Kim H T, Kim D K, Cho Y B, Kim T S, Jung I, Kim K H, Heo D S, Bang Y J, Shin S G, Kim N K
Life Science Research Center, Sunkyong Industries, Kyungki-Do, Korea.
Cancer Chemother Pharmacol. 1998;41(2):109-16. doi: 10.1007/s002800050716.
The effect of exposure time on the in vitro cytotoxicity of a new platinum complex, cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolan e]platinum(II) (SKI 2053R) and cisplatin (CDDP) toward two human lung-adenocarcinoma cell lines (PC-9, PC-14) and two human stomach-adenocarcinoma cell lines (KATO III, MKN-45) was investigated by variation of the exposure time (1, 4, 12, and 24 h) and drug concentration to yield a constant product of drug concentration times exposure time (C x T). Exposure of cancer cells to low concentrations of SKI 2053R for 12 or 24 h resulted in a greater killing effect than did 1- or 4-h exposure to 24- or 6-fold higher concentrations; the inhibitory effects of SKI 2053R on the colony formation of all tumor cell lines except for KATO III were significantly increased with increasing exposure time (P < 0.05). However, the inhibitory effects of CDDP against all tumor cell lines tested except for PC-14 were inversely correlated with increasing exposure time (P < 0.05). The intracellular accumulation of SKI 2053R and CDDP was measured under the same conditions used in the cell-survival assay using MKN-45 cells. The amount of platinum accumulated from SKI 2053R into MKN-45 cells was greater for the treatment involving low concentrations and long-term exposures (12 and 24 h) than for that using high concentrations and short-term exposures (1 and 4 h) at the constant C x T values; however, the increased accumulation of CDDP was more prominent as the concentration was increased, even if the exposure time became shorter. The pharmacokinetics studies of SKI 2053R following 1-, 4-, 12-, and 24-h infusions were performed in beagle dogs. A single dose of SKI 2053R (5.0 mg/kg) was successively given over various infusion periods to three beagle dogs at 3-week intervals. The peak levels of ultrafiltrable platinum observed for SKI 2053R at the 1-, 4-, 12-, and 24-h infusions were 3.10+/-0.49 (mean +/- SD), 1.24+/-0.06, 0.43+/-0.07, and 0.25+/-0.04 microg/ml, respectively. The mean binding ratios of platinum from SKI 2053R to plasma protein at the end of 1-, 4-, 12-, and 24-h infusions were approximately 91%, 73%, 53%, and 51%, respectively. The steady-state level of free platinum was maintained during long-term infusions (12 and 24 h) after short periods (1-3 h) from the start of the infusion. This study strongly suggests that the therapeutic efficacy of SKI 2053R given by continuous long-term infusion should be investigated in future clinical studies.
通过改变暴露时间（1、4、12和24小时）和药物浓度，以产生药物浓度与暴露时间的恒定乘积（C×T），研究了暴露时间对新型铂配合物顺式丙二酸根[(4R,5R)-4,5-双(氨甲基)-2-异丙基-1,3-二氧戊环]铂(II)（SKI 2053R）和顺铂（CDDP）对两种人肺腺癌细胞系（PC-9、PC-14）及两种人胃腺癌细胞系（KATO III、MKN-45）的体外细胞毒性的影响。将癌细胞暴露于低浓度的SKI 2053R 12或24小时，比暴露于高24或6倍浓度的SKI 2053R 1或4小时产生的杀伤效果更好；SKI 2053R对除KATO III外的所有肿瘤细胞系集落形成的抑制作用随暴露时间的增加而显著增强（P<0.05）。然而，CDDP对除PC-14外的所有测试肿瘤细胞系的抑制作用与暴露时间的增加呈负相关（P<0.05）。在使用MKN-45细胞进行细胞存活试验的相同条件下，测定了SKI 2053R和CDDP在细胞内的蓄积情况。在恒定的C×T值下，与高浓度短时间暴露（1和4小时）相比，低浓度长时间暴露（12和24小时）使SKI 2053R进入MKN-45细胞的铂含量更高；然而，即使暴露时间缩短，随着CDDP浓度的增加，其蓄积增加更为显著。对3只比格犬每隔3周在1、4、12和24小时输注后进行SKI 2053R的药代动力学研究。以5.0 mg/kg的单次剂量SKI 2053R在不同输注期连续给予3只比格犬。在1、4、12和24小时输注时，SKI 2053R观察到的可超滤铂的峰值水平分别为3.10±0.49（平均值±标准差）、1.24±0.06、0.43±0.07和0.25±0.04 μg/ml。在1、4、12和24小时输注结束时，SKI 2053R中铂与血浆蛋白的平均结合率分别约为91%、73%、53%和51%。从输注开始短时间（1 - 3小时）后，在长时间输注（12和24小时）期间维持游离铂的稳态水平。本研究强烈表明，未来的临床研究应探讨持续长期输注SKI 2053R的治疗效果。
