Weaver J R, Wientjes M G, Au J L
College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
Cancer Chemother Pharmacol. 1999;44(4):335-42. doi: 10.1007/s002800050986.
Human solid tumor histocultures represent a clinically relevant experimental system for pharmacodynamic study. The evaluation of the drug-induced antiproliferative effect in histocultures is usually performed by manual microscopic scoring of individual cells. This procedure, because of its labor intensive nature, is performed on a single microscopic field, i.e. the field with the highest proliferative activity. Because regional heterogeneity in a solid tumor may result in different drug sensitivities in different parts of a tumor, there is the question as to whether the pharmacodynamic data determined in the most proliferative field is representative of those in the whole tumor. This question was addressed in the present study.
A recently developed automated image analysis method was used to measure the labeling index of tumor cells. The drug-induced inhibition of DNA precursor incorporation into nuclei of cells in the region with the highest proliferative activity was compared to the inhibition in cells in the entire histoculture. This study was performed in human bladder tumor histocultures treated with several drugs (doxorubicin, mitomycin C, paclitaxel and 5-fluorouridine). A total of 724 pairs of data obtained from untreated and drug-treated histocultures (each data point representing the average of 1 to 6 tumor histocultures) were analyzed.
The absolute value of the labeling index in the most proliferative region (LI(one)) was significantly higher than the absolute value of the labeling index in the whole tumor (LI(all)), in both untreated and drug treated samples (mean difference of 18%, range 1-27%). However, when the absolute LI values in drug-treated samples were normalized to the values in untreated controls and expressed as a percentage of control, and used to construct the concentration-response curves, the two curves obtained using LI(one) and LI(all) yielded comparable pharmacodynamic parameters, i.e. curve shape parameters and drug concentrations that produce 30, 50, and 70% inhibition.
These results indicate comparable pharmacodynamics in the most proliferative region and the whole tumor, and confirm the validity of using the most proliferative field for evaluating chemosensitivity in solid tumor histocultures.
人类实体瘤组织培养物是一种用于药效学研究的临床相关实验系统。在组织培养物中评估药物诱导的抗增殖作用通常通过对单个细胞进行手动显微镜评分来完成。由于该过程劳动强度大，所以仅在单个显微镜视野（即增殖活性最高的视野）上进行。由于实体瘤中的区域异质性可能导致肿瘤不同部位对药物的敏感性不同，因此存在这样一个问题，即在增殖最活跃的视野中确定的药效学数据是否代表整个肿瘤的数据。本研究旨在解决这个问题。
使用一种最近开发的自动图像分析方法来测量肿瘤细胞的标记指数。将药物诱导的DNA前体掺入增殖活性最高区域细胞细胞核的抑制作用与整个组织培养物中细胞的抑制作用进行比较。本研究在接受几种药物（阿霉素、丝裂霉素C、紫杉醇和5-氟尿苷）治疗的人膀胱肿瘤组织培养物中进行。共分析了从未经处理和经药物处理的组织培养物中获得的724对数据（每个数据点代表1至6个肿瘤组织培养物的平均值）。
在未经处理和经药物处理的样本中，增殖最活跃区域的标记指数绝对值（LI(one)）均显著高于整个肿瘤的标记指数绝对值（LI(all)）（平均差异为18%，范围为1 - 27%）。然而，当将经药物处理样本中的绝对LI值相对于未经处理对照中的值进行归一化，并表示为对照的百分比，用于构建浓度 - 反应曲线时，使用LI(one)和LI(all)获得的两条曲线产生了可比的药效学参数，即曲线形状参数以及产生30%、50%和70%抑制作用的药物浓度。
这些结果表明增殖最活跃区域和整个肿瘤具有可比的药效学，并证实了使用增殖最活跃视野评估实体瘤组织培养物化学敏感性的有效性。
