The duocarmycin family is a group of potent cytotoxic agents originally isolated from the bacterium Streptomyces. This discovery has spurred significant interest due to duocarmycins’ unique chemical structures and powerful mechanism of action. This review comprehensively details the history of the duocarmycin family, the current understanding of their therapeutic potential, and the major clinical trials that have been conducted. Chemically, the duocarmycin family is characterized by a DNA-binding unit that confers specificity, a subunit-linking amide that positions the molecule within the DNA helix, and an alkylating unit that interacts with the DNA. This configuration allows them to bind selectively to the minor groove of DNA and alkylate adenine bases, a notable deviation from the more common guanine targeting performed by other alkylating agents. Duocarmycin’s mechanism of action involves the formation of covalent adducts with DNA, leading to the disruption of the DNA architecture and subsequent inhibition of replication and transcription. Recent advancements in drug delivery systems, such as antibody–drug conjugates (ADCs), have further elevated the therapeutic prospects of duocarmycin analogs by providing a promising mechanism for enhancing intracellular concentrations and selective tumor delivery. Preclinical studies have highlighted the efficacy of duocarmycin derivatives in various in vitro models, providing a strong foundation for translational research. However, further biological research is required to fully understand the toxicology of duocarmycin family members before it can be clinically relevant. The major focus of this review is to cache the major biologically relevant findings of different duocarmycin analogs as well as their biological shortcomings to propose next steps in the field of cancer therapy with these potent therapeutics.
杜卡霉素家族是一类最初从链霉菌属细菌中分离出的强效细胞毒性药物。由于其独特的化学结构和强大的作用机制，该家族的发现引起了广泛关注。本综述全面阐述了杜卡霉素家族的发展历史、当前对其治疗潜力的认识以及已开展的主要临床试验。从化学结构上看，杜卡霉素家族的特征在于：赋予特异性的DNA结合单元、将分子定位于DNA螺旋内的亚基连接酰胺，以及与DNA相互作用的烷基化单元。这种结构使其能够选择性结合DNA小沟并烷基化腺嘌呤碱基，这与其他烷基化剂更常见的鸟嘌呤靶向作用形成显著区别。杜卡霉素的作用机制涉及与DNA形成共价加合物，导致DNA结构破坏，进而抑制复制和转录过程。近年来，抗体药物偶联物等药物递送系统的进展，通过提供增强细胞内浓度和选择性肿瘤递送的可行机制，进一步提升了杜卡霉素类似物的治疗前景。临床前研究已在多种体外模型中证实了杜卡霉素衍生物的有效性，为转化研究奠定了坚实基础。然而，在实现临床转化之前，仍需开展进一步的生物学研究以全面理解该家族成员的毒理学特性。本综述的核心目标在于系统梳理不同杜卡霉素类似物的主要生物学研究成果及其生物学局限性，从而为这类强效治疗剂在癌症治疗领域的后续发展指明方向。
A Comprehensive Review of the Antitumor Properties and Mechanistic Insights of Duocarmycin Analogs
肿瘤(癌症)患者之家