Traganos F, Darzynkiewicz Z, Melamed M R
Cancer Res. 1981 Nov;41(11 Pt 1):4566-76.
The effects of the L isomer (+)-1,2-bis(3,5-dioxopiperazine-1-yl)propane (ICRF 159; NSC 169780) on cell viability, growth, and progression through the cell cycle were investigated in suspension cultures of murine leukemia (Friend leukemia and L1210) cells and normal human lymphocytes stimulated with phytohemagglutinin and in adherent cultures derived from human neuroblastoma and Chinese hamster ovary (CHO) cells. CHO cell colony formation was inhibited by 50% following either an 8.5-hr exposure of exponentially growing cells to 10 micrograms ICRF 159 per ml or a 24-hr exposure to 3 micrograms ICRF 159 per ml. This effect was cell cycle phase specific; early G1- and G2-phase cells were more sensitive than were late-G1- or early and mid-S-phase CHO cells. Stationary-phase CHO cells were unaffected by the drug at concentrations up to 500 micrograms/ml. Incubation of L1210 cells with 3 micrograms ICRF 159 per ml for 24 hr or with 10 micrograms ICRF 159 per ml for 6 hr inhibited cell growth by 50%. In contrast, 24-hr incubation of human lymphocytes with up to 50 micrograms ICRF 159 per ml had no effect on their viability or on their ability to be stimulated by phytohemagglutinin. Constant exposure of Friend leukemia, L1210, human neuroblastoma, and phytohemagglutinin-stimulated human lymphocytes to 10.0 to 50 micrograms ICRF 159 per ml resulted in inhibition of cell division which led to cell growth at higher ploidy levels. Thus, proliferating human cells of normal or tumor origin and murine leukemic cell lines all had a similar sensitivity to the drug. Detailed analysis of cell cycle progression in L1210 cells in the presence of the drug determined that cell progression through G1 phase (G1A to G1B transition) was slowed by approximately 50%. The rate of traverse of cells through S phase was also slowed. However, the most pronounced effect was the accumulation of cells in G2 phase occurring almost immediately after addition of the drug. The data suggest that the L isomer has a range of cytotoxicity and identical cytokinetic effects similar to that of the clinically tested racemate (+/-)-ICRF 159 (NSC 129943) and, therefore, that the more soluble L isomer may have increased clinical applicability.
研究了L型异构体（+）-1,2-双（3,5-二氧代哌嗪-1-基）丙烷（ICRF 159；NSC 169780）对小鼠白血病（Friend白血病和L1210）细胞悬浮培养物、经植物血凝素刺激的正常人淋巴细胞以及来自人神经母细胞瘤和中国仓鼠卵巢（CHO）细胞的贴壁培养物的细胞活力、生长及细胞周期进程的影响。指数生长的CHO细胞在每毫升10微克ICRF 159中暴露8.5小时或在每毫升3微克ICRF 159中暴露24小时后，其集落形成受到50%的抑制。这种作用具有细胞周期时相特异性；G1期早期和G2期细胞比G1期晚期或S期早期及中期的CHO细胞更敏感。静止期CHO细胞在浓度高达每毫升500微克的该药物作用下不受影响。将L1210细胞在每毫升3微克ICRF 159中孵育24小时或在每毫升10微克ICRF 159中孵育6小时，细胞生长受到50%的抑制。相比之下，将正常人淋巴细胞在每毫升高达50微克ICRF 159中孵育24小时，对其活力或对植物血凝素刺激的反应能力没有影响。将Friend白血病细胞、L1210细胞、人神经母细胞瘤细胞和经植物血凝素刺激的人淋巴细胞持续暴露于每毫升10.0至50微克ICRF 159中，导致细胞分裂受到抑制，从而使细胞在更高倍体水平上生长。因此，正常或肿瘤来源地增殖人细胞以及小鼠白血病细胞系对该药物均具有相似的敏感性。对存在该药物时L1210细胞的细胞周期进程进行详细分析发现，细胞通过G1期（从G1A到G1B转变）的进程减慢了约50%。细胞通过S期的速率也减慢。然而，最显著的作用是在添加药物后几乎立即出现细胞在G2期的积累。数据表明，L型异构体具有一系列细胞毒性作用以及与临床测试的消旋体（+/-）-ICRF 159（NSC 129943）相似的细胞动力学效应，因此，更易溶解的L型异构体可能具有更高的临床适用性。
