Meijer C, Mulder N H, Timmer-Bosscha H, Sluiter W J, Meersma G J, de Vries E G
Division of Medical Oncology, University Hospital, Groningen, The Netherlands.
Cancer Res. 1992 Dec 15;52(24):6885-9.
The role of glutathione (GSH) in the effectiveness of and resistance to 7 platinum compounds [5 Pt(II) and 2 Pt(IV) drugs] was evaluated in a 8.6-fold cisplatin (CDDP)-resistant human small cell lung cancer cell line (GLC4/CDDP), the parent GLC4 line, a 3.7-fold CDDP-resistant human embryonal carcinoma cell line (Tera-CP), and the parent Tera line (NTera2/D1). Resistance factors for both CDDP-resistant cell lines were determined after continuous incubation (4 days) with CDDP. Continuous incubation with the other studied platinum drugs revealed complete cross-resistance for carboplatin (CBDCA) and zeniplatin but less for enloplatin (ENLO) and iproplatin in both models. Tetraplatin and lobaplatin showed, respectively, partial and complete cross-resistance in GLC4/CDDP but no cross-resistance in Tera-CP. GSH level, but not glutathione S-transferase activity, of the 4 cell lines correlated with platinum drug concentrations inhibiting cell survival by 50% after continuous incubation (r = 0.86, P < 0.05). GSH depletion by DL-buthionine-S,R-sulfoximine (BSO) increased sensitivity, as measured after a 4-h exposure to the drugs, of GLC4/CDDP for CDDP 2.0-fold, for CBDCA 1.7-fold, for zeniplatin 1.7-fold, and almost to the level of the sensitive GLC4 for ENLO, whereas no effect was observed for lobaplatin and the Pt(IV) compounds iproplatin and tetraplatin. BSO-modulating effect was higher in the sensitive GLC4 line for most compounds; therefore reduction of resistance could be achieved only for CDDP and ENLO. In contrast to GLC4, no modulation occurred in Tera. In Tera-CP BSO increased sensitivity for CDDP 1.5-fold, for CBDCA 1.9-fold, and for zeniplatin 1.2-fold; no effect was observed for ENLO, lobaplatin, and the Pt(IV) compounds. Reduction of CDDP resistance by BSO was known to occur with identical cellular platinum levels and higher Pt-DNA binding in GLC4/CDDP. However, pretreatment with BSO followed by 4 h ENLO incubation increased cellular platinum levels in both GLC4 and GLC4/CDDP while Pt-DNA binding remained unchanged. In conclusion, GSH reflected sensitivity to platinum-containing drugs. However, since the involvement of GSH differed between the models and the various platinum drugs, the effect of modulation with BSO was unpredictable.
在一株对顺铂（CDDP）耐药8.6倍的人小细胞肺癌细胞系（GLC4/CDDP）、其亲本GLC4细胞系、一株对CDDP耐药3.7倍的人胚胎癌细胞系（Tera-CP）以及亲本Tera细胞系（NTera2/D1）中，评估了谷胱甘肽（GSH）在7种铂类化合物（5种Pt(II)和2种Pt(IV)药物）有效性及耐药性中的作用。在与CDDP持续孵育（4天）后，测定了两种CDDP耐药细胞系的耐药因子。与其他所研究的铂类药物持续孵育显示，在两种模型中，卡铂（CBDCA）和泽铂存在完全交叉耐药，而恩洛铂（ENLO）和异丙铂的交叉耐药性较低。四铂和洛铂在GLC4/CDDP中分别表现出部分和完全交叉耐药，但在Tera-CP中无交叉耐药。4种细胞系的GSH水平而非谷胱甘肽S-转移酶活性与持续孵育后抑制细胞存活50%的铂类药物浓度相关（r = 0.86，P < 0.05）。用DL-丁硫氨酸-S，R-亚砜亚胺（BSO）消耗GSH可增加GLC4/CDDP对药物的敏感性，在接触药物4小时后测定，对CDDP敏感性增加2.0倍，对CBDCA增加1.7倍，对泽铂增加1.7倍，对ENLO几乎增加到敏感GLC4的水平，而对洛铂以及Pt(IV)化合物异丙铂和四铂未观察到影响。对于大多数化合物，BSO在敏感GLC4细胞系中的调节作用更高；因此，仅对CDDP和ENLO可实现耐药性降低。与GLC4不同，在Tera细胞中未发生调节作用。在Tera-CP中，BSO使对CDDP的敏感性增加1.5倍，对CBDCA增加1.9倍，对泽铂增加1.2倍；对ENLO、洛铂和Pt(IV)化合物未观察到影响。已知在GLC4/CDDP中，通过BSO降低CDDP耐药性时，细胞内铂水平相同且Pt-DNA结合增加。然而，用BSO预处理后再进行4小时ENLO孵育，在GLC4和GLC4/CDDP中均增加了细胞内铂水平，而Pt-DNA结合保持不变。总之，GSH反映了对含铂药物的敏感性。然而，由于GSH在不同模型和各种铂类药物中的作用不同，用BSO进行调节的效果不可预测。
