Fujiwara Y, Nakamura M, Yokoo S
Department of Radiation Biophysics and Genetics, Kobe University School of Medicine, Japan.
Br J Cancer. 1993 Jun;67(6):1285-92. doi: 10.1038/bjc.1993.239.
Interstrand cross-linking, repair and lethal effects of (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato++ +) platinum(II) (DWA2114R) were studied in normal human. Fanconi's anaemia (FA) and xeroderma pigmentosum group A (XPA) cells. Interstrand crosslinking by DWA2114R was slower than that by cisplatin (CDDP), since DWA2114R produced mainly Pt(II)-monoadducts after 1 h treatment, followed by progressive interstrand crosslinking to a maximum 5 h post-incubation, while CDDP induced rapidly interstrand crosslinks in approximately 70% DNA during the 1 h treatment, followed by a approximately 30% residual increase. At the maximum rate, DWA2114R was 18 times less interstrand-crosslinking than CDDP on the 1 mM basis. FA cells were specifically defective in the first half-excision of DWA2114R and CDDP-induced Pt(II) interstrand crosslinks, but XPA cells were as proficient as normal cells (t1/2 = 5-7 h). On the contrary, XPA cells were deficient in excision repair of intrastrand crosslinks, but FA cells were normal. In clonogenic survival curves of all types of cells, mean lethal doses (Do) of DWA2114R were an order of magnitude greater than those of CDDP. FA cells were most (3.5 times) sensitive (Do = 25.1 +/- 0.96 microM) and XPA cells were 1.9 times more sensitive (Do = 47.1 +/- 0.17 microM) to DWA2114R than normal cells (Do = 87.6 +/- 5.65 microM). DWA2114R and carboplatin with a cyclobutanedicarboxylato group exhibited almost similar lethal effects on each of normal, FA and XPA strains. FA (Do = 3.44 +/- 0.44 microM) and XPA cells (Do = 3.84 +/- 0.17 microM) were similarly 3-fold more sensitive to CDDP than normal (Do = 9.97 +/- 0.15 microM). On the basis of a single lethal hit (Do), thus DWA2114R and carboplatin effectively killed more FA cells defective in interstrand crosslink repair than XPA cells defective in intrastrand crosslink repair.
研究了(-)-(R)-2-氨甲基吡咯烷(1,1-环丁烷二羧酸根合++)铂(II)(DWA2114R)在正常人、范可尼贫血(FA)细胞和A型着色性干皮病(XPA)细胞中的链间交联、修复及致死效应。DWA2114R诱导的链间交联比顺铂(CDDP)慢，因为DWA2114R在处理1小时后主要产生Pt(II)-单加合物，随后在孵育5小时后链间交联逐渐增加至最大值，而CDDP在1小时处理期间能迅速在约70%的DNA中诱导链间交联，随后还有约30%的残余增加。以1 mM为基础，DWA2114R的链间交联速率比CDDP低18倍。FA细胞在DWA2114R和CDDP诱导的Pt(II)链间交联的首次半切除中存在特异性缺陷，但XPA细胞与正常细胞一样 proficient (t1/2 = 5 - 7小时)。相反，XPA细胞在内链交联的切除修复方面存在缺陷，但FA细胞正常。在所有类型细胞的克隆存活曲线中，DWA2114R的平均致死剂量(Do)比CDDP大一个数量级。FA细胞对DWA2114R最敏感(3.5倍，Do = 25.1 +/- 0.96 microM)，XPA细胞比正常细胞(Do = 87.6 +/- 5.65 microM)对DWA2114R敏感1.9倍。DWA2114R和带有环丁烷二羧酸根的卡铂对正常、FA和XPA各菌株的致死效应几乎相似。FA(Do = 3.44 +/- 0.44 microM)和XPA细胞(Do = 3.84 +/- 0.17 microM)对CDDP的敏感性同样比正常细胞(Do = 9.97 +/- 0.15 microM)高3倍。因此，基于单一致死打击(Do)，DWA2114R和卡铂对链间交联修复缺陷的FA细胞的杀伤作用比对内链交联修复缺陷的XPA细胞更有效。
