博来霉素 | 11056-06-7

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 中文名称: 博来霉素
• 中文别名: 争光霉素；博莱霉素
• 英文名称: Bleomycin
• 英文别名: 3-[[2-[2-[2-[[(2S,3R)-2-[[(2S,3S,4R)-4-[[(2S,3R)-2-[[6-amino-2-[(1S)-3-amino-1-[[(2S)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[3-[4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3-(1H-imidazol-5-yl)propanoyl]amino]-3-hydroxy-2-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]ethyl]-1,3-thiazol-4-yl]-1,3-thiazole-4-carbonyl]amino]propyl-dimethylsulfanium
• CAS: 11056-06-7
• 化学式: C55H84N17O21S3+
• 分子量: 1415.6
• InChiKey: OYVAGSVQBOHSSS-WXFSZRTFSA-O

物化性质

• 溶解度：
  在水中的溶解度20 mg/mL
• 物理描述：
  Bleomycin appears as colorless or yellowish powder. Possible bluish color depending on copper content. (NTP, 1992)
• 颜色/状态：
  Colorless to yellow powder
• 熔点：
  71 °C
• 稳定性/保质期：
  In vitro, bleomycin is inactivated by agents containing sulfhydryl groups, hydrogen peroxide, and ascorbic acid. Bleomycin sulfate sterile powder is stable under refrigeration at 2-8 °C and should not be used after the expiration date is reached.

计算性质

• 辛醇/水分配系数(LogP)：
  -7.5
• 重原子数：
  96
• 可旋转键数：
  36
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  685
• 氢给体数：
  20
• 氢受体数：
  31

ADMET

代谢

肝脏的

Hepatic

来源:DrugBank

代谢

生物转化尚不清楚；可能是通过组织中的酶降解（基于动物研究）。组织酶活性不同，这可能会决定博来霉素的毒性和抗肿瘤效果... 目前尚不清楚是否有任何代谢物具有活性。

Biotransformation is unknow; probably by enzymatic degradation in tissues (based on animal studdies). Tissue enzyme activity varies, which may determine toxicity and antitumor effect of bleomycin... It is not known if any of the metabolites are active.

来源:Hazardous Substances Data Bank (HSDB)

代谢

链霉素可被细胞质中的半胱氨酸蛋白酶酶——链霉素水解酶失活。这种酶在正常组织中广泛分布，除了皮肤和肺，这两个部位是链霉素毒性的靶标。通过酶促降解的药物系统性消除在肾功能严重受损的患者中可能才重要。

Bleomycin is inactivated by a cytosolic cysteine proteinase enzyme, bleomycin hydrolase. The enzyme is widely distributed in normal tissues with the exception of the skin and lungs, both targets of bleomycin toxicity. Systemic elimination of the drug by enzymatic degradation is probably only important in patients with severely compromised renal function.

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏 消除途径：据报道，中度严重肾衰竭的患者通过尿液排出的剂量不到20%。 半衰期：115分钟

Hepatic Route of Elimination: It was reported that patients with moderately severe renal failure excreted less than 20% of the dose in the urine. Half Life: 115 minutes

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

有人建议，博来霉素会增加对氧中毒的敏感性，最近的研究支持了促炎症细胞因子IL-18和IL-1beta在博来霉素引起肺损伤机制中的作用。（维基百科）在原代肺内皮细胞中，博来霉素通过外在途径启动凋亡（A15408）。关于博来霉素引起的硬化病，博来霉素对皮肤构成细胞（如成纤维细胞、角质形成细胞和内皮细胞）以及免疫细胞产生各种影响。博来霉素在培养的人皮肤成纤维细胞中上调了细胞外基质蛋白以及纤维生成细胞因子（如TGF-β和CTGF）的基因表达。此外，体外研究表明，博来霉素以剂量依赖性方式刺激内皮细胞分泌胶原蛋白合成，这一作用可被抗TGF-β抗体抑制。（A15409）。

