CN114903895A - 一种抗肿瘤药物 - Google Patents
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Abstract
本发明提供了一种抗肿瘤药物，具体是用于治疗肝内胆管细胞癌的药物，所述的药物是夫拉平度(Flavopiridol,Alvocidib)。本发明研究结果显示，夫拉平度具有显著抑制肝内胆管癌细胞生长和显著抑制肿瘤细胞迁移的作用，以夫拉平度为药物活性成份，加入制药学上可以接受的添加剂或/和赋形剂或/和载体，可以制成用于治疗肝内胆管细胞癌的药物制剂，如片剂、颗粒剂、液体制剂等。
Description
技术领域
本发明属于医学和药学领域，涉及抗肿瘤的药物，具体涉及用于治疗肝内胆管细胞癌的药物。
背景技术
肝内胆管细胞癌(intrahepatic cholangiocarcinoma iCCA)是起源于肝内胆管上皮的恶性肿瘤，是发病率仅次于肝细胞肝癌的第二大肝脏原发恶性肿瘤，约占肝脏原发恶性肿瘤的10％-15％，近年来发病率呈上升趋势。由于其发病隐匿，细胞学及病理学诊断敏感性不高等特点，大多数病人被确诊时已是疾病进展期。目前iCCA的诊断主要依赖于病人症状体征，CT/MRI等影像学检查，CA-19-9等血清学指标，缺乏敏感特异的诊断标记物，大多数病人被发现时已处于疾病进展期，失去根治性切除机会，iCCA病人预后极差，手术切除肿瘤被认为是主要治疗手段，但只有约35％的早期病人具有根治性切除的指证。单纯的化学药物治疗应用于肝内胆管细胞癌的效果不佳，目前仍缺乏根治iCCA的药物治疗手段。ICC的发病高峰是55岁到75岁，不到10％的病例发生在45岁之前。对年龄大于45岁合并高危因素的人群进行定期筛查，有助于ICC的早期诊断和及时治疗。与肝细胞肝癌男性高发不同，ICC男女发病比例约为2:3。黄志强院士在《肝胆管外科的发展方向》一文中指出，我国的胆管癌患者占全世界的55％[参见：黄志强.肝胆管外科的发展方向[J].外科理论与实践,2011,16(4):329-331]。考虑到ICC在胆管癌中的占比，可知我国的ICC患者基数也是相当庞大的。本病恶性度高，预后不佳，少有长期生存者。ICC早期无明显临床症状，多数患者发现时已失去手术时机，因此对ICC的早期诊断和及时治疗提出了更高的要求。外科手术是延长ICC患者生存期的首选治疗方式，根治性手术切除范围取决于癌肿的部位与大小，方式包括左、右半肝切除、左、右肝大部切除、肝叶楔形切除、肝段切除等。根治性手术切除术可明显延长患者生存期。而行姑息性外科切除、保守治疗及未治疗者均无5年生存者。ICC具有淋巴侵袭性，较易发生淋巴结转移。ICC术后复发率较高。因肿瘤体积较大或位置不适合手术的患者，应先行药物化疗，使肿瘤降期后再行相关手术治疗。影响ICC的治疗效果和复发的因素争议较多，且ICC患者发现时多已失去手术时机及术后复发率高，因此临床医生需要选择合适的辅助治疗方式以达到治愈或减少复发的目的。术后辅以化疗应该要比单纯手术效果更好，存在淋巴结转移和(或)血管侵犯时则需行化学药物治疗。单纯化学药物治疗主要应用于有肝外转移、失去其他治疗措施可能的患者。因为此时化学药物治疗成为延长患者生存期的可能途径，但目前现有化学药物治疗应用于ICC的效果并不佳。因此研究和寻找治疗ICC的有效化学药物是当前面临的重要课题。
发明内容
本发明的任务是提供一种抗肿瘤药物，具体是用于治疗肝内胆管细胞癌的药物。
实现本发明的技术方案是：
本发明提供的用于治疗肝内胆管细胞癌的药物是夫拉平度(Flavopiridol,Alvocidib)。
夫拉平度(Flavopiridol,Alvocidib)分子式为C21H20ClNO5，分子量为401.84，化学结构式如以下式Ⅰ所示，大日本住友制药目前正就夫拉平度开展针对复发/难治性急性髓系白血病的II期临床研究。生命科学试剂供应商如selleck、MCE(MedChemExpress)均可提供该抑制剂。
