bleomycin | 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
• 英文名称: bleomycin
• 英文别名: Bleocin；3-[[2-[2-[2-[[(2S,3R)-2-[[(2S,3S,4R)-4-[[(2S)-2-[[6-amino-2-[(1S)-3-amino-1-[[(2S)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2R,3S,4S,5S,6S)-3-[(2R,3S,4S,5R,6R)-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: 1415.57
• InChiKey: OYVAGSVQBOHSSS-QRQYLRPSSA-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
• 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

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... 目前尚不清楚任何代谢物是否具有活性。

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

链霉素通过细胞质半胱氨酸蛋白酶酶——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，这两个都是链霉素毒性的靶标。通过酶促降解消除药物的系统性作用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)

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）的升高通常是无症状的和暂时的，停止化疗后一个月内会恢复正常。在许多情况下，由于患者接触了其他可能对肝脏有毒性的药物，很难将肝功能测试异常归因于博来霉素。在接受博来霉素治疗的患者中，有罕见报道出现临床明显的肝损伤，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综合征。在使用含有博来霉素方案的霍奇金病化疗期间，有描述肝内胆管消失综合征的情况，但这种独特的肝脏损伤也发生在未治疗的霍奇金病患者中；有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得到很好的描述，但在动物模型中，它会导致肝脏脂肪变性。在一例病例报告中，描述了在用博来霉素进行肝血管瘤的动脉栓塞后数年出现的胆管狭窄和硬化性胆管炎样综合征。

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

• 致癌性证据

评估：人类对于依托泊苷致癌性的证据有限。有充分的人类证据表明，依托泊苷与顺铂和博来霉素联合使用具有致癌性。在实验动物中，对于依托泊苷的致癌性证据不足。总体评估：依托泊苷可能对人类具有致癌性（2A组）。在得出此评估时，工作组注意到依托泊苷会在白血病细胞中引起独特的细胞遗传学损伤，这些损伤可以轻易与由烷化剂诱导的损伤区分开来。这些白血病的短暂潜伏期与由烷化剂诱导的白血病潜伏期形成对比。在体外的人类细胞和体内动物细胞中，会发生强烈的蛋白质遮蔽DNA断裂和致裂变效应。依托泊苷与顺铂或博来霉素联合使用对人类具有致癌性。/依托泊苷与顺铂或博来霉素联合使用/

Evaluation: There is limited evidence in humans for the carcinogenicity of etoposide. There is sufficient evidence in humans for the carcinogenicity of etoposide given in combination with cisplatin and bleomycin. There is inadequate evidence in experimental animals for the carcinogenicity of etoposide. Overall evaluation: Etoposide is probably carcinogenic to humans (Group 2A). In reaching this evaluation, the Working Group noted that etoposide causes distinctive cytogenetic lesions in leukemic cells that can be readily distinguished from those induced by alkylating agents. The short latency of these leukemias contrasts with that of leukemia induced by alkylating agents. Potent protein masked DNA breakage and clastogenic effects occur in human cells in vitro and animal cells in vivo. Etoposide in combination with cisplatin or bleomycin is carcinogenic to humans. /Etoposide in combination with cisplatin or bleomycin/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌物分类

国际癌症研究机构致癌剂：博来霉素

IARC Carcinogenic Agent:Bleomycins

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构（IARC）致癌物分类：2B组：可能对人类致癌

IARC Carcinogenic Classes:Group 2B: Possibly carcinogenic to humans

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构专著：第26卷：（1981年）一些抗癌和免疫抑制剂

IARC Monographs:Volume 26: (1981) Some Antineoplastic and Immunosuppressive Agents

来源:International Agency for Research on Cancer (IARC)

吸收、分配和排泄

硫酸博来霉素从胃肠道吸收不明显，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均为45%，与静脉推注给药相比。

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，给予患者每平方米15单位静脉注射 bolus 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)

吸收、分配和排泄

bleomycin的蛋白质结合率非常低（1%）。

Protein binding of bleomycin is very low (1%).

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。

反应信息

• 作为反应物：
  描述：

  bleomycin 、 2-sulfo-9-fluoreylmethoxycarbonyl N-hydroxysuccinimide 在 碳酸氢钠 作用下， 反应 2.0h， 生成
  参考文献：
  名称：

  Converting bleomycin into a prodrug that undergoes spontaneous reactivation under physiological conditions

  摘要：

  Bleomycin is an anticancer antibiotic effective against a range of human malignancies. Yet its usefulness is limited by serious side effects. In this study, we converted bleomycin into a prodrug by covalently linking 2-sulfo, 9 fluorenylmethoxycarbonyl (FMS) to the primary amino side chain of bleomycin. FMS-bleomycin lost its efficacy to bind transition metal ions and therefore was converted into an inactive derivative. Upon incubation in vitro under physiological conditions, the FMS-moiety undergoes spontaneous hydrolysis, generating native bleomycin possessing full anti-bacterial potency. FMS hydrolysis and reactivation takes place with a t(1/2) value of 17 +/- 1 h. In silico simulation predicts a narrow therapeutic window in human patients of seven hours, starting 40 min after administration. In mice, close agreement was obtained between the experimental and the simulated pharmacokinetic profiles for FMS-bleomycin. FMS-bleomycin is thus shown to be a classical prodrug: it is inactive at the time of administration and the non-modified (active) bleomycin is released with a desirable pharmacokinetic profile following administration, suggesting it may have therapeutic value in the clinic.

  DOI：

  10.1016/j.taap.2019.114782

文献信息

• Material and methods for treating or preventing HER-3 associated diseases
  申请人：Daiichi Sankyo Europe GmbH

  公开号：EP2719708B1

  公开（公告）日：2017-10-25
• MATERIAL AND METHODS FOR TREATING OR PREVENTING HER-3 ASSOCIATED DISEASES
  申请人：Daiichi Sankyo Europe GmbH

  公开号：EP3351558B1

  公开（公告）日：2020-03-11
• USE OF HER3 BINDING AGENTS IN PROSTATE TREATMENT
  申请人：HETTMANN Thore

  公开号：US20120156130A1

  公开（公告）日：2012-06-21

  Described herein are materials and methods for using a HER3 binding agent for prostate treatment. The HER3 binding agent can be, for example, an antibody, and can be used to treat conditions such as benign prostate hyperplasia (BPH) and prostate cancer.
• Combination Therapies for the Treatment of Proliferative Disorders
  申请人：Orlemans Everardus O.

  公开号：US20150328188A1

  公开（公告）日：2015-11-19

  Provided is a pharmaceutical composition comprising a combination of an Hsp90 inhibitor and at least one anti-cancer therapeutic. Also provided are methods for treating a proliferative disorder, disease or condition in a subject in need thereof, using a pharmaceutical composition described herein.
• FUCOIDAN NANOGELS AND METHODS OF THEIR USE AND MANUFACTURE
  申请人：MEMORIAL SLOAN KETTERING CANCER CENTER

  公开号：US20150328254A1

  公开（公告）日：2015-11-19

  Described herein are polymeric drug-carrying nanogels that are capable of targeting to P-selectin for the treatment of cancer and other diseases and conditions associated with P-selectin. Furthermore, in certain embodiments, the nanogels presented here offer a drug release mechanism based on acidic pH in the microenvironment of a tumor, thereby providing improved treatment targeting capability and allowing use of lower drug doses, thereby reducing toxicity.