Bleomycin is produced by Streptomyces verticillis. The Bleomycin molecule has two main structural components; a bithiazole component which partially intercalates into the DNA helix, parting the strands, as well as pyrimidine and imidazole structures, which bind iron and oxygen forming an activated complex capable of releasing damaging oxidants in close proximity to the polynucleotide chains of DNA. This may lead to chain scission or structural modifications leading to release of free bases or their propenal derivatives. It has potent tumor killing properties which have gained it an critical role in cancer chemotherapy. It causes little marrow suppression, but the major adverse is pulmonary toxicity effect.[1]
In vitro, Bleomycin reacts with DNA which has previously been treated with a sulfhydryl compound, and cause a decrease in its melting temperature (Tm). In the reactions in vitro, strand scission in DNA has been confirmed which indicate that in the presence of a sulfhydryl compound in vitro, Bleomycin binds to DNA, and causes single-strand scission. The scission of DNA may be the cause of the inhibition of thymidine incorporation into DNA of growing cells and the inhibition of cell division. [2]
In vivo study demonstrated that Bleomycin-induced pulmonary toxicity and fibrosis could be significantly affected by Soluble epoxide hydrolase (sEH) inhibitors AUDA. In vivo, AUDA significantly improved Bleomycin -induced decline in lung function and body weight, and inhibited inflammatory cell accumulation and the mRNA and protein expression of interleukin (IL)-1β, TGF-β1, and matrix metalloproteinase 9 (MMP-9) in lung tissue. [3]
References:
[1]. John H. et al. Mechanisms of Bleomycin-induced lung damage. Arch Toxicol (1991) 65:81-94.
[2]. Suzuki H, et al. On the mechanism of action of Bleomycin: scission of DNA strands in vitro and in vivo. J Antibiot (Tokyo). 1969 Sep;22(9):446-8.
[3]. Xin-wei D, et al. Soluble epoxide hydrolase inhibitor AUDA decreases Bleomycin-induced pulmonary toxicity in mice by inhibiting the p38/Smad3 pathways. Toxicology 389 (2017) 31–41.
博来霉素由链霉菌产生。博来霉素分子有两个主要结构成分；一种双噻唑成分,部分嵌入 DNA 螺旋结构,分开链,以及嘧啶和咪唑结构,它们结合铁和氧形成活化复合物,能够在靠近 DNA 多核苷酸链的地方释放有害氧化剂。这可能会导致断链或结构修饰,从而导致游离碱基或其丙烯醛衍生物的释放。它具有强大的肿瘤杀伤特性,这使其在癌症化学疗法中发挥了关键作用。它几乎没有骨髓抑制作用,但主要的副作用是肺毒性作用。[1]
在体外,博来霉素与先前用巯基化合物处理过的 DNA 发生反应,导致其熔解温度 (Tm) 降低。在体外反应中,已证实 DNA 链断裂,这表明在体外存在巯基化合物的情况下,博来霉素与 DNA 结合,并导致单链断裂。 DNA 的断裂可能是抑制胸苷掺入生长细胞的 DNA 和抑制细胞分裂的原因。 [2]
体内研究表明,可溶性环氧化物水解酶 (sEH) 抑制剂 AUDA 可显着影响博来霉素诱导的肺毒性和纤维化。在体内,AUDA 显着改善博来霉素引起的肺功能和体重下降,并抑制炎症细胞积聚和白细胞介素 (IL)-1β、TGF-β1 和基质金属蛋白酶 9 (MMP-9) 的 mRNA 和蛋白表达肺组织。 [3]