本发明揭示，夫拉平度能显著抑制肿瘤细胞生长和肿瘤细胞迁移，能用于制备用于治疗肿瘤的药物。
本发明的一个实施例将肝内胆管癌细胞株HCCC-9810细胞以1000个细胞/孔铺于96孔细胞培养板中，加入100μl含10％胎牛血清(FBS)的RPMI1640培养基(采购于Hyclone公司)，在37℃含5％CO2培养箱中培养16小时后，换入100μl含10％胎牛血清(FBS)的RPMI1640培养基；将该96孔细胞培养板分为两个区域，在其中的一个区域加入溶于二甲基亚砜(DMSO)溶剂的母液为10mM的夫拉平度(MCE公司，货号：HY-10005)5.9x10-3μl至终浓度为590nm作为实验组，于另一区域加入不含夫拉平度的二甲基亚砜(DMSO)溶剂5.9x10-3μl作为未加药处理组，将该96孔细胞培养板在37℃含5％CO2培养箱中培养五天，于第五天采用CCK8方法检测细胞增殖情况，该结果显示，夫拉平度能显著抑制肿瘤细胞生长，见图1和实施例1中的表1。
本发明的另一个实施例将HCCC-9810细胞以4x105个细胞/孔铺于6孔板中，在37℃含5％CO2培养箱中培养16小时待细胞贴壁后，换入1.5ml含10％胎牛血清(FBS)的RPMI1640培养基，加入溶于二甲基亚砜(DMSO)溶剂的母液为10mM的夫拉平度8.85x10-2μl至终浓度为590nm培养24小时后，弃去上清，收集细胞并计数，将1x105 HCCC-9810细胞重悬于200μl无血清的RPMI1640培养基中，铺至transwell细胞迁移板(Corning公司，货号3422)8μm上层小室，在下层小室中加入500μl含10％血清的RPMI1640培养基，将同一块6孔板分为两区，于另一区中加入不含夫拉平度的二甲基亚砜(DMSO)溶剂8.85x10-2μl作为未加药处理组，同样培养条件及时间处理后，收集细胞以同样的细胞数量和条件铺入同一块transwell细胞迁移板不同上层小室，下层小室加入同条件培养基后，将该板于37℃含5％CO2培养箱中培养24小时后用0.5％结晶紫对迁移过聚碳酸酯膜的细胞进行染色，光学显微镜统计细胞数表明夫拉平度能显著抑制肿瘤细胞迁移，见图2和实施例2中的表2。
本发明研究结果显示，夫拉平度能显著抑制肝内胆管癌细胞生长和迁移，能用于制备治疗肝内胆管细胞癌(intrahepatic cholangiocarcinoma iCCA)的药物。以夫拉平度为药物活性成份，加入制药学上可以接受的添加剂或/和赋形剂或/和载体，可以制成用于治疗肝内胆管细胞癌的药物制剂，如片剂、颗粒剂、液体制剂等。
附图说明
图1：CCK8实验检测肝内胆管癌细胞增殖。实验重复三次，结果表明，与未给药处理组相比，夫拉平度显著抑制肿瘤细胞HCCC-9810生长。Ctrl，未加药处理组。Alvocidib，夫拉平度实验组。Absorbance，CCK8实验吸光值。***p<0.001。
图2：Transwell细胞迁移实验检测肝内胆管癌细胞迁移。实验重复三次，结果表明，与未给药处理组细胞相比，夫拉平度显著抑制肿瘤细胞HCCC-9810迁移。Mock，未加药处理组。Alvocidib，夫拉平度实验组。Number of migrated 9810cells，迁移过聚碳酸酯膜的HCCC-9810细胞数量。***p<0.001。
具体实施方式
实施例1：夫拉平度显著抑制肿瘤细胞生长
将肝内胆管癌细胞株HCCC-9810细胞以1000个细胞/孔铺于96孔细胞培养板中，加入100μl含10％胎牛血清(FBS)的RPMI1640培养基(采购于Hyclone公司)，在37℃含5％CO2培养箱中培养16小时后，换入100μl含10％胎牛血清(FBS)的RPMI1640培养基；将该96孔细胞培养板分为两个区域，在其中的一个区域加入溶于二甲基亚砜(DMSO)溶剂的母液为10mM的夫拉平度(MCE公司，货号：HY-10005)5.9x10-3μl至终浓度为590nm作为实验组，于另一区域加入不含夫拉平度的二甲基亚砜(DMSO)溶剂5.9x10-3μl作为未加药处理组，将该96孔细胞培养板在37℃含5％CO2培养箱中培养五天，于第五天采用CCK8方法检测细胞增殖情况，该结果显示，夫拉平度能显著抑制肿瘤细胞生长，见图1和表1。
