豆球蛋白是阿霉素和豆科菌素可裂解的肽接头的新型缀合物。已经开发了它来改善阿霉素的副作用。荷瘤小鼠的生物分布,急性耐受,并评估了豆类素对Sprague-Dawley大鼠和比格犬的潜在全身毒性作用。豆类蛋白进入循环后主要作为蛋白质复合物存在于血浆中。与小鼠等摩尔剂量的常规阿霉素相比,我们发现肿瘤中阿霉素的暴露量较高(约1.7倍增加),而正常组织中的暴露量较低(约3.26-,3.46-,心脏减少1.29倍,肾,和等离子体,分别)静脉注射豆类素后的荷瘤小鼠。在雌性大鼠中,豆类霉素的急性最大耐受剂量(MTD)>16mg/kg阿霉素当量,11mg/kg阿霉素在雄性大鼠中的当量(常规阿霉素的LD50为10.51mg/kg),和>8mg/kg多柔比星在狗中的当量(常规多柔比星的MTD为1.5mg/kg)。在大鼠(每周一次5、10和25mg/kg/剂)和狗(每周一次3/1.5、10/5和20/10mg/kg/剂)中进行了为期四周的静脉内豆球蛋白重复剂量毒性研究;由于不可耐受的豆球蛋白相关毒性为20mg/kg,因此剂量水平从第二剂量降低。毒性的主要器官包括胃肠道,淋巴和造血器官,肾,皮肤,肝脏,生殖器官,和周围神经,都与阿霉素有关.然而,仅在MTD剂量水平下观察到心脏毒性.总之,我们的研究结果证实,与常规阿霉素相比,豆霉素的安全性得到了改善,并支持了其在治疗癌症方面的临床获益.
Legubicin is a novel conjugate of doxorubicin and a
legumain-cleavable peptide linker. It has been developed to ameliorate the side effects of doxorubicin. Biodistribution in tumor-bearing mice, acute tolerance, and potential systemic toxic effects in Sprague-Dawley rats and beagle dogs of legubicin were assessed. Legubicin exists mainly as a protein complex in plasma after entering the circulation. Compared with conventional doxorubicin at an equal molar dose in mice, we found higher exposure to doxorubicin in tumor (approximately 1.7-fold increase) while lower exposure in normal tissues (an ~3.26-, 3.46-, and 1.29-fold reduction in heart, kidney, and plasma, respectively) in tumor-bearing mice after intravenous injection of legubicin. The acute maximum tolerance dose (MTD) of legubicin was >16 mg/kg doxorubicin equivalent in female rats, 11 mg/kg doxorubicin equivalent in male rats (LD50 of conventional doxorubicin is 10.51 mg/kg), and >8 mg/kg doxorubicin equivalent in dogs (MTD of conventional doxorubicin is 1.5 mg/kg). Four-week repeat-dose toxicity studies of intravenous legubicin were conducted in rats (5, 10, and 25 mg/kg/dose once weekly) and dogs (3/1.5, 10/5, and 20/10 mg/kg/dose once weekly); the dose levels were reduced from the second dose due to intolerable legubicin-associated toxicity at 20 mg/kg. Major organs of toxicity included the gastrointestinal tract, lymphoid and hematopoietic organs, kidney, skin, liver, reproductive organs, and peripheral nerves, which are all associated with doxorubicin. However, cardiotoxicity was only noted at MTD dose levels. Altogether, our results confirm an improved safety profile of legubicin over conventional doxorubicin and support its clinical benefit for treating cancer.