Abstract：
Metronomic chemotherapy refers to the frequent administration of chemotherapeutic agents at a lower dose and presents an attractive alternative to conventional chemotherapy with encouraging response rates. However, the schedule of the therapy, including the dosage of the drug, is usually based on empiricism. The confounding effects of tumor-endothelial-immune interactions during metronomic administration of drugs have not yet been explored in detail, resulting in an incomplete assessment of drug dose and frequency evaluations. The present study aimed to gain a mechanistic understanding of different actions of metronomic chemotherapy using a mathematical model. We have established an analytical condition for determining the dosage and frequency of the drug depending on its clearance rate for complete tumor elimination. The model also brings forward the immune-mediated clearance of the tumor during the metronomic administration of the chemotherapeutic agent. The results from the global sensitivity analysis showed an increase in the sensitivity of drug and immune-mediated killing factors toward the tumor population during metronomic scheduling. Our results emphasize metronomic scheduling over the maximum tolerated dose (MTD) and define a model-based approach for approximating the optimal schedule of drug administration to eliminate tumors while minimizing harm to the immune cells and the patient\'s body.
摘要：
节制化学疗法是指以较低剂量频繁施用化学治疗剂，并以令人鼓舞的反应率提供了常规化学疗法的有吸引力的替代方案。然而,治疗的时间表，包括药物的剂量，通常基于经验主义。肿瘤-内皮-免疫相互作用在药物节律给药过程中的混杂效应尚未被详细探讨。导致对药物剂量和频率评估的评估不完整。本研究旨在使用数学模型对节拍化疗的不同作用进行机械理解。我们已经建立了一种分析条件，用于确定药物的剂量和频率，这取决于其完全消除肿瘤的清除率。该模型还提出了在化学治疗剂的节拍给药期间免疫介导的肿瘤清除。全局敏感性分析的结果表明，在节拍计划期间，药物和免疫介导的杀伤因子对肿瘤人群的敏感性增加。我们的结果强调了最大耐受剂量（MTD）的节拍计划，并定义了一种基于模型的方法，用于近似最佳的药物给药计划，以消除肿瘤，同时最大程度地减少对免疫细胞和患者身体的伤害。
