Mpekris Fotios, Baish James W, Stylianopoulos Triantafyllos, Jain Rakesh K
Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia 1678, Cyprus.
Department of Biomedical Engineering, Bucknell University, Lewisburg, PA 17837.
Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):1994-1999. doi: 10.1073/pnas.1700340114. Epub 2017 Feb 7.
Metronomic dosing of chemotherapy-defined as frequent administration at lower doses-has been shown to be more efficacious than maximum tolerated dose treatment in preclinical studies, and is currently being tested in the clinic. Although multiple mechanisms of benefit from metronomic chemotherapy have been proposed, how these mechanisms are related to one another and which one is dominant for a given tumor-drug combination is not known. To this end, we have developed a mathematical model that incorporates various proposed mechanisms, and report here that improved function of tumor vessels is a key determinant of benefit from metronomic chemotherapy. In our analysis, we used multiple dosage schedules and incorporated interactions among cancer cells, stem-like cancer cells, immune cells, and the tumor vasculature. We found that metronomic chemotherapy induces functional normalization of tumor blood vessels, resulting in improved tumor perfusion. Improved perfusion alleviates hypoxia, which reprograms the immunosuppressive tumor microenvironment toward immunostimulation and improves drug delivery and therapeutic outcomes. Indeed, in our model, improved vessel function enhanced the delivery of oxygen and drugs, increased the number of effector immune cells, and decreased the number of regulatory T cells, which in turn killed a larger number of cancer cells, including cancer stem-like cells. Vessel function was further improved owing to decompression of intratumoral vessels as a result of increased killing of cancer cells, setting up a positive feedback loop. Our model enables evaluation of the relative importance of these mechanisms, and suggests guidelines for the optimal use of metronomic therapy.
节拍化疗（定义为低剂量频繁给药）在临床前研究中已被证明比最大耐受剂量治疗更有效，目前正在临床中进行测试。尽管已经提出了多种从节拍化疗中获益的机制，但这些机制如何相互关联以及对于给定的肿瘤-药物组合哪种机制起主导作用尚不清楚。为此，我们开发了一个纳入各种提出机制的数学模型，并在此报告肿瘤血管功能的改善是节拍化疗获益的关键决定因素。在我们的分析中，我们使用了多种给药方案，并纳入了癌细胞、干细胞样癌细胞、免疫细胞和肿瘤脉管系统之间的相互作用。我们发现节拍化疗可诱导肿瘤血管功能正常化，从而改善肿瘤灌注。灌注的改善减轻了缺氧，这将免疫抑制性肿瘤微环境重编程为免疫刺激，并改善了药物递送和治疗效果。实际上，在我们的模型中，血管功能的改善增强了氧气和药物的递送，增加了效应免疫细胞的数量，并减少了调节性T细胞的数量，这反过来又杀死了更多的癌细胞，包括癌干细胞样细胞。由于癌细胞杀伤增加导致肿瘤内血管减压，血管功能进一步改善，从而建立了一个正反馈回路。我们的模型能够评估这些机制的相对重要性，并为节拍疗法的最佳使用提供指导。
