Kim D K, Kim H T, Tai J H, Cho Y B, Kim T S, Kim K H, Park J G, Hong W S
Life Science Research Center, Sunkyong Industries, Kyungki-Do, Korea.
Cancer Chemother Pharmacol. 1995;37(1-2):1-6.
The pharmacokinetics and ex vivo pharmacodynamics studies on cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1, 3- dioxolane]platinum(II) (SKI 2053R, NSC D644591), cisplatin (CDDP), and carboplatin (CBDCA) were performed in beagle dogs. Equitoxic doses of SKI 2053R, CDDP, and CBDCA (7.5, 2.5, and 15.0 mg/kg, respectively) were given by i.v. bolus to three beagle dogs in a randomized crossover study. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for the three drugs declined in a biexponential fashion. The mean area under the concentration-time curve (AUC0-->infinity) determined for ultrafiltrable platinum derived from SKI 2053R, as an active component, was 7.72 +/- 2.74 micrograms h ml-1 (mean +/- SD), with an initial half-life of 0.37 +/- 0.20 h, a terminal half-life of 2.19 +/- 0.93 h, a total clearance of 16.83 +/- 4.76 ml min-1 kg-1, and a steady-state volume of distribution of 1.57 +/- 0.30 l/kg. The ex vivo antitumor activity of SKI 2053R was assessed using the ultrafiltrable plasma against two human lung-adenocarcinoma cell lines (PC-9 and PC-14) and five stomach-adenocarcinoma cell lines (MKN-45, KATO III, SNU-1, SNU-5, and SNU-16) by tetrazolium-dye (MTT) assay and was compared with that of CDDP and CBDCA using an antitumor index (ATI) determined from the ex vivo pharmacodynamic results of inhibition rates (%) versus time curves. The mean ATI value was shown to be ranked in the following order: SKI 2053R > CBDCA > CDDP. The mean ATI values recorded for SKI 2053R and CBDCA were significantly (P < 0.05) higher than that noted for CDDP; however, no statistically significant difference was observed between SKI 2053R and CBDCA, suggesting that the antitumor activity of SKI 2053R is superior to that of CDDP and is equivalent to that of CBDCA. These results suggest that SKI 2053R is a promising candidate for further development as a clinically useful anticancer drug.
在比格犬身上进行了顺式丙二酸根[(4R,5R)-4,5-双(氨甲基)-2-异丙基-1,3-二氧戊环]铂(II)(SKI 2053R,NSC D644591)、顺铂(CDDP)和卡铂(CBDCA)的药代动力学及体外药效学研究。在一项随机交叉研究中，对3只比格犬静脉推注等毒性剂量的SKI 2053R、CDDP和CBDCA(分别为7.5、2.5和15.0 mg/kg)。通过无火焰原子吸收分光光度法分析血浆样本中的铂。三种药物的总铂和超滤铂的血浆浓度呈双指数下降。由SKI 2053R衍生的作为活性成分的超滤铂的浓度-时间曲线下平均面积(AUC0→∞)为7.72±2.74微克·小时·毫升-1(平均值±标准差)，初始半衰期为0.37±0.20小时，终末半衰期为2.19±0.93小时，总清除率为16.83±4.76毫升·分钟-1·千克-1，稳态分布容积为1.57±0.30升/千克。通过四唑盐染料(MTT)试验，使用超滤血浆评估SKI 2053R对两种人肺腺癌细胞系(PC-9和PC-14)和五种胃腺癌细胞系(MKN-45、KATO III、SNU-1、SNU-5和SNU-16)的体外抗肿瘤活性，并使用从抑制率(%)对时间曲线的体外药效学结果确定的抗肿瘤指数(ATI)与CDDP和CBDCA的进行比较。平均ATI值显示按以下顺序排列：SKI 2053R＞CBDCA＞CDDP。SKI 2053R和CBDCA记录的平均ATI值显著高于CDDP记录的值(P＜0.05)；然而，SKI 2053R和CBDCA之间未观察到统计学上的显著差异，这表明SKI 2053R的抗肿瘤活性优于CDDP且等同于CBDCA。这些结果表明，SKI 2053R作为一种临床上有用的抗癌药物有进一步开发的前景。