It has been suggested that bleomycin induces sensitivity to oxygen toxicity and recent studies support the role of the proinflammatory cytokines IL-18 and IL-1beta in the mechanism of bleomycin-induced lung injury. (Wikipedia) In primary pulmonary endothelial cells, bleomycin initiates apoptosis via the extrinsic pathway (A15408). In relation to bleomycin-induced scleroderma, bleomycin exerts various effects on skin-constituted cells such as fibroblasts, keratinocytes, and endothelial cells, as well as immunocytes. Bleomycin upregulates gene expression of ECM proteins as well as fibrogenic cytokines such as TGF-β and CTGF in cultured human skin fibroblasts. Also, in vitro studies showed a dose-dependent stimulation of endothelial cell secretion of collagen synthesis by bleomycin, which was inhibited by the anti-TGF-β antibody. (A15409).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

使用博来霉素进行化疗并结合其他药物时，10%至40%的患者会出现血清酶水平升高，1%至7%的患者血清酶水平会超过正常上限（ULN）的5倍，具体取决于剂量和其他联合使用的药物。丙氨酸氨基转移酶（ALT）的升高通常是无需症状的，且在停止化疗后一个月内会恢复。在许多情况下，由于患者还暴露于其他可能对肝脏有毒性的药物，很难将肝功能测试异常归咎于博来霉素。在接受博来霉素治疗的患者中，有报告称罕见明显的临床肝损伤病例，但发病时间和损伤模式差异很大，通常归因于其他原因，如乙型肝炎的再激活或其他烷化剂引起的门脉阻塞性综合征。在使用含有博来霉素的方案治疗霍奇金病时，有描述在化疗过程中出现消失胆管综合征的情况，但这种独特的肝脏损伤形式也发生在未治疗的霍奇金病患者中；一些病例在淋巴瘤诊断之前出现。博来霉素肝毒性的肝脏组织学特征尚未被很好地描述，但它在动物模型中会导致肝脏脂肪变性。在一例个案报告中，描述了在用博来霉素进行肝血管瘤的动脉栓塞后几年出现的胆管狭窄和类似于硬化性胆管炎的综合症。

Chemotherapy with bleomycin in combination with other agents is associated with serum enzyme elevations in 10% to 40% of patients and with levels above 5 times ULN in 1% to 7% of patients, depending upon the dose and other agents used. The ALT elevations are usually asymptomatic and transient, resolving within a month of stopping chemotherapy. In many instances, it is difficult to attribute the liver test abnormalities to bleomycin because of the exposure to other potentially hepatotoxic agents. Rare instances of clinically apparent liver injury have been reported in patients receiving bleomycin, but the time to onset and pattern of injury has varied greatly and was usually attributed to other causes such as reactivation of hepatitis B or to sinusoidal obstruction syndrome due to other alkylating agents. Vanishing bile duct syndrome has been described during chemotherapy of Hodgkin disease with bleomycin containing regimens, but this distinctive form of liver injury also occurs in Hodgkin disease patients who are not treated; some instances arising before the diagnosis of lymphoma. The liver histology of bleomycin hepatotoxicity has not been well characterized, but it causes hepatic steatosis in animal models. In a single case report, biliary strictures and a sclerosing cholangitis-like syndrome was described arising several years after intra-arterial embolization of a large hepatic hemangioma with bleomycin.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：博来霉素

Compound:bleomycin

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：模糊的 DILI 关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

系统吸收率大约为45%。

Systemic absorption is approximately 45%.

来源:DrugBank

吸收、分配和排泄

• 消除途径

据报道，中度至重度肾功能衰竭的患者，有少于20%的剂量通过尿液排出。

It was reported that patients with moderately severe renal failure excreted less than 20% of the dose in the urine.

