Hayashi Sachiko, Hatashita Masanori, Matsumoto Hideki, Jin Zhao-Hui, Shioura Hiroki, Kano Eiichi
Department of Experimental Radiology, Faculty of Medical Science, Fukui University, Matsuoka, Japan.
Int J Mol Med. 2005 Sep;16(3):381-7.
The effects of amrubicin (AMR) and its active metabolite, amrubicinol (AMROH), on the sensitivity of human lung adenocarcinoma A549 cell line to hyperthermia at 44 degrees C were investigated. The cell phase response as well as the kinetics of apoptosis and necrosis induction were also analyzed. The cytocidal effects of 44 degrees C hyperthermia on A549 cells exhibited low thermosensitivity with a T(0) value of 12 min. The slope of the survival curve in the exponential phase, described semilogarithmically, in 44 degrees C hyperthermia combined treatment with AMROH (0.02 microg/ml) was approximately parallel to 44 degrees C hyperthermia alone. The initial shoulder shape portion of the survival curve from 44 degrees C hyperthermia alone, indicating the repair of sublethal thermal damage (SLTDR), was reduced with the sequential combined treatment of AMR or AMROH. Sequential treatments with AMR or AMROH prior to 44 degrees C hyperthermia resulted in additive thermo-enhancement effect by reducing not only survival but was shoulder wide. Furthermore, like AMR and AMROH, adriamycin (ADM) and etoposide (VP-16) are DNA topoisomerase II inhibitors, and the effects of these 4 agents on 44 degrees C hyperthermia were compared. All 4 agents exhibited comparable thermo-enhancement effects. Using synchronized A549 cells, AMR or AMROH did not elicit cell phase responses, irrespective of the concentration. The induction of apoptosis was investigated at 48 and 72 h after AMROH treatment, 44 degrees C hyperthermia or the combined treatment, in which apoptosis was not significantly induced after any treatment. Furthermore, the incidence of necrosis was examined as well as apoptosis. The incidence of necrosis at 48 and 72 h after AMROH was 2.4 and 4.3%, respectively; after 44 degrees C hyperthermia was 3.3 and 4.0%, respectively; and after the combined treatment it was 10.7 and 8.7%, respectively. The necrosis induced after the combined treatment was circa 3 times higher than that in either of the single treatments.
研究了氨柔比星（AMR）及其活性代谢产物氨柔比星醇（AMROH）对人肺腺癌A549细胞系在44℃热疗敏感性的影响。还分析了细胞周期反应以及凋亡和坏死诱导的动力学。44℃热疗对A549细胞的杀伤作用表现出低热敏感性，T(0)值为12分钟。在44℃热疗与AMROH（0.02μg/ml）联合治疗中，以半对数描述的指数期存活曲线斜率与单独的44℃热疗大致平行。单独44℃热疗存活曲线的初始肩形部分表明亚致死热损伤修复（SLTDR），在AMR或AMROH的序贯联合治疗中降低。在44℃热疗之前用AMR或AMROH进行序贯治疗通过不仅降低存活率而且使肩宽变窄而产生相加热增强作用。此外，与AMR和AMROH一样，阿霉素（ADM）和依托泊苷（VP-16）是DNA拓扑异构酶II抑制剂，并比较了这4种药物对44℃热疗的影响。所有4种药物均表现出相当的热增强作用。使用同步化的A549细胞，无论浓度如何，AMR或AMROH均未引发细胞周期反应。在AMROH治疗、44℃热疗或联合治疗后48和72小时研究凋亡诱导，其中任何治疗后均未显著诱导凋亡。此外，检查了坏死的发生率以及凋亡。AMROH后48和72小时的坏死发生率分别为2.4%和4.3%；44℃热疗后分别为3.3%和4.0%；联合治疗后分别为10.7%和8.7%。联合治疗后诱导的坏死比单一治疗中的任何一种高约三倍。
