Annu Int Conf IEEE Eng Med Biol Soc. 2021 Nov;2021:4374-4378. doi: 10.1109/EMBC46164.2021.9629493.
Doxorubicin (DOXO) is a well-established chemotherapy drug for treatment of different tumors, ranging from breast cancer, melanoma to multiple myeloma (MM). Here, we present a coupled experimental/modeling approach to study DOXO pharmacokinetics in MM cells, investigate its distribution among the extracellular and intracellular compartments during time. Three model candidates are considered and identified. Model selection is performed based on its ability to describe the data both qualitatively and in terms of quantitative indexes. The most parsimonious model consists of a nonlinear structure with a saturation-threshold control of intracellular DOXO efflux by the DOXO bound to the cellular DNA. This structure could explain the hypothesis that MM cells are drug-resistant, likely due to the involvement of P-glycoproteins.The proposed model is able to predict the intracellular (free and bound) DOXO and suggests the presence of a saturation-threshold drug-resistant mechanism.Clinical Relevance- The model can be used to properly understand and guide further experimental setup, e.g., to investigate multiple myeloma cell variability among different cell lines.
多柔比星（DOXO）是一种广泛应用于治疗多种肿瘤的化疗药物，包括乳腺癌、黑色素瘤和多发性骨髓瘤（MM）等。在这里，我们提出了一种联合实验/建模的方法来研究 DOXO 在 MM 细胞中的药代动力学，研究其在细胞外和细胞内隔室之间随时间的分布。我们考虑了三种候选模型，并对其进行了识别。模型选择基于其定性和定量指标描述数据的能力。最简单的模型由一个非线性结构组成，该结构通过 DOXO 与细胞 DNA 结合来控制细胞内 DOXO 外流的饱和阈值。这种结构可以解释 MM 细胞耐药的假说，可能是由于 P-糖蛋白的参与。所提出的模型能够预测细胞内（游离和结合）DOXO 的浓度，并提示存在饱和阈值耐药机制。临床意义-该模型可用于正确理解和指导进一步的实验设计，例如，研究不同细胞系之间多发性骨髓瘤细胞的变异性。
