Kobayashi K, Kudoh S, Takemoto T, Hino M, Hayashihara K, Nakahiro K, Ando M, Niitani H
Fourth Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
J Cancer Res Clin Oncol. 1995;121(12):715-20. doi: 10.1007/BF01213317.
The log/log relationship between the IC50 of cisplatin or carboplatin and the exposure time, determined by human tumor clonogenic assay (HTCA) and MTTAI (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay with additional incubation) using PC-14 cells, exhibited a straight line with a slope of -1, indicating that both drugs have AUC-dependent cytotoxicity (AUC, area under the c/t curve). The combined effect of cisplatin and carboplatin was estimated by the median-effect analysis using HTCA, and it was additive when the AUC ratio (AUC of free platinum from carboplatin/that from cisplatin) was low (3.2, 6.5 or 13.1 in each of PC-7, PC-9, PC-14, H-69, and K562). However, it was significantly worse at a higher AUC ratio (19.5 in PC-7, PC-9, and PC-14). The log/log relationship of each drug, determined by MTTAI using human bone marrow cells, showed that each drug exerts an AUC-dependent cytotoxicity on marrow granulocytes. When cisplatin and carboplatin were combined at an AUC ratio of 14, the therapeutic index was significantly better than that of carboplatin alone and less than that of cisplatin alone using K562, PC-9 and PC-14, indicating the usefulness of this combined therapy for tumor cells with high sensitivity to platinum compounds at this AUC ratio.
采用人肿瘤克隆形成试验（HTCA）和MTTAI（额外孵育的3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐试验），利用PC-14细胞测定顺铂或卡铂的IC50与暴露时间之间的对数/对数关系，呈现出斜率为-1的直线，表明这两种药物均具有AUC依赖性细胞毒性（AUC，c/t曲线下面积）。通过HTCA采用中位效应分析评估顺铂和卡铂的联合效应，当AUC比值（卡铂游离铂的AUC/顺铂游离铂的AUC）较低时（PC-7、PC-9、PC-14、H-69和K562中分别为3.2、6.5或13.1），联合效应为相加作用。然而，在较高的AUC比值下（PC-7、PC-9和PC-14中为19.5），联合效应明显更差。采用人骨髓细胞通过MTTAI测定每种药物的对数/对数关系，结果表明每种药物对骨髓粒细胞均具有AUC依赖性细胞毒性。当顺铂和卡铂以AUC比值14联合使用时，对于K562、PC-9和PC-14，治疗指数明显优于单独使用卡铂，且低于单独使用顺铂，表明在该AUC比值下这种联合疗法对铂化合物高度敏感的肿瘤细胞有用。
