5—氟脲嘧啶对耐顺铂人肺腺癌细胞A549^DDP的程序依赖性逆转作用

用耐顺铂（ＣＤＤＰ）人肺腺癌细胞系Ａ５４９ＤＤＰ作模型，研究了５－ＦＵ对ＣＤＤＰ耐药的程序依赖性逆转作用。５－氟脲嘧啶（５－ＦＵ）预处理Ａ５４９ＤＤＰ２４ｈ后立即给予ＣＤＤＰ，ＣＤＤＰ细胞毒性增加３．９倍；５－ＦＵ预处理Ａ５４９ＤＤＰ后间隔２４或４８ｈ再给予ＣＤＤＰ，其细胞毒性分别增加２０倍和２５０倍，甚至较亲代细胞Ａ５４９更为敏感；如先给ＣＤＤＰ后给５－ＦＵ则细胞毒性仅增加１．８倍。５－ＦＵ对亲代细胞亦有类似效应但细胞毒性增加程度明显低于耐药细胞。５－ＦＵ预处理后间隔２４，４８ｈ，细胞内ＧＳＨ含量逐渐降低，与细胞毒性逐渐增加相一致。如用ＢＳＯ耗竭Ａ５４９ＤＤＰ细胞内ＧＳＨ，ＣＤＤＰ细胞毒性增加６．４倍，仅能部分逆转ＣＤＤＰ耐药。５－ＦＵ明显抑制ＭＲＰ的表达，但对ＧＳＴπ的表达无影响。在５－ＦＵ预处理后的无药间隔时间内，给予无毒浓度的三苯氧胺则有明显的协同效应。结论：程序性给予５－ＦＵ通过降低细胞内ＧＳＨ含量和抑制ＭＲＰ的表达能完全逆转ＣＤＤＰ耐药

Schedule dependent Reversion of Cisplatin Resistance by 5 fluorou racil in Human Lung Adenocarcinoma Cell line A 549 DDP

Using cisplatin resistant human lung carcinoma A 549 DDP cell line,schedule dependent reversion of cisplatin resistance by 5 fluorouracil (5 Fu)was studied. A 549 DDP pretreated with 5 Fu for 24 hrs was exposed to CDDP immediately after which the cytotoxicity of CDDP was increased 3.9 fold. A 549 DDP pretreated with 5 Fu with an interval of 24 or 48 hrs when exposed to DDP strengthened in cytotoxicity to 20 or 250 fold respectively becoming even more sensitive than its parent cell line. In case when 5 Fu was administered after exposure to CDDP the cytotoxicity increased 1.8 fold only. In parallel with the increased cytotoxicity,the GSH content in A 549 DDP reduced significantly after 24 or 48 hr drug free interval by 5 Fu pretreatment. However, depletion of cellular GSH by buthionine sulfoximine (BSO) only resulted in partial reversion of CDDP resistance. 5 Fu could also inhibit expression of multidrug resistance associated protein (MRP),but it had no effect on the expression of glutathione transferase (GST). During the drug free interval, administration of non toxic tamoxifen resulted in tremendously synergistic effect. Our study suggested that the scheduled administration of 5 Fu could reverse CDDP completely through the inhibition of GSH and expression of MRP.