Kelland L R, Kimbell R, Hardcastle A, Aherne G W, Jackman A L
CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Belmont, Sutton, Surrey, U.K.
Eur J Cancer. 1995 Jun;31A(6):981-6. doi: 10.1016/0959-8049(95)00198-0.
Possible relationships between tumour resistance to cisplatin and the folate-based thymidylate synthase (TS) inhibitors, CB3717 and ZD1694 (tomudex), have been investigated in vitro using a panel of tumour cell lines (predominantly human ovarian), either parental or possessing acquired resistance to cisplatin or ZD1694. Across eight parent human tumour cell lines, ZD1694 was the most potent drug (mean IC50 of 1.9 x 10(-8) M), being over 250 times as potent as its prototype CB3717 (mean IC50 of 4.8 x 10(-6) M). In five pairs of acquired cisplatin-resistant human tumour cell lines (three ovarian, one cervical and one testicular) which encompass all of the main known mechanisms of platinum drug resistance, ZD1694, CB3717 and the DHFR inhibitor, methotrexate, all exhibited non-cross-resistance. The cervical line, HX/155cisR, showed collateral sensitivity to ZD1694, CB3717, 5-fluorouracil (FUra) and fluorodeoxyuridine (FdUrd). One cell line, A2780cisR, showed a low level of cross-resistance to FUra (resistance factor, RF, of 1.5) and FdUrd (RF of 3.8). A2780cisR, in common with two other cisplatin-resistant lines, did not possess elevated TS activity compared with its parent. Cisplatin retained activity in four acquired ZD1694-resistant cell lines (encompassing reduced folate transport, elevated TS and defective polyglutamation mechanisms of resistance). Furthermore, combinations of ZD1694 with each of the platinum-based drugs, cisplatin, carboplatin and the recently introduced orally administrable, JM216, all showed additive growth inhibitory effects by median effect analysis. These data suggest that the tumour inhibitory properties of the recently introduced highly potent TS inhibitor, ZD1694, and cisplatin, and, moreover, their respective mechanisms of resistance, do not overlap. Therefore, these drugs may be considered for combination in the clinic.
利用一组肿瘤细胞系（主要是人类卵巢癌细胞系），包括亲本细胞系或对顺铂或ZD1694具有获得性耐药的细胞系，在体外研究了肿瘤对顺铂的耐药性与基于叶酸的胸苷酸合成酶（TS）抑制剂CB3717和ZD1694（拓扑替康）之间可能存在的关系。在八种亲本人类肿瘤细胞系中，ZD1694是最有效的药物（平均IC50为1.9×10^(-8) M），其效力是其原型CB3717（平均IC50为4.8×10^(-6) M）的250倍以上。在五对获得性顺铂耐药的人类肿瘤细胞系（三对卵巢癌、一对宫颈癌和一对睾丸癌）中，涵盖了铂类药物耐药的所有主要已知机制，ZD1694、CB3717和二氢叶酸还原酶（DHFR）抑制剂甲氨蝶呤均表现出非交叉耐药性。宫颈癌细胞系HX/155cisR对ZD1694、CB3717、5-氟尿嘧啶（FUra）和氟脱氧尿苷（FdUrd）表现出协同敏感性。一个细胞系A2780cisR对FUra（耐药因子RF为1.5）和FdUrd（RF为3.8）表现出低水平的交叉耐药性。与其他两个顺铂耐药细胞系一样，A2780cisR与其亲本相比，TS活性并未升高。顺铂在四个获得性ZD1694耐药细胞系中仍保持活性（包括叶酸转运减少、TS升高和耐药的多聚谷氨酸化机制缺陷）。此外，ZD1694与每种铂类药物顺铂、卡铂以及最近引入的口服药物JM216的组合，通过中位效应分析均显示出相加的生长抑制作用。这些数据表明，最近引入的高效TS抑制剂ZD1694和顺铂的肿瘤抑制特性，以及它们各自的耐药机制并不重叠。因此，这些药物在临床上可考虑联合使用。
