5×106个细胞/ml。小鼠分别随机分为2组，每组10只。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T-2毒素按照2.0mg/kg体重的剂量瘤内注射。试验结果见表1，试验结果表明T-2毒素对肺肿瘤的生长有明显的抑制作用。
表1 T-2毒素对肺癌的抑制作用
＊＊P＜0.01
实施例3：T-2毒素对肝癌治疗作用的实验研究
采用小鼠H22肝癌细胞株，ICR小鼠腹腔传代。无菌条件下抽取腹腔保种7-9天，生长旺盛的H22肝癌细胞，用生理盐水调节细胞浓度为5×106/ml，清洁剂ICR小鼠20只，6-8周龄，雄性，18-22g，随机分为2组，每组10只。均左腋皮下接种瘤细胞悬液0.2ml。接种7天后，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T-2毒素按照2.0mg/kg体重的剂量瘤内注射。分组给药后隔日用游标卡尺测量肿瘤长径(L)和短径(W)，计算肿瘤体积和肿瘤生长抑制率，结果见表2。试验结果表明T-2毒素对肝肿瘤的生长有明显的抑制作用。
表2 T-2毒素对肺癌的抑制作用
＊＊P＜0.01
实施例4：T-2毒素对肾细胞癌治疗作用的实验研究
采用妊娠透明细胞癌细胞系RCC-949，体外培养后调整细胞浓度为1×107/ml，0.2ml注入裸鼠都右腿背侧皮下，接种7天后，取出瘤组织剪成1mm3小块，进行鼠间传代，取第26代细胞调整细胞浓度为1×107/ml，1％戊巴比妥钠腹腔注射麻醉(50μg/10g)裸鼠，左侧腰背部纵切口，剪开肌肉层，暴露左肾脏，进行肾包膜下注射，0.1ml/只，接种7天后，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T-2毒素按照2.0mg/kg体重的剂量瘤内注射。分组给药后隔日用游标卡尺测量肿瘤长径(L)和短径(W)，计算肿瘤体积和肿瘤生长抑制率。试验结果表明T-2毒素对肾细胞癌的生长抑制率达48.35％。
实施例5：T-2毒素对脑肿瘤治疗作用的实验研究
取对数生长期人脑肿瘤SF763细胞，生理盐水调节浓度为1×106/ml，对BALB/cA小鼠进行接种，接种体积为0.025ml，接种点为一等边三角形的定点，底边为右耳与右眼的连线，高为5mm左右，接种深度为2mm左右。将小鼠用4.35％三氯水合氯醛麻醉后，酒精消毒，用注射器接种。接种7天后，小鼠分别随机分为2组，每组10只。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T-2毒素按照2.0mg/kg体重的剂量瘤内注射。观察和记录动物死亡时间，记算平均生存天数和生命延长率，生命延长率以实验组平均生存天数与对照组平均生存天数的差值除以对照组平均生存天数所得的百分数计算，结果见表3。试验结果表明T-2毒素对脑肿瘤的生长有明显的抑制作用。
表3 T-2毒素对脑肿瘤的治疗作用
＊＊P＜0.01
实施例6：T-2毒素对前列腺癌治疗作用的实验研究
前列腺癌PC-3细胞培养于含10％胎牛血清的RPM11640培养基中，添加100u·ml-1青霉素及100mg·L-1链霉素，37℃含5％二氧化碳的条件下常规培养，取指数生长期约5×106/ml细胞传代及接种于24孔板中，培养12h后加人溶解于乙醇生理盐水混合液的T-2毒素。药物作用48小时后出现显著的生长抑制作用。抑制率为51.79％。
实施例7：T-2毒素瘤内注射制剂的制备
取T-2毒素60mg，溶于17ml1mol/L的NaOH溶液中，加入50ml丙二醇，最后加入注射用水至100ml。
Claims (4)
1.T-2毒素在制备治疗肺癌的药物中的应用。
2.根据权利要求1所述的应用，其特征在于：所述T-2毒素的有效治疗量为0.1～20mg/Kg体重。
3.根据权利要求2所述的应用，其特征在于：所述T-2毒素的有效治疗量为0.5～8mg/Kg体重。
4.根据权利要求1所述的应用，其特征在于：是将T-2毒素制成瘤内注射制剂。
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