来源:DrugBank

吸收、分配和排泄

硫酸博来霉素从胃肠道吸收不显著，必须通过非胃肠道途径给药。博来霉素可以通过胸膜内或腹腔内给药被系统吸收。据报道，胸膜内给药后博来霉素的系统吸收率为45%。

Bleomycin sulfate is not significantly absorbed from the GI tract and the drug must be administered parenterally. Bleomycin is absorbed systemically following intrapleural or intraperitoneal administration. Systemic absorption of 45% has been reported following intrapleural administration of bleomycin.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

博来霉素通过肌肉注射（IM）、皮下注射（SC）、腹腔注射（IP）或胸膜腔注射（IPL）给药后能够迅速吸收，给药后30至60分钟达到血浆峰值浓度。博来霉素的系统性生物利用度在肌肉注射后为100%，皮下注射后为70%，而腹腔注射和胸膜腔注射后为45%，与静脉推注和bolus（一次性）给药相比。

Bleomycin is rapidly absorbed following either intramuscular (IM), subcutaneous (SC), intraperitoneal (IP) or intrapleural (IPL) administration reaching peak plasma concentrations in 30 to 60 minutes. Systemic bioavailability of bleomycin is 100% and 70% following IM and SC administrations, respectively, and 45% following both IP and IPL administrations, compared to intravenous and bolus administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

博来霉素在体内广泛分布，患者静脉注射15单位/平方米的剂量后，平均分布体积为17.5升/平方米。

Bleomycin is widely distributed throughout the body with a mean volume of distribution of 17.5 L/sq m in patients following a 15 units/sq m IV bolus dose.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  T
• 安全说明：
  S36/37,S45,S53
• 危险类别码：
  R40,R46

制备方法与用途

概述

博莱霉素（Blcomycin, BLM）由梅泽滨夫博士等人首次从轮丝链霉（Streptomyces verticillus）中分离，属于糖肽类抗肿瘤抗生素。BLM进入人体后很快集聚于皮下、肺部、睾丸等部位，在治疗淋巴瘤、鳞状细胞癌、肺癌和睾丸癌等方面疗效显著。它无明显骨髓抑制或免疫功能抑制作用，但可能会引起肺炎样症状和肺纤维化等严重毒副反应。博莱霉素因其独特的化学结构和作用机制而对特定肿瘤具有选择性效果，在抗肿瘤抗生素领域占据重要地位。

国外使用的Blanoxane的主要成分为BLMA2，我国发现的平阳霉素主要成分是BLMA5。这两种药物毒性小、抗癌作用强，已在临床中广泛应用。

药代动力学

博莱霉素口服无效，需通过肌肉或静脉注射给药。注射后在血中迅速消失，并广泛分布于肝、脾、肾等组织中，尤其是皮肤和肺部较多，因该处细胞中酰胺酶活性低，博来霉素水解失活较少。其他正常组织则迅速失活。部分药物可透过血脑屏障，血浆蛋白结合率仅为1%。

连续静脉滴注4～5日，每日30 mg时，24小时内血药浓度稳定在146 ng/mL；一次量静脉注射后初期和终末消除半衰期分别为24分钟及4小时。肌注或静注博来霉素15 mg后的血药浓度分别为1μg/mL和3μg/mL。

主要通过肝脏代谢，并可通过尿液排泄，需注意监测肝功能与肾功能。

作用机制

博莱霉素的作用机制涉及DNA的破坏、细胞周期的抑制等。在高剂量下可导致肺纤维化，在低剂量下可能具有抗肿瘤作用。

毒性分级

博莱霉素属于高毒物质。急性毒性：腹腔-大鼠 LD50: 168 毫克/公斤；腹腔-小鼠LD50: 35 毫克/公斤。

刺激数据：眼睛-兔 1 毫克 轻度

可燃性危险特性

热分解排出有毒氮氧化物气体，需注意避免明火或高温引发火灾。

储运特性

库房通风低温干燥保存，并采取防火措施。

灭火剂

水、干粉、干砂、二氧化碳及1211灭火剂均可用于扑灭博莱霉素引起的火灾。

用法与用量

成人：肌肉或静脉注射，每次15 mg，每日一次或每周2～3次；总量不宜超过400 mg。胸腔内注射时，在尽量抽净胸腔积液后注入20～40 mg，并让病人变换体位使药液均匀分布。

