Physiologically Based Mathematical Models to Optimize Therapies Against Metastatic Colorectal Cancer: A Mini-Review
Physiologically Based Mathematical Models to Optimize Therapies Against Metastatic Colorectal Cancer: A Mini-Review
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DOI：
10.2174/138161282001140113123441
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发表时间：
2014-01-01
影响因子：
3.1
通讯作者：
Clairambault, Jean
中科院分区：
文献类型：
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作者：
Ballesta, Annabelle;Clairambault, Jean
了解和改善转移性结直肠癌(MCRC)联合药物治疗的效果是一个多学科和多尺度的问题，可以从系统生物学方法中受益。尽管已有相当数量的活性药物被批准用于临床，但临床上实际上使用了多种联合给药方案，因此在它们之间进行选择或设计新的方案并不是一项显而易见的任务，这需要基于生理原理进行一些合理化。我们为临床上使用的主要细胞毒药物提出了一些基于生理学的分子药代动力学-药效学模型，并呼吁建立其他模型来描述最近使用的药物，例如与单抗相关的药物。我们还主张同时设计在治疗控制下的增殖细胞群体的模型，因为癌症主要是对组织增殖的生理控制的破坏。这两类模型都是基于微分方程式来连续描述药物在生物体中的命运，从输注到药理作用，以及它们对细胞群体、健康细胞和肿瘤细胞增殖的影响。结直肠癌的多尺度特性，从细胞内通路的破坏到在宏观水平上观察到的肿瘤生长，以及它在诊断时通过在机体的各种健康组织中同时转移而频繁的多局部扩散，以及后来的需要多尺度的数学模型。因此，我们提出了临床上细胞毒性药物使用的多层次愿景，其中包括临床医生手中的武器、药物组合方案、其作用的靶点--想要的和不想要的--、细胞群体增殖的分子途径以及后者在整个生物体中的环境，以便为适当的射击设计一个合理的基础，即在患者定制的约束下进行治疗优化。
Understanding and improving the effects of combined drug treatments in metastatic colorectal Cancer (mCRC) is a multidisciplinary and multiscale problem, that can benefit from a systems biology approach. Although a quite limited number of active drugs have been approved for clinical applications, a variety of combined delivery regimen options are actually used in the clinic, so that choosing between them, or designing new ones, is not an obvious task, which calls for some rationalization based on physiological principles. We propose some physiologically based molecular pharmacokinetics-pharmacodynamics models for the main cytotoxic drugs used in the clinic and call for others describing more recently used agents, such as associated with monoclonal antibodies. We also advocate simultaneously designing models of the proliferating cell populations under therapeutic control, as cancer is primarily a disruption of physiological control on tissue proliferation. These two types of models are based on differential equations to continuously describe both the fate of drugs in the organism, from infusion until pharmacological effects, and their impact on the proliferation of cell populations, healthy and tumor. The multiscale nature of colorectal cancer, from the disruption of intracellular pathways to tumor growth observed at the macroscopic level, together with its frequent multilocal extension by simultaneous metastases in various healthy tissues of the organism at the time of diagnosis, and later, call for multiscale mathematical models. We thus propose a multi-level vision of cytotoxic drug use in the clinic, in which the weapon in the hands of clinicians, a drug combination regimen, the targets -wanted and unwanted -on which it exerts its effects, molecular pathways in proliferating cell populations, and the environment of the latter in a whole organism, are all considered in order to design a rationale for appropriate shooting, i.e., treatment optimization under patient-tailored constraints.