CN113082037B - 小分子组合物在制备治疗肝内胆管细胞癌药物中的应用 - Google Patents

小分子组合物在制备治疗肝内胆管细胞癌药物中的应用 Download PDF

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CN113082037B
CN113082037B CN202110438921.6A CN202110438921A CN113082037B CN 113082037 B CN113082037 B CN 113082037B CN 202110438921 A CN202110438921 A CN 202110438921A CN 113082037 B CN113082037 B CN 113082037B
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cholangiocellular carcinoma
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CN113082037A (zh
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龚渭华
刘晨
苗小龙
孔德强
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Zhejiang University ZJU
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

本发明提供小分子组合物在制备治疗肝内胆管细胞癌药物中的应用，所述小分子组合物由BET布罗莫结构域抑制剂与磷酸肌醇‑3‑激酶‑雷帕霉素靶点抑制因子组合，组合比例为50mg/kg:60mg/kg。本发明利用水动力转染法构建小鼠肝内胆管细胞癌模型，经实验证明，治疗后，观察组合物治疗组小鼠的荷瘤生存时间延长最显著。本发明组合物为治疗晚期肝内胆管细胞癌提供新的治疗药物，可在肝内胆管细胞癌治疗中的应用。

Description

小分子组合物在制备治疗肝内胆管细胞癌药物中的应用
技术领域
本发明属于医学生物工程领域，涉及小分子组合物在制备治疗肝内胆管细胞癌药物中的应用，是JQ1(BET布罗莫结构域抑制剂)与BEZ235(磷酸肌醇-3-激酶-雷帕霉素靶点抑制因子)组合物在制备治疗肝内胆管细胞癌药物中的应用。
背景技术
肝内胆管细胞癌(intrahepatie cholangiocarcinoma，ICC)发生于二级胆管以上的末梢侧肝内小胆管，起自肝内胆管上皮细胞，占胆管细胞癌的5％～10％。肝内胆管细胞癌是继肝细胞癌之后的第二大常见的原发性肝脏恶性肿瘤。近几年肝内胆管癌(ICC)发病率迅速上升。患者通常在晚期被诊断出来，这将他们排除在手术切除的范围之外，保守药物治疗成为唯一可能的治疗方法。吉西他滨/奥沙利铂方案作为晚期ICC的标准化疗方案，但其疗效相当有限。因此，我们迫切需要开发新的治疗策略来治疗这种致命的恶性肿瘤。
肝内胆管癌(ICC)药物治疗的研究进展非常缓慢。近年来，小分子抑制剂治疗的发展非常迅速，有望成为新的ICC治疗方向。mTOR(哺乳动物雷帕霉素靶蛋白)抑制剂在多种晚期肿瘤的治疗中已经取得了巨大的成功。然而大量临床试验显示mTOR抑制剂对ICC的治疗效果并不理想。
磷酸肌醇-3-激酶-雷帕霉素靶点抑制因子Dactolisib(BEZ235)是一种双重ATP竞争性PI3K和mTOR抑制剂,通过抑制肿瘤增殖发挥抗肿瘤效应。然而我们在前期试验中发现BEZ235直接用于治疗小鼠肝内胆管细胞癌的疗效不佳。有研究发现肝内胆管癌中高表达转录共激活因子相关蛋白YAP，其能够对BEZ235起到一定程度的耐药作用，这可能成为磷酸肌醇-3-激酶-雷帕霉素靶点抑制因子治疗ICC效果不佳的原因。