小儿：每次按体表面积给予10 mg/m²。

制剂与规格

注射液：5 mg、10 mg、15 mg。

参考文献

• 邹国林, 李鹏. 博莱霉素研究进展[J]. 生命的化学(中国生物化学会通讯), 1994, 05: 42-44.
• 张宏印, 李电东. 博莱霉素作用机制研究进展[J]. 国外医药(抗生素分册), 1999, 06: 266-270.
• 陈少萍, 陈卓辉, 陈佩珠 主编. 口腔临床药物手册. 广州：华南理工大学出版社, 2005.
• 张庆宪 主编. 常用新药精汇手册. 郑州：河南科学技术出版社, 2009. 第633-634页.
• 王晓慧 主编. 临床医护用药手册. 天津：天津科学技术出版社, 2009. 第453页.
• 徐红, 王开贞, 王玉奎 主编. 临床常用药物. 济南：山东科学技术出版社, 2005. 第317页.

用途：抗肿瘤药。

类别：有毒物质

毒性分级：高毒

急性毒性：腹腔-大鼠 LD50: 168 毫克/公斤; 腹腔-小鼠LD50: 35 毫克/公斤

刺激数据：眼睛-兔 1 毫克 轻度

可燃性危险特性：热分解排出有毒氮氧化物气体

储运特性：库房通风低温干燥保存，并采取防火措施。

灭火剂：水、干粉、干砂、二氧化碳及1211灭火剂均可用于扑灭博莱霉素引起的火灾。

文献信息

• Devices and methods for determining and/or isolating cells such as circulating cancer or fetal cells
  申请人：Analiza, Inc.

  公开号：US10928405B2

  公开（公告）日：2021-02-23

  Some embodiments of the present invention generally relate to devices and methods for determining and/or isolating cells. For example, one aspect is generally directed to methods and devices for detecting, identifying, counting, and/or potentially sorting cells of interest in blood or other biological sample. In some embodiments, blood samples (or other biological fluids) may be treated with signaling entities, such as pH-sensitive entities, that change color or otherwise produce a signal in suitable internal environments. For example, certain cells, such as cancer or fetal cells, may have differences in intracellular pH compared to other cells, which can be detected using pH-sensitive entities. In certain embodiments, the cells may be sorted based on such signaling entities; for example, illumination of cells in a suitable machine for sorting cells (e.g., using fluorescent light) may allow determination of the cells, which may also be recovered or isolated for further manipulation in some cases.

  本发明的一些实施方案一般涉及用于确定和/或分离细胞的装置和方法。例如，一个方面一般涉及用于检测、识别、计数和/或可能分选血液或其他生物样本中相关细胞的方法和装置。在某些实施方案中，血液样本（或其他生物液体）可以用信号实体（如 pH 敏感实体）处理，这些实体会变色或在合适的内部环境中产生信号。例如，某些细胞（如癌细胞或胎儿细胞）与其他细胞相比，细胞内 pH 值可能存在差异，可使用 pH 值敏感实体进行检测。在某些实施方案中，可根据此类信号实体对细胞进行分选；例如，在用于分选细胞的合适机器中对细胞进行照射（如使用荧光灯），可对细胞进行测定，在某些情况下，还可对细胞进行回收或分离，以便进一步操作。
• DEVICES AND METHODS FOR DETERMINING AND/OR ISOLATING CELLS SUCH AS CIRCULATING CANCER OR FETAL CELLS
  申请人：Analiza, Inc.

  公开号：US20190178901A1

  公开（公告）日：2019-06-13

  Some embodiments of the present invention generally relate to devices and methods for determining and/or isolating cells. For example, one aspect is generally directed to methods and devices for detecting, identifying, counting, and/or potentially sorting cells of interest in blood or other biological sample. In some embodiments, blood samples (or other biological fluids) may be treated with signaling entities, such as pH-sensitive entities, that change color or otherwise produce a signal in suitable internal environments. For example, certain cells, such as cancer or fetal cells, may have differences in intracellular pH compared to other cells, which can be detected using pH-sensitive entities. In certain embodiments, the cells may be sorted based on such signaling entities; for example, illumination of cells in a suitable machine for sorting cells (e.g., using fluorescent light) may allow determination of the cells, which may also be recovered or isolated for further manipulation in some cases.