Department of Pharmaceutics, School of Pharmaceutical sciences, Peking University, Beijing, 100191, China.
Center for Precision Medicine Multi-Omics Research, Peking University Health Science Center, Beijing, 100191, China.
AAPS J. 2020 Feb 10;22(2):45. doi: 10.1208/s12248-020-0428-5.
The self-renewal and differentiation of cancer stem-like cells (CSCs) leads to cellular heterogeneity, causing one of the greatest challenges in cancer therapy. Growing evidence suggests that CSC-targeting therapy enhances the effect of concomitant antitumour therapy. To gain an in-depth understanding of this enhanced effect, the kinetic profile of estimated CSC frequency (the fraction of CSCs in tumour) was evaluated for in vivo characterization of cellular heterogeneity using sunitinib and dopamine as a paradigm combination therapy. Female MCF-7/Adr xenografted Balb/c nude mice were treated with sunitinib (p.o., 20 mg/kg) and dopamine (i.p., 50 mg/kg), alone or in combination. Estimated CSC frequency and tumour size were measured over time. Mechanistic PK/PD modelling was performed to quantitatively describe the relationship between drug concentration, estimated CSC frequency and tumour size. Sunitinib reduced tumour size by inducing apoptosis of differentiated tumour cells (DTCs) and enriched CSCs by stimulating its proliferation. Dopamine exhibited anti-CSC effects by suppressing the capacity of CSCs and inducing its differentiation. Simulation and animal studies indicated that concurrent administration was superior to sequential administration under current experimental conditions. Alongside tumour size, the current study provides mechanistic insights into the estimation of CSC frequency as an indicator for cellular heterogeneity. This forms the conceptual basis for in vivo characterization of other combination therapies in preclinical cancer studies.
癌症干细胞样细胞 (CSC) 的自我更新和分化导致细胞异质性，这是癌症治疗中最大的挑战之一。越来越多的证据表明，CSC 靶向治疗增强了伴随抗肿瘤治疗的效果。为了深入了解这种增强的效果，使用舒尼替尼和多巴胺作为范例联合治疗，通过体内特征描述细胞异质性，评估了估计的 CSC 频率（肿瘤中 CSC 的分数）的动力学特征。用舒尼替尼（口服，20mg/kg）和多巴胺（腹腔内，50mg/kg）单独或联合处理雌性 MCF-7/Adr 异种移植 Balb/c 裸鼠。随着时间的推移测量估计的 CSC 频率和肿瘤大小。进行机制 PK/PD 建模以定量描述药物浓度、估计的 CSC 频率和肿瘤大小之间的关系。舒尼替尼通过诱导分化肿瘤细胞 (DTC) 的凋亡和刺激其增殖来缩小肿瘤体积并富集 CSCs。多巴胺通过抑制 CSCs 的能力和诱导其分化来表现出抗 CSC 作用。模拟和动物研究表明，在当前实验条件下，联合给药优于序贯给药。除了肿瘤大小外，本研究还深入了解了作为细胞异质性指标的 CSC 频率估计，为临床前癌症研究中的其他联合治疗的体内特征描述提供了概念基础。
