环丙沙星增强抗体偶联药物 （RC48） 对HER2阳性肿瘤细胞增殖的抑制作用

Ciprofloxacin Enhances the Inhibitory Effect of Antibody-drug Conjugate(RC48) on the Proliferation of HER2 Positive Tumor Cells

关键词:  环丙沙星  抗体药物偶联物  溶酶体  联合用药

Key words:  ciprofloxacin  antibody-drug conjugates  lysosome  drug combination

摘要:

目的 探讨环丙沙星与抗HER2抗体药物偶联物RC48联合用药时的抑瘤活性及机制。方法 CCK-8法分别检测环丙沙星单药、RC48单药及两者联合用药(在不同配比条件下同时或序贯用药)对HER2阳性肿瘤细胞增殖的抑制作用。联合指数法评价2种药物联用的效果。结果 RC48单药对SK-BR-3及NCI-N87细胞增殖有显著的抑制作用，IC₅₀分别为(4.91±1.15)ng·mL^–1及(14.54±0.85)ng·mL^–1，最大抑制率分别为87.2%及82.3%。环丙沙星单药剂量在234.38~7500ng·mL^–1内无显著的抗肿瘤作用。当环丙沙星与RC48同时给药时，显著降低了RC48的抗肿瘤活性(P<0.05)，两者表现为拮抗作用；但当其与RC48序贯给药(先给RC48后给环丙沙星，用药间隔为6~48h)时，抗肿瘤活性显著升高(P<0.05)，2种药物表现为协同作用，且在联合药效高达95.3%时，依然保持协同作用。结论 RC48与环丙沙星序贯给药(间隔6~48h，6h最佳)可增强抗肿瘤效果，两者有协同作用。

Abstract:

OBJECTIVE To investigate the antitumor activity and mechanism of ciprofloxacin combined with RC48 which is an anti-HER2 antibody-drug conjugate.METHODS CCK-8 assay was used to detect the inhibitory effect of ciprofloxacin, RC48 and their combination(simultaneously or sequentially with different proportions) on the proliferation of HER2 positive tumor cells. The combined index method was used to evaluate the combined effect of the two drugs.RESULTS RC48 displayed a significant inhibitory effect on the proliferation of SK-BR-3 and NCI-N87 cells with the IC₅₀ values of(4.91±1.15)ng·mL^–1and (14.54+0.85)ng·mL^–1respectively, and the maximum inhibition rates were 87.2% and 82.3% respectively. Ciprofloxacin alone had no significant antitumor effect in the dose range of 234.38-7 500 ng·mL^–1. When it was given with RC48 at the same time, the anti-tumor effect of RC48 was significantly reduced(P<0.05) and the two drugs showed an antagonistic effect. However, when it was used successively with RC48 was administered first and then ciprofloxacin, with an interval of 6-48 h, the antitumor activity increased significantly(P<0.05). The two drugs showed synergistic effect, and the synergistic effect was still maintained when the combined efficacy was as high as 95.3%.CONCLUSION Sequential administration of RC48 and ciprofloxacin, at 6-48 h intervals, especially at 6 h intervals, can enhance the anti-tumor efficacy, and the two drugs show a synergistic effect.