Evaluation of synergism in drug combinations and reference models for future orientations in oncology.
Evaluation of synergism in drug combinations and reference models for future orientations in oncology.
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DOI：
10.1016/j.crphar.2022.100110
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发表时间：
2022
影响因子：
--
通讯作者：
Vale, Nuno
中科院分区：
文献类型：
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作者：
Duarte, Diana;Vale, Nuno
目前的癌症治疗包括多种策略，这些策略可以仅包括一种类型的治疗或多种治疗的组合。化疗仍然是癌症治疗的黄金标准，尽管有时与不良副作用和耐药性的发展有关。出于这个原因，药物组合是一种已经提出来克服与单药治疗相关的问题的方法，并且一些研究已经证明了组合疗法与单药治疗相比的优越性。设计和评价药物组合时的主要目标是通过证明组合效应大大上级单一药物的累加效应的预期来实现协同效应，从而允许剂量减少并因此降低毒性。然而，协同作用的量化不是一个简单的任务，由于不同的定义和多年来的加和性和几个参考模型已经提出了基于不同的假设和不同的数学框架。在这篇综述中，我们开始涵盖了癌症治疗的可用治疗方案，重点是药物组合在癌症治疗中的重要性。接下来，我们描述了经典的参考模型，已提出的协同作用的评价，通常分为基于效果和基于剂量效应的方法，与这些模型的局限性的简要分析。我们还在这里描述了新的方法，在联合治疗中的药物相互作用的准确定量。在本文的最后，我们介绍了一些最新的临床前和临床联合研究，这些研究反映了适当、准确和精确应用本文所述的概念和方法对评价协同作用的重要性。药物联合旨在实现积极的联合相互作用效应。现有的参考模型有不同的数学框架。到目前为止，还没有一个标准的参考模型来评估协同作用。参考模型必须适用于现有数据和研究类型。临床试验中的协同作用通常得到临床前研究数据的支持。
Current cancer therapy includes a variety of strategies that can comprise only one type of treatment or a combination of multiple treatments. Chemotherapy is still the gold standard for cancer therapy, though sometimes associated with undesired side effects and the development of drug resistance. For this reason, drug combination is an approach that has been proposed to overcome the problems related to monotherapy and several studies have already demonstrated the superiority of combined therapies compared to monotherapy. The main goal when designing and evaluating drug combinations is to achieve synergistic effects by demonstrating that the combined effects are greatly superior to the expected from the additive effects of the single drugs, allowing for dosage reduction and therefore decreasing toxicity. Nevertheless, synergism quantification is not a simple task due to the different definitions of additivity and over the years several reference models have been proposed based on different assumptions and with different mathematical frameworks. In this review, we begin to cover the available treatment options for cancer therapy, with emphasis on the importance of drug combinations in cancer therapy. We next describe the classical reference models that have been proposed for synergism evaluation, usually classified as effect-based and dose-effect based methods, with a brief analysis of the current limitations of these models. We also describe here the novel methods for the accurate quantification of drug interactions in combined treatments. At the end of this manuscript, we covered some of the most recent preclinical and clinical combination studies that reflect the importance of the appropriate, accurate and precise application of the concepts and methodologies here described for the evaluation of synergism. Drug combination aims to achieve positive combination interaction effects. The available reference models have different mathematical frameworks. To date, there is not a standard reference model to evaluate synergism. Reference models must be adequate to the available data and type of study. Synergism in clinical trials is usually supported by data from preclinical studies.