BIOCONJUGATE DERIVATIVES OF COENZYME B-12

我们正在使用维生素 B12 受体来靶向输送 细胞毒性抗癌药物对快速分裂的白血病细胞 实体瘤。特定药物-B12生物结合物（通用术语包括 合成药物-钴胺素或药物-类咕啉生物结合物） 通过将各种细胞毒性弹头附加到钴胺素或结构上 通过钴原子相关的类咕啉。活性细胞毒药物是 未成熟的白血病细胞内自发释放，但没有 当受体介导的内吞作用被阻断时，就会观察到毒性。 用维生素 B12 使 B12 受体预饱和。在实体瘤中 和所有其他组织一样，前药在被激活之前是无毒的 使用组织穿透红光进行光解，或使用声波分解 聚焦超声。我们准备了苯丁酸钴胺和 我们对人类白血病细胞和人类结肠肿瘤的体外结果 细胞显示这是一种非常有效的方法来增加 药物治疗指数。 在最近的预算期间，我们将准备生物结合物 另外五种细胞毒性抗癌药物：卡铂、白消安、 阿霉素、依托泊苷和拓扑替康。正宗 B12 的生物结合物 （钴胺素），以及 B12 的近似类似物，其具有更多的作用 将使用红色区域中有利的吸收光谱。的 这些生物结合物的稳定性以及它们在条件下的分解 将研究光解和声解条件及其毒性 将在体外评估针对各种 NCI 人类癌细胞系的效果。 在体外表现出良好活性的生物共轭物将提供给 梅奥诊所的独立动物测试合作者。

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.