文章：

博莱霉素：迈向更好的治疗方法

Bleomycins: towards better therapeutics

原文发布日期：2005-02-01

DOI: 10.1038/nrc1547

类型: Review Article

开放获取: 否

要点：

1. Bleomycins are a family of glycopeptide antibiotics with antitumour activity. They are used clinically in combination chemotherapy against lymphomas, squamous-cell carcinomas and germ-cell tumours.
2. The side effects of the bleomycins are dose-dependent and involve lung inflammation that often proceeds to lung fibrosis.
3. Bleomycins bind transition metals (Fe(II) or Cu(I)) and oxygen and, in the presence of a one-electron reductant, can catalyse formation of single-stranded (ss) and double-stranded (ds) DNA lesions. The damage is similar to that generated by ionizing radiation.
4. In vitro studies indicate that a single molecule of bleomycin is sufficient to generate lesions on both strands of DNA, the proposed source of cytotoxicity. Hot spots for dsDNA cleavage have been identified and have led to empirical rules about the sequences leading to dsDNA lesions.
5. Studies on a large number of bleomycin analogues, made possible by total synthesis of bleomycin, have indicated that the whole molecule is much greater than the sum of its parts. The linker between the metal and the bithiazole DNA-binding domain and the flexibility of the bithiazole moiety itself are essential for efficient dsDNA cleavage.
6. The cellular responses to bleomycin treatment are complex and are cell-line- and genotype-dependent. Extended cell-cycle arrest, apoptosis and mitotic cell death are the most common outcomes of bleomycin treatment.
7. Bleomycins are hydrophilic molecules that are unable to cross cell membranes by free diffusion. Studies indicate that the positively charged tail of bleomycin might be key to cellular uptake.
8. Biosynthetic genes for bleomycin have been identified and some of the proteins in the pathway have been characterized. These studies, in concert with chemical synthesis, open the door to making libraries of bleomycin analogues.

要点翻译：

1. 博莱霉素是一类具有抗肿瘤活性的糖肽抗生素，临床上常与化疗联合用于治疗淋巴瘤、鳞状细胞癌和生殖细胞肿瘤。
2. 博莱霉素的副作用呈剂量依赖性，主要表现为肺部炎症，常进展为肺纤维化。
3. 博莱霉素可结合过渡金属（Fe(II)或Cu(I)）和氧气，在单电子还原剂存在下能催化产生单链和双链DNA损伤。这种损伤与电离辐射所致损伤相似。
4. 体外研究表明，单个博莱霉素分子足以在DNA双链上产生损伤，这被认为是其细胞毒性的来源。研究已确定双链DNA断裂的热点区域，并总结出导致双链损伤的序列经验法则。
5. 通过对博莱霉素全合成获得的多种类似物研究表明，其整体分子功能远优于各部分功能之和。连接金属结合区与双噻唑DNA结合域的连接区以及双噻唑基团本身的柔韧性，对实现高效双链DNA断裂至关重要。
6. 细胞对博莱霉素的治疗反应复杂，且具有细胞系和基因型特异性。细胞周期长期阻滞、细胞凋亡和有丝分裂期死亡是博莱霉素治疗最常见的结果。
7. 博莱霉素是亲水性分子，不能通过自由扩散跨过细胞膜。研究表明其带正电荷的尾部可能是细胞摄取的关键。
8. 博莱霉素的生物合成基因已被识别，该通路中的部分蛋白质特性也已明确。这些研究与化学合成相结合，为构建博莱霉素类似物库开辟了道路。

英文摘要：

Bleomycins are a family of glycopeptide antibiotics that have potent antitumour activity against a range of lymphomas, head and neck cancers and germ-cell tumours. The therapeutic efficacy of the bleomycins is limited by development of lung fibrosis. The cytotoxic and mutagenic effects of the bleomycins are thought to be related to their ability to mediate both single-stranded and double-stranded DNA damage, which requires the presence of specific cofactors (a transition metal, oxygen and a one-electron reductant). Progress in understanding the mechanisms involved in the therapeutic efficacy of the bleomycins and the unwanted toxicity and elucidation of the biosynthetic pathway of the bleomycins sets the stage for developing a more potent, less toxic therapeutic agent.

摘要翻译： 

博来霉素是一类具有强大抗肿瘤活性的糖肽类抗生素，对多种淋巴瘤、头颈部癌症和生殖细胞肿瘤有效。其临床应用受限于可能引发肺纤维化的副作用。博来霉素的细胞毒性和致突变性被认为与其介导单链和双链DNA损伤的能力有关，这一过程需要特定辅因子（过渡金属、氧和单电子还原剂）的存在。随着对其治疗机制、毒性作用以及生物合成途径认识的深入，为开发更高效、低毒的博来霉素类治疗药物奠定了基础。

原文链接：

Bleomycins: towards better therapeutics