Rising evidence has shown the development of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors in the practices of cancer therapy. It is reported that the efficacy of axitinib (AX), a VEGFR inhibitor, is limited in the treatment of breast cancer as a single agent or in combination with other chemotherapeutic drugs due to the probability of rising population of cancer stem-like cells (CSCs) caused by AX. The present study evaluated the effect of dopamine (DA) improving AX's efficacy on MCF-7/ADR breast cancer in vitro and in vivo, and developed a pharmacokinetic-pharmacodynamic (PK-PD) model describing the in vivo experimental data and characterizing the interaction of effect between AX and DA. The results showed that AX up-regulated the expression of breast CSC (BCSC) markers (CD44+/CD24-/low) in vivo, and DA significantly synergized the inhibitory effect on tumor growth by deducting the BCSC frequency. The PK-PD model quantitatively confirmed the synergistic interaction with the parameter estimate of interaction factor ψ 2.43. The dose regimen was optimized as 60 mg/kg AX i.g. b.i.d. combined with 50 mg/kg DA i.p. q3d in the simulation study on the basis of the PK-PD model. The model where DA synergistically enhances the effect of AX in an all-or-none manner provides a possible solution in modeling the agents like DA. Moreover, the outcome of AX and DA combination therapy in MCF-7/ADR breast cancer provided further insight of co-administering DA in the treatment of the possible CSC-causing AX-resisting breast cancer. And this combination therapy has the prospect of clinical translation.

中文翻译：

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阿昔替尼联合多巴胺和PK-PD模型在人乳腺癌异种移植物中的抗肿瘤作用。

越来越多的证据表明，在癌症治疗实践中，对血管内皮生长因子受体（VEGFR）抑制剂的耐药性正在发展。据报道，VEGFR抑制剂阿西替尼（AX）作为单一药物或与其他化疗药物联合治疗乳腺癌的疗效受到限制，原因是癌症干细胞样细胞（CSCs）的数量可能增加）由AX引起。本研究评估了多巴胺（DA）在体外和体内改善AX对MCF-7 / ADR乳腺癌的疗效，并开发了描述体内实验数据并表征相互作用的药代动力学-药效学（PK-PD）模型和AX之间的效果。结果显示AX在体内上调了乳腺CSC（BCSC）标记（CD44 + / CD24- / low）的表达，DA可以通过降低BCSC频率来显着增强对肿瘤生长的抑制作用。PK-PD模型与相互作用因子ψ2.43的参数估计值定量确认了协同相互作用。在模拟研究中，基于PK-PD模型，将剂量方案优化为60 mg / kg AX igbid联合50 mg / kg DA ip q3d。DA以全有或全无的方式协同增强AX效果的模型为建模诸如DA的代理提供了一种可能的解决方案。而且，在MCF-7 / ADR乳腺癌中AX和DA联合治疗的结果为在可能的CSC致AX抗性乳腺癌的治疗中联合使用DA提供了进一步的见解。并且这种联合疗法具有临床翻译的前景。