Lee K S, Kim H K, Moon H S, Hong Y S, Kang J H, Kim D J, Park J G
Department of Internal Medicine, Catholic University Medical College, Seoul, Korea.
Korean J Intern Med. 1992 Jul;7(2):111-7. doi: 10.3904/kjim.1992.7.2.111.
Chemotherapy failure remains a significant medical problem in the treatment of neoplastic disease and is thought to be due to many different factors including membrane transport, p-glycoprotein in multidrug resistance, glutathione and its related enzymes, topoisomerase II and DNA repair. Glutathione is a major constituent of non-protein thiol and participates in detoxification of chemotherapy and radiation. Thus, glutathione concentration is correlated with sensitivity to alkylating agents and radiation, and increased in resistant cell lines. Buthionine sulfoximine (BSO) is an inhibitor of glutathione biosynthesis and may increase cytotoxicities of alkylating agents, including melphalan and cisplatin, and radiation in sensitive and resistant cell lines. We studied effects on cellular glutathione levels and cytotoxicities of cisplatin, carboplatin and radiation by BSO treatment in human stomach cancer cell line (SNU-1) and ovarian cancer cell line (OVCAR-3). The results were as follow: 1) After BSO treatment of 1 mM and 2 mM for 2 days, the intracellular thiol concentration was depleted to 75.7% and 76.2% in SNU-1, and 74.1% and 63.0% in OVCAR-3, respectively. 2) The intracellular thiol concentration in SNU-1 was depleted to 33.4% after BSO 2 mM for only 2 hours incubation and 71.5% after small amount of BSO (0.02 mM) for 2 days. 3) The recovery of intracellular thiol concentration required more than 3 days after BSO removal. 4) BSO inhibited partially the growth of SNU-1 and OVCAR-3. 5) The cytotoxicities of cisplatin and carboplatin were markedly enhanced both in SNU-1 and OVCAR-3 by BSO treatment. 6) The cytotoxicities of radiation was increased in OVCAR-3 and SNU-1 by BSO treatment. Therefore, it is concluded that BSO can deplete effectively the intracellular thiol concentration and enhance the cytotoxicities of cisplatin, carboplatin and radiation.
化疗失败仍然是肿瘤疾病治疗中的一个重大医学问题，被认为是由许多不同因素导致的，包括膜转运、多药耐药中的P -糖蛋白、谷胱甘肽及其相关酶、拓扑异构酶II和DNA修复。谷胱甘肽是非蛋白硫醇的主要成分，参与化疗和放疗的解毒过程。因此，谷胱甘肽浓度与对烷化剂和放疗的敏感性相关，并且在耐药细胞系中升高。丁硫氨酸亚砜胺（BSO）是谷胱甘肽生物合成的抑制剂，可能会增加烷化剂（包括美法仑和顺铂）的细胞毒性，以及在敏感和耐药细胞系中的放疗细胞毒性。我们研究了在人胃癌细胞系（SNU - 1）和卵巢癌细胞系（OVCAR - 3）中，通过BSO处理对细胞内谷胱甘肽水平以及顺铂、卡铂和放疗细胞毒性的影响。结果如下：1）在1 mM和2 mM的BSO处理2天后，SNU - 1细胞内硫醇浓度分别降至75.7%和76.2%，OVCAR - 3细胞内硫醇浓度分别降至74.1%和63.0%。2）在SNU - 1细胞中，仅2小时的2 mM BSO孵育后，细胞内硫醇浓度降至33.4%，而少量BSO（0.02 mM）处理2天后降至71.5%。3）去除BSO后，细胞内硫醇浓度的恢复需要超过3天。4）BSO部分抑制了SNU - 1和OVCAR - 3的生长。5）通过BSO处理，SNU - 1和OVCAR - 3中顺铂和卡铂的细胞毒性均显著增强。6）通过BSO处理，OVCAR - 3和SNU - 1中放疗细胞毒性增加。因此，得出结论：BSO可以有效耗尽细胞内硫醇浓度，并增强顺铂、卡铂和放疗的细胞毒性。