近年来，BET(bromo-and extra-terminal domain)蛋白家族的抑制剂作为例如：代谢性疾病，白血病，癌症，炎症及自身免疫性疾病多种疾病的重要治疗靶点而受到关注。在哺乳动物中，BET家族包括4个亚族，包括BRD2，BRD3，BRD4和BRDT。BRD4是BET蛋白家族成员，其可以与组蛋白乙酰化的赖氨酸残基结合，从而招募转录因子影响靶基因表达。JQ1是BRD4的一种抑制剂，可以进入细胞质与BRD4发生竞争性结合，导致BRD4不能与乙酰化的组蛋白结合，进而导致乙酰化的组蛋白不能招募转录调节因子，继而影响相关基因的表达，从而导致细胞周期的静止和促进细胞凋亡。我们在前期研究中发现JQ1能够明显降低转录共激活因子相关蛋白YAP，但应用于肝内胆管细胞癌中，疗效欠佳。
发明内容
发明的目的是提供小分子组合物在制备治疗肝内胆管细胞癌药物中的应用，所述小分子组合物由JQ1与BEZ235组合，组合比例为50mg/kg:60mg/kg。所述药物由小分子组合物与要用辅料制备。
本发明提供了JQ1与BEZ235组合的小分子组合物，利用水动力转染法构建小鼠肝内胆管细胞癌模型(见图1和图2)，经实验证明，治疗后，观察组合物治疗组小鼠的肝重/体重、脾重/体重明显下降(见图3)，小鼠生存时间延长最显著(见图4)。本发明组合物解决了肝内胆管细胞癌治疗效果不佳导致生存率低的难题，为治疗晚期肝内胆管细胞癌提供新的治疗药物，可在肝内胆管细胞癌治疗中的应用。
附图说明
图1为通过水动力转染法构建小鼠肝内胆管癌模型及用药方法。
图2为构建小鼠肝内胆管癌模型的大体观、HE及CK19。
图3为肿瘤负荷小鼠肝脏重量、脾脏重量与小鼠体重的比值的结果示意图。
图4为小鼠肿瘤负荷生存时间以及荷瘤指标的结果示意图。
图5为免疫组化检测小鼠荷瘤Ki-67表达情况。
具体实施方式
本发明结合附图和实施例作进一步的说明。
实施例1
通过构建小鼠肝内胆管细胞癌模型,并检测JQ1与BEZ235组合物对荷瘤生存时间及荷瘤指标的影响。
1.构建小鼠肝内胆管细胞癌模型
1.1实验动物及主要材料：雄性纯系C57小鼠，体重20-25g，购于上海斯莱科公司。癌症诱导质粒YAP及AKT购买自addgene。
1.2方法：选取野生型C57小鼠，构建质粒诱导小鼠ICC模型。配备分别编码人YAP基因、人AKT基因和“睡美人”转座酶基因的质粒混合液，量取占小鼠体重10％的质粒混合液通过小鼠尾静脉注入，于2周、4周及6周后分别行小鼠安乐死，称取体重，测量ICC肿瘤负荷指标，留取肝组织(结果见图2)。将小鼠随机分入对照组、JQ1单用组(50mg/kg)、BEZ235单用组(60mg/kg)以及组合物组(JQ1 50mg/kg+BEZ235 60mg/kg)，水动力转染质粒2周后开始分别给予治疗(见图1)。一部分小鼠在质粒注射6周后处死，称取体重，测量ICC肿瘤负荷指标，并留取肝组织行Ki67免疫组化染色(结果见图5)；另一部分小鼠在6周后继续随访观察，记录小鼠荷瘤存活天数(结果见图4)。
2.实验结果
水动力转染质粒6周后，JQ1或BEZ235单用均未能明显改变肿瘤负荷的指标(肝重/体重比)；而组合物组治疗显著性降低了肿瘤负荷(结果见于图3)。组合物组肝癌区域的Ki67阳性率显著性降低(结果见图5)。生存分析发现组合物组小鼠的荷瘤生存时间延长最显著(结果见图4)。

Claims (2)

1.一种小分子组合物在制备治疗肝内胆管细胞癌药物中的应用，其特征在于，所述小分子组合物由BET布罗莫结构域抑制剂JQ1与磷酸肌醇-3-激酶-雷帕霉素靶点抑制因子BEZ235组合，组合比例为50mg/kg:60mg/kg。
2.根据权利要求1所述的应用，其特征在于，所述药物由组合物与药用辅料制备。
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