右雷佐生 (DEX) 是临床上唯一批准用于治疗阿霉素引起的心脏毒性 (DIC) 的药物，但其对 DOX 抗癌功效的影响尚未得到广泛研究。在这篇手稿中，进行了一项体外概念验证研究，以定量表征 DOX 和 DEX 的抗癌作用，并通过将实验数据与建模方法相结合来确定它们在癌细胞中药物相互作用的性质。首先，我们确定了 DOX 和 DEX 在乳腺癌细胞系 JIMT-1 和 MDA-MB-468 中的静态浓度反应。通过使用竞争性相互作用模型的三维 (3D) 响应面分析，我们将它们的相互作用表征为在 MDA-MB-468 中适度协同或在 JIMT-1 细胞中适度拮抗。其次，开发了细胞水平的药效学 (PD) 模型来捕获两种药物的时程效应，该模型分别确定 DOX 和 DEX 在 MDA-MB-468 和 JIMT-1 中的加和和拮抗相互作用。最后，我们利用 DOX 和 DEX 临床给药方案进行体外到体内的转化，该方案先前被认为具有最大的心脏保护作用，以驱动肿瘤细胞 PD 模型。由此产生的模拟结果表明，在三个周期的 Q3W DOX 方案中，DEX:DOX 剂量比为 10:1，基于 MDA-MB-468（相加效应）估计的疗效相当，而基于 JIMT-1（拮抗效应）的疗效较低DOX DEX 组合与单独 DOX 相比的估计值。因此，我们开发的基于细胞的 PD 模型可用于模拟不同的场景并更好地设计临床前体内研究，以进一步优化 DOX 和 DEX 组合。版权所有 © 2023 Mody、Vaidya、Lezeau、Taha 和 Ait-Oudhia。

Dexrazoxane (DEX) is the only drug clinically approved to treat Doxorubicin-induced cardiotoxicity (DIC), however its impact on the anticancer efficacy of DOX is not extensively studied. In this manuscript, a proof-of-concept in vitro study is carried out to quantitatively characterize the anticancer effects of DOX and DEX and determine their nature of drug-drug interactions in cancer cells by combining experimental data with modeling approaches. First, we determined the static concentration-response of DOX and DEX in breast cancer cell lines, JIMT-1 and MDA-MB-468. With a three-dimensional (3D) response surface analysis using a competitive interaction model, we characterized their interaction to be modestly synergistic in MDA-MB-468 or modestly antagonistic in JIMT-1 cells. Second, a cellular-level, pharmacodynamic (PD) model was developed to capture the time-course effects of the two drugs which determined additive and antagonistic interactions for DOX and DEX in MDA-MB-468 and JIMT-1, respectively. Finally, we performed in vitro to in vivo translation by utilizing DOX and DEX clinical dosing regimen that was previously identified to be maximally cardioprotective, to drive tumor cell PD models. The resulting simulations showed that a 10:1 DEX:DOX dose ratio over three cycles of Q3W regimen of DOX results in comparable efficacy based on MDA-MB-468 (additive effect) estimates and lower efficacy based on JIMT-1 (antagonistic effect) estimates for DOX + DEX combination as compared to DOX alone. Thus, our developed cell-based PD models can be used to simulate different scenarios and better design preclinical in vivo studies to further optimize DOX and DEX combinations.Copyright © 2023 Mody, Vaidya, Lezeau, Taha and Ait-Oudhia.