BIOCONJUGATE DERIVATIVES OF COENZYME B-12

我们使用维生素B12受体来靶向递送 细胞毒性抗癌药物对白血病中快速分裂细胞的作用， 实体瘤特定药物-B12生物缀合物（通用术语包括 药物-钴胺素或药物-类可啉生物缀合物 通过将各种细胞毒性弹头连接到钴胺素或结构上， 通过钴原子与corrinoid相关。活性细胞毒性药物是 在未成熟的白血病细胞内自发释放， 当受体介导的内吞作用被 用维生素B12预饱和B12受体。实体瘤 和所有其他组织，前药是无毒的，直到它被激活， 用穿透组织的红光进行光解，或用 聚焦超声波我们准备了苯丁酸氮芥-钴胺素， 我们的结果在体外与人白血病细胞和人结肠肿瘤 细胞显示这是一种非常有效的方法， 药物治疗指数 在本预算期内，我们将制备 五种另外的细胞毒性抗癌药：卡铂，白消安， 阿霉素、依托泊苷和拓扑替康。真实B12的生物缀合物 （钴胺素），以及B12的密切类似物，具有更多的 将使用红色区域中有利的吸收光谱。的 这些生物缀合物的稳定性以及它们在 将研究光解和超声降解条件， 将评估针对各种NCI人癌细胞系的体外抗肿瘤活性。 在体外显示有利活性的生物缀合物将被提供给 马约诊所的合作者进行独立的动物试验。

We are using the vitamin B12 receptor to target the delivery of cytotoxic anticancer drugs to rapidly dividing cells in leukemia and to solid tumors. Specific drug-B12 bioconjugates (general term to include either drug-cobalamin or drug-corrinoid bioconjugates) are synthesized by attaching various cytotoxic warheads to cobalamin or a structurally- related corrinoid through the cobalt atom. The active cytotoxic drug is released spontaneously inside of immature leukemia cells, but no toxicity is observed when receptor-mediated endocytosis is blocked by presaturation of the B12 receptors with vitamin B12. In solid tumors and all other tissues, the pro-drug is nontoxic until it is activated by photolysis with tissue-penetrating red light, or with sonolysis with focused ultrasound. We have prepared chlorambucil-cobalamin and our results in vitro with human leukemia cells and human colon tumor cells show this to be a very effective method to increase the therapeutic index of drugs. For the immediate budget period, we will prepare bioconjugates of five additional cytotoxic anticancer drugs: carboplatin, busulfan, doxorubicin, etoposide, and topotecan. Bioconjugates of authentic B12 (cobalamin), as well as a close analogue of B12 that has a more favorable absorption spectrum in the red region will be used. The stability of these bioconjugates, as well as their decomposition under photolytic and sonolytic conditions will be studied, and their toxicity against various NCI human cancer cell lines in vitro will be evaluated. Bioconjugates that show favorable activity in vitro will be provided to a collaborator at the Mayo Clinic for independent animal testing.