表1：展示了未给药处理组和夫拉平度处理组的CCK8检测细胞增殖的三次重复实验结果。Ctrl，未加药处理组。Alvocidib，夫拉平度实验组。Absorbance，CCK8实验吸光值。
| Absorbance | Ctrl | Alvocidib |
| 1 | 1.459 | 0.010 |
| 2 | 1.434 | 0.044 |
| 3 | 1.531 | 0.034 |
实施例2：夫拉平度显著抑制肿瘤细胞迁移
将HCCC-9810细胞以4x105个细胞/孔铺于6孔板中，在37℃含5％CO2培养箱中培养16小时待细胞贴壁后，换入1.5ml含10％胎牛血清(FBS)的RPMI1640培养基，加入溶于二甲基亚砜(DMSO)溶剂的母液为10mM的夫拉平度8.85x10-2μl至终浓度为590nm培养24小时后，弃去上清，收集细胞并计数，将1x105 HCCC-9810细胞重悬于200μl无血清的RPMI1640培养基中，铺至transwell细胞迁移板(Corning公司，货号3422)8μm上层小室，在下层小室中加入500μl含10％血清的RPMI1640培养基，将同一块6孔板分为两区，于另一区中加入不含夫拉平度的二甲基亚砜(DMSO)溶剂8.85x10-2μl作为未加药处理组，同样培养条件及时间处理后，收集细胞以同样的细胞数量和条件铺入同一块transwell细胞迁移板不同上层小室，下层小室加入同条件培养基后，将该板于37℃含5％CO2培养箱中培养24小时后用0.5％结晶紫对迁移过聚碳酸酯膜的细胞进行染色，光学显微镜统计细胞数表明夫拉平度能显著抑制肿瘤细胞迁移，见图2和表2。
表2：未给药处理组和夫拉平度处理组在Transwell实验中细胞的迁移数量，实验重复三次，共选取六个观察视野。Mock，未加药处理组。Alvocidib，夫拉平度实验组。
Claims (6)
1.夫拉平度(Flavopiridol,Alvocidib)在制备用于治疗肿瘤药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述的夫拉平度(Flavopiridol,Alvocidib)的化学结构式如式Ⅰ所示：
3.一种治疗肿瘤的药物，其特征在于，含有作为活性成分的夫拉平度(Flavopiridol,Alvocidib)。
4.一种治疗肿瘤的药物制剂，其特征在在于，它是以夫拉平度(Flavopiridol,Alvocidib)为活性成分加上制药学上可接受的添加剂或/和赋形剂或/和载体制成的药物制剂。
5.根据权利要求4所述的药物制剂，其特征在于，所述的药剂为片剂、颗粒剂或液体制剂。
6.权利要求1、3或4中所述的肿瘤是肝内胆管细胞癌。
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Non-Patent Citations (1)
| Title |
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| SAOWALUK SAISOMBOON等: "Antitumor effects of flavopiridol, a cyclin-dependent kinase inhibitor, on human cholangiocarcinoma in vitro and in an in vivo xenograft model" * |
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