Akamatsu K, Endo K, Matsumoto T, Kamisango K, Morikawa K, Koizumi M, Mitsui H, Koizumi K, Matsuno T
Exploratory Research Laboratories, Chugai Pharmaceutical Co. Ltd., Gotemba.
Gan To Kagaku Ryoho. 1990 Jan;17(1):73-8.
Antitumor activity of a new platinum complex, (R)-(-)-2-aminomethylpyrrolidine (1, 1-cyclobutanedicarboxylato) platinum (II) (DWA 2114 R) against cisdiamminedichloroplatinum (II) (CDDP)-resistant tumor was examined in in vitro and in vivo experiments. CDDP-resistant line was established from L 1210 mouse leukemia cells by continuous exposure to CDDP in dose-escalation manner. Six clones were isolated from parental resistant line and one of these clones, clone f, which was found to be highly resistant (30-40 fold) to CDDP, was used in the following experiments. Clone f showed 4-7 fold cross-resistance to DWA 2114 R and 11-19 fold to cisdiammine-1, 1-cyclobutanedicarboxylatoplatinum (II) (CBDCA) in in vitro growth inhibition assay. DWA 2114 R showed the most effective antitumor activity against mice transplanted with the resistant cells in the increase of life span (ILS%). About 100% of ILS and cured mice were observed in the treatment with DWA 2114 R. On the other hand, CDDP or CBDCA showed a little increase in the survival time (less than 40% of ILS) and all mice died. These results suggest that DWA 2114 R seemed to be more effective against CDDP-resistant tumors clinically than CDDP and CBDCA.
在体外和体内实验中研究了一种新型铂配合物（R）-（-）-2-氨甲基吡咯烷（1,1-环丁烷二羧酸根）铂（II）（DWA 2114 R）对顺二氨二氯铂（II）（CDDP）耐药肿瘤的抗肿瘤活性。通过以剂量递增方式持续暴露于CDDP，从L 1210小鼠白血病细胞建立了CDDP耐药系。从亲本耐药系中分离出六个克隆，其中一个克隆f被发现对CDDP具有高度耐药性（30-40倍），用于以下实验。在体外生长抑制试验中，克隆f对DWA 2114 R表现出4-7倍的交叉耐药性，对顺二氨-1,1-环丁烷二羧酸根铂（II）（CBDCA）表现出11-19倍的交叉耐药性。在延长寿命（ILS%）方面，DWA 2114 R对移植了耐药细胞的小鼠显示出最有效的抗肿瘤活性。在用DWA 2114 R治疗中观察到约100%的ILS和治愈小鼠。另一方面，CDDP或CBDCA的存活时间略有增加（ILS小于40%），所有小鼠均死亡。这些结果表明，临床上DWA 2114 R对CDDP耐药肿瘤似乎比CDDP和CBDCA更有效。
