Bergamo Alberta, Riedel Tina, Dyson Paul J, Sava Gianni
Callerio Foundation Onlus, via A. Fleming 22-31/b, 34127, Trieste, Italy.
Invest New Drugs. 2015 Feb;33(1):53-63. doi: 10.1007/s10637-014-0175-5. Epub 2014 Oct 23.
The tumor metastases targeting ruthenium complex NAMI-A synergistically improves the activity of gemcitabine in combination therapies. High-throughput screening was used to identify other potential drug combinations from a library of FDA approved drugs. Doxorubicin was identified as a hit compound and was therefore evaluated in combination with NAMI-A in vitro and in a preclinical in vivo model.
High-throughput screening identified eight structurally diverse compounds that synergize with NAMI-A including doxorubicin. The combination index on MCF-7 cells showed synergism as the concentration of NAMI-A increases independent of the doxorubicin concentration. In MCa mammary carcinoma of CBA mice, NAMI-A (35 mg/kg/day i.p. on days 7-12) followed by doxorubicin (10 mg/kg i.p. on day 16), significantly increased the effects of the individual drugs on metastases with 70 % animals resulting free of macroscopically detectable tumor nodules in the lungs at sacrifice. NAMI-A, unlike doxorubicin, cured 60 % of the treated mice but the combination therapy was toxic to the animals.
The combined therapy of NAMI-A with doxorubicin synergizes on lung metastasis in a preclinical mouse model. The combination therapy at the maximum tolerated doses of the two drugs is toxic. Hence, this combination is not suitable for clinical studies using maximum tolerated doses.
靶向肿瘤转移的钌配合物NAMI - A在联合治疗中可协同提高吉西他滨的活性。利用高通量筛选从美国食品药品监督管理局（FDA）批准的药物库中识别其他潜在的药物组合。阿霉素被鉴定为一种活性化合物，因此对其与NAMI - A进行了体外和临床前体内模型评估。
高通量筛选鉴定出八种与NAMI - A协同作用的结构多样的化合物，包括阿霉素。在MCF - 7细胞上的联合指数显示，随着NAMI - A浓度的增加呈现协同作用，且与阿霉素浓度无关。在CBA小鼠的MCa乳腺癌模型中，先给予NAMI - A（第7 - 12天，腹腔注射，35 mg/kg/天），随后给予阿霉素（第16天，腹腔注射，10 mg/kg），显著增强了两种药物对转移的抑制效果，处死时70%的动物肺部无肉眼可检测到的肿瘤结节。与阿霉素不同，NAMI - A治愈了60%的受试小鼠，但联合治疗对动物有毒性。
在临床前小鼠模型中，NAMI - A与阿霉素联合治疗对肺转移具有协同作用。两种药物最大耐受剂量的联合治疗有毒性。因此，这种联合用药不适合采用最大耐受剂量进行临床研究。
