Lethality, DNA alkylation, and cell cycle effects of adozelesin (U-73975) on rodent and human cells.
Lethality, DNA alkylation, and cell cycle effects of adozelesin (U-73975) on rodent and human cells.
复制标题
adozelesin (U-73975) 对啮齿动物和人类细胞的致死率、DNA 烷基化和细胞周期影响。
作者：
Bijoy K. Bhuyan;Kathy S. Smith;E. G. Adams;G. Petzold;J. Mcgovren
阿多斯丁(U-73975)对中国仓鼠卵巢和肺(CHO和V79)、小鼠黑色素瘤(B16)和人卵巢癌(A2780)细胞体外作用2小时后，杀伤率分别为90%、0.33、0.19、0.2和0.025 ng/ml。在相似条件下，阿霉素和顺铂对CHO细胞的致死率分别为150 ng/ml(=249 nM)和6800 ng/ml(=2266 nM)。A2780、GT、V79、B16、CHO细胞株的相对药物敏感性与[~3H]阿多泽林与DNA烷基化的相对含量相关。A2780的较高敏感性是由于(A)不同药物剂量下DNA的烷基化程度较高，以及(B)A2780的本征敏感性较高，从而导致在类似的DNA烷基化情况下细胞杀伤率较高。时相毒性研究表明，阿多泽莱辛对处于有丝分裂和极早期G1期的CHO细胞的致死率最低。随着细胞向G1期发展，杀伤力逐渐增强，并在G1期晚期达到最大值，早期S期细胞的药物摄取率和药物结合率均低于G1期和S期细胞。然而，基于每微克脱氧核糖核酸中烷化药物的数量，M、G1和S的细胞同样敏感。因此，M期细胞的敏感性较低是由于药物摄取率较低所致。阿多斯莱辛对CHO、V79、B16和A2780细胞周期有三种不同的作用：(A)通过S延缓细胞生长，使细胞周期中S期细胞比例显著增加；这种效应是暂时的；(B)G2中的细胞进程被阻断了很长一段时间；(C)细胞系对G2阻断的反应不同。CHO和V79细胞通过分裂逃过G2期，进入二倍体DNA周期或未发生胞质分裂而成为四倍体。相反，B16和A2780细胞在G2期仍处于阻断状态，未形成四倍体。当M期、G1期或S期细胞的同步化群体暴露于阿多泽莱辛时，细胞进程也以类似的方式受到抑制。
Adozelesin (U-73975) is an extremely potent cytotoxic agent which causes 90% lethality, after 2 h exposure in vitro, of Chinese hamster ovary and lung (CHO and V79), mouse melanoma (B16), and human ovarian carcinoma (A2780) cells at 0.33, 0.19, 0.2, and 0.025 ng/ml, respectively. Under similar conditions, Adriamycin and cisplatin had 90% lethality values in CHO cells of 150 ng/ml (= 249 nM) and 6800 ng/ml (= 2266 nM), respectively. The relative drug sensitivity of the cell lines (A2780 > V79, B16, CHO) was correlated to the relative amounts of [3H]adozelesin alkylated to DNA. The greater sensitivity of A2780 was due to (a) greater DNA alkylation at different drug doses and (b) greater intrinsic sensitivity of A2780 which resulted in greater cell kill at comparable DNA alkylation. Phase specific toxicity studies show that adozelesin was least lethal to CHO cells in mitosis and very early G1. Lethality increased as cells progressed through G1 and was maximal in late G1 and early S. Mitotic cells had lower drug uptake and correspondingly less drug binding to DNA than G1 or S-phase cells. However, based on the amount of drug alkylated per micrograms of DNA, cells in M, G1, and S were equally sensitive. Therefore, the lower sensitivity of M-phase cells was due to lower drug uptake. Adozelesin had three different effects on progression of CHO, V79, B16, and A2780 through the cell cycle: (a) slowed progression through S which resulted in significantly increasing the percentage of S-phase cells. This effect was transient; (b) cell progression was blocked in G2 for a long time period; (c) the response of the cell lines to the G2 block differed. CHO and V79 cells escaped G2 block by dividing and entered the diploid DNA cycle or did not undergo cytokinesis and became tetraploid. On the contrary, B16 and A2780 cells remained blocked in G2 and did not become tetraploid. Cell progression was inhibited in a similar manner when a synchronized population of M, G1, or S-phase cells were exposed to adozelesin.
影响因子：
10.3
作者：
SORENSON, CM;BARRY, MA;EASTMAN, A
通讯作者：
EASTMAN, A
CC-1065 (NSC 298223) 与 DNA 相互作用的机制。
影响因子：
11.2
作者：
Swenson,DH;Li,LH;Hurley,LH;Rokem,JS;Petzold,GL;Dayton,BD;Wallace,TL;Lin,AH;Krueger,WC
通讯作者：
Krueger,WC
DOI：
10.1073/pnas.87.24.9553
发表时间：
1990-12-01
影响因子：
11.1
作者：
KUNG, AL;SHERWOOD, SW;SCHIMKE, RT
通讯作者：
SCHIMKE, RT