Old Dominion University, School of Medical Laboratory and Radiation Sciences College of Health Sciences, Norfolk, VA 23529, USA.
Expert Opin Drug Metab Toxicol. 2010 Jan;6(1):75-81. doi: 10.1517/17425250903393745.
Understanding fully the mechanism(s) of action of current and novel anticancer drugs is essential to optimize treatment regimens for oncology patients, to improve or extend drug efficacy and reduce patient side effects. Nucleoside analogues, either alone or in combination with additional therapeutic agents, are an essential part of first-line and salvage regimens directed against neoplastic diseases. However, many mechanistic studies on this class of drugs have been carried out in vitro or ex vivo at drug concentrations that are orders of magnitude higher than levels achieved in vivo.
In this paper, we focus on the anti-leukemic drug and nucleoside analogue, cladribine (2-chloro-2'-deoxyadenosine), to illustrate the difficulty in interpreting the significance of in vitro results obtained using drug concentrations that would be markedly deleterious to patients.
We review numerous research reports that have been conducted at pharmacologically achievable drug levels compared to those using toxic concentrations and contrast the respective results.
We propose that cellular responses to supra-pharmacological drug concentrations occur via distinctly different mechanisms and signaling pathways compared to the much lower plasma concentrations achieved with clinically relevant doses, and thus may not provide appropriate insights into a drug's mechanism of action.
充分了解当前和新型抗癌药物的作用机制对于优化肿瘤患者的治疗方案至关重要，可提高或延长药物疗效并减少患者的副作用。核苷类似物单独使用或与其他治疗药物联合使用，是针对肿瘤疾病的一线和挽救治疗方案的重要组成部分。然而，许多关于这类药物的机制研究都是在体外或离体进行的，药物浓度比体内实际达到的浓度高几个数量级。
在本文中，我们重点研究抗白血病药物和核苷类似物克拉屈滨（2-氯-2'-脱氧腺苷），以说明在使用对患者有明显毒性的药物浓度时，解释体外结果的意义存在困难。
我们回顾了许多在药理学上可达到的药物浓度下进行的研究报告，与使用毒性浓度的报告进行对比，并分别展示各自的结果。
我们提出，细胞对超药理学药物浓度的反应通过与临床相关剂量下血浆浓度明显不同的机制和信号通路发生，因此可能无法为药物的作用机制提供适当的见解。
