Studies on the resistance of a murine leukemia L1210 cell line cis-diamminedichloroplatinum (II).
Studies on the resistance of a murine leukemia L1210 cell line cis-diamminedichloroplatinum (II).
复制标题
小鼠白血病L1210细胞系顺式二氯二氨铂（II）耐药性的研究。
DOI：
10.1016/0006-2952(81)90546-3
复制
发表时间：
1981
影响因子：
5.8
通讯作者：
Bresnick,E
中科院分区：
文献类型：
--
作者：
Eastman,A;Bresnick,E
金属配合物，特别是铂的配合物，在实验动物和人体中都被证明是有效的抗肿瘤药物，其中研究最多的是cam-二氨二氯铂（I1）（c&DDP）*，其作用机制最近已被综述[1]。顺式-DDP与DNA双功能地反应以形成DNA-链间和DNA-链内交联以及DNA-蛋白质交联。在大多数以前的研究中的性质的关键病变（S），顺式DDP进行了比较，其异构体，trans-DDP，这是无效的抗癌剂。另一种方法是通过开发耐药细胞系，其中耐药机制可以反映药物的作用机制。在这方面，已经开发出小鼠白血病L1210细胞系（L1210 IDDP），其对比其亲本细胞系（L1210/0）高30 μ l浓度的顺式-DDP具有抗性[2]。以前的作者已经报道了来自步行者癌[3]和鼠L1210细胞系[4]的亚系，两者都具有对美法仑AL-苯丙氨酸氮芥的获得性抗性。另一种引起DNA-链间交联的药物也对c&DDP交叉耐药。然而，交叉耐药性并不像曾经认为的那样[5]对所有烷化剂都是普遍的，而是许多细胞系表现出可变的交叉耐药性模式[4，6]。因此，本通讯分析了顺式-DDP敏感性和耐药Ll 210细胞对多种DNA损伤剂可能的交叉耐药性。药物来源如下：cti-DDP@ SC 119875）。布里斯托实验室，-锡拉丘兹，纽约州：fmns-DDP和cab-二氯乙二胺四乙酸盐~ m（II）（顺式-DEP），Alfa Gluron，Da&em，MA;美法仑（NSC 8806），Burroughs Wellcome Co.，北卡罗来纳州三角研究园;新制癌素（NSC 69856）和氮丙啶基苯醌（NSC 1829861，Developmental Therapeutics Program，National Cancer Institute，Bethesda，MD：甲磺酸甲酯和N-甲基-N ′-硝基-N-亚硝基胍（MNNG），Aldrich Chemical Co.，威斯康星州密尔沃基。所有培养基和供应品均购自Gibco，Grand island，NY。鼠白血病L121010和顺式-DDP-抗性亚系（L1210/DDP）从纽约的Sloan Kettering研究所的J. Burchenal博士处获得，并已在佛蒙特州大学的佛蒙特州区域癌症中心保存2年。细胞在塑料培养管中在补充有青霉素、链霉素、两性霉素B和15%小牛血清的6 ml McCoys 5a（改良）培养基中生长。每周两次，用新鲜培养基以1：11（v/v）稀释L121010的储备培养物。将L12101 DDP细胞用含有25 μ g/ml DDP的新鲜培养基以1：5稀释。Z]。L1210 IDDP细胞总是在不存在顺式DDP的情况下生长3天，以允许从先前的药物处理中恢复。将来自储备培养物的细胞以900 g沉淀5分钟
Metal coordination complexes, particularly those of platinum, have been shown to be effective antineoplastic agents in both experimental animals and man. The most extensively investigated complex is cam-diamminedichloroplatinum (I1)(c&DDP)* whose mechanism of action has been reviewed recently [l]. cis-DDP reacts bifunctionally with DNA to form both DNA-interstrand and DNA-intrastrand cross-links as well as DNA-protein cross-links. In most previous investigations of the nature of the critical lesion (s), cis-DDP has been compared to its isomer, truns-DDP, which is ineffective as an anticancer agent. An alternative approach is made possible by the development of resistant cell lines in which the mechanism of resistance may reflect the mechanism of action of a drug. In this regard, a murine leukemia L1210 cell line (L1210IDDP) has been develoued which is resistant to concentrations’ of cis-DDP 30-iold higher than its parent cell line (L1210/0)[2]. Previous authors have reported that sublines derived from the Walker carcinoma [3] and the murine L1210 cell lines [4], both with acquired resistance to melphalan AL-phenylalanine mustard). another drug which causes DNA-intersrrand cross-links, were also cross-resistant to c&DDP. Crossresistance is not, however, as once thought to be [5], universal for all alkylating agents but instead many cell Iines exhibit variable patterns of cross-resistance [4, 6]. This communication therefore analyzes the possible cross-resistance of both cis-DDP-sensitive and-resistant Ll210 cells to a variety of DNA damaging agents. The drugs were obtained from the following sources: cti-DDP@ SC 119875). Bristol Laboratories,-Syracuse, NY: fmns-DDP and cab-dichloroethvlenediamineolatin~ m (II)(cis-DEP), Alfa Ventron, Da&em, MA; melphalan (NSC 8806), Burroughs Wellcome Co., Research Triangle Park, NC; neocarzinostatin (NSC 69856) and aziridinyl benzoquinone (NSC 1829861, Developmental Therapeutics Program, National Cancer Institute, Bethesda, MD: methyl methanesulfonate and N-methyl-N’-nitro-N-nitrosoguanidine(MNNG), Aldrich Chemical Co., Milwaukee, WI. All culture media and supplies were obtained from Gibco, Grand island, NY. A murine leukemia L121010 and a cis-DDP-resistant subline (Ll2lO/DDP) were obtained from Dr. J. Burchenal of the Sloan Kettering Institute, New York, and have been maintained in the Vermont Regional Cancer Center, University of Vermont, for 2 years. Cells were grown in plastic culture tubes in 6 ml McCoys 5a (modified) medium supplemented with penicillin, streptomycin, fungizone and 15% calf serum. Twice weekly, stock cultures of L121010 were diluted I: 11 (v/v) with fresh medium. The L12iOi DDP cells were diluted 1: 5 with fresh medium containing 2 &g/ml &DDP.Growth inhibition studies were performed by a modification of the method of Burchenal et ai.] Z]. L1210IDDP cehs were always grown for 3 days in the absence of cis-DDP to permit recovery from previous drug treatment. Cells from stock cultures were pelleted at 9OOg for 5 min