Modeling of the time-dependency of in vitro drug cytotoxicity and resistance.
Modeling of the time-dependency of in vitro drug cytotoxicity and resistance.
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发表时间：
1998-12
期刊：
影响因子：
11.2
通讯作者：
L. Levasseur;H. Slocum;Y. Rustum;W. Greco
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文献类型：
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作者：
L. Levasseur;H. Slocum;Y. Rustum;W. Greco
对于体外结果的潜在临床外推，将抗癌剂的测量效果与浓度和暴露时间联系起来是有意义的。希尔模型（A。V. Hill，J. Physiol.，40：iv-vii，1910）通常用于描述药效学（PD）效应，包括药物诱导的体外癌细胞生长抑制。IC（X）n x T = k关系，其中IC（X）是使细胞生长减少X%所需的药剂浓度，T是暴露时间，n和k是可估计的参数，首先应用于细菌消毒剂作用，然后成功地用于建模抗癌药物效价作为暴露时间的函数（D. J.亚当斯，癌症研究，49：6615-6620，1989）。我们的目标是创建一个新的全球PD建模范式，以促进定量评估抗癌药物的生长抑制作用作为浓度和暴露时间的函数。将对顺铂（A2780/CP 3）、多柔比星（A2780/DX 5 B）和雷替曲塞（RTX）（HCT-8/DW 2）耐药的野生型人卵巢A2780和回盲部HCT-8癌细胞和亚系暴露于各种抗癌剂（顺铂、多柔比星、紫杉醇、曲美曲塞、RTX、甲氨蝶呤和AG 2034）1 - 96 h。细胞生长抑制用磺酰罗丹明B蛋白染料测定法测量。药物效力的时间依赖性，浓度-效应曲线的斜率和相对耐药程度的模式进行了表征。将经验数学表达式纳入总体浓度-时间-效应模型。然后使用迭代重新加权非线性回归将总体PD模型拟合至浓度-时间-效应数据。在特定的治疗条件下，对浓度-效应曲线的斜率和形状的检查显示药物反应存在较大的异质性，例如，浓度-效应曲线较浅或呈双峰或三峰“过山车”式浓度-效应曲线。这些模式在紫杉醇和曲美蝶呤的亲代和耐药细胞中或仅在RTX、甲氨蝶呤和AG 2034的耐药HCT-8/DW 2细胞中在中间暴露时间观察到，揭示了前一种情况的机制见解，但后一种情况可能存在方法学伪影。抗癌药物细胞毒性作用的全面PD建模表明，通过改变暴露于药物的时间，可以调节药物效应、反应异质性和耐药性。这种方法将有助于：（a）描述复杂的浓度-时间-效应表面;（B）改进数据的生物学解释;（c）提供关于药物作用和耐药性机制的见解;以及（d）产生抗癌药物临床使用的线索。
For potential clinical extrapolation of in vitro findings, it is of interest to relate the measured effect of an anticancer agent to concentration and exposure time. The Hill model (A. V. Hill, J. Physiol., 40: iv-vii, 1910) is commonly used to describe pharmacodynamic (PD) effects, including drug-induced growth inhibition of cancer cells in vitro. The IC(X)n x T = k relationship, in which IC(X) is the concentration of agent required to reduce cell growth by X%, T is the exposure time, and n and k are estimable parameters, was first applied to bacterial disinfectant action and then was successfully used to model anticancer drug potency as a function of exposure time (D. J. Adams, Cancer Res., 49: 6615-6620, 1989). Our goal was to create a new global PD modeling paradigm to facilitate the quantitative assessment of the growth-inhibitory effect of anticancer agents as a function of concentration and exposure time. Wild-type human ovarian A2780 and ileocecal HCT-8 carcinoma cells and sublines that were resistant to cisplatin (A2780/CP3), doxorubicin (A2780/DX5B), and raltitrexed (RTX) (HCT-8/DW2) were exposed to various anticancer agents, cisplatin, doxorubicin, paclitaxel, trimetrexate, RTX, methotrexate, and AG2034, for periods ranging from 1 to 96 h. Cell growth inhibition was measured with the sulforhodamine B protein dye assay. Patterns of time-dependency of drug potency, slope of the concentration-effect curves, and relative degree of resistance were characterized. Empirical mathematical expressions were built into a global concentration-time-effect model. The global PD model was then fit to the concentration-time-effect data with iteratively reweighted nonlinear regression. Under specific treatment conditions, the examination of the slope and the shape of the concentration-effect curves revealed a large heterogeneity in drug response, e.g., shallow concentration-effect curve or double or triple Hill "roller coaster" concentration-effect curve. These patterns, which were observed at intermediate exposure times in parental and resistant cells for paclitaxel and trimetrexate or only in resistant HCT-8/DW2 cells for RTX, methotrexate, and AG2034, revealed mechanistic insights for the former cases but possible methodological artifacts for the latter cases. The comprehensive PD modeling of the cytotoxic effect of anticancer agents showed that it was possible to modulate drug effect, response heterogeneity, and drug resistance by altering the time of exposure to the agents. This approach will be useful for: (a) describing complex concentration-time-effect surfaces; (b) refining biological interpretations of data; (c) providing insights on mechanisms of drug action and resistance; and (d) generating leads for clinical use of anticancer drugs.