Collateral sensitivity to gemcitabine (2′,2′ -difluorodeoxycytidine) and cytosine arabinoside of daunorubicin- and VM-26-resistant variants of human small cell lung cancer cell lines
Collateral sensitivity to gemcitabine (2′,2′ -difluorodeoxycytidine) and cytosine arabinoside of daunorubicin- and VM-26-resistant variants of human small cell lung cancer cell lines
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DOI：
10.1016/s0006-2952(01)00627-x
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发表时间：
2001-06-01
影响因子：
5.8
通讯作者：
Peters, GJ
中科院分区：
文献类型：
--
作者：
Bergman, AM;Munch-Petersen, B;Peters, GJ
多药耐药（MDR）的特征是对许多天然毒素相关化合物的交叉耐药，可能是由药物外排泵（例如P-糖蛋白（P-gP）、多药耐药蛋白MRP 1 -3或BCRP/MXR）的过度表达引起的。对于DNA拓扑异构酶II活性药物，是由称为改变的拓扑异构酶MDR（at-MDR）的靶分子的酶活性降低引起的。然而，人小细胞肺癌（SCLC）细胞系对2 '，2'-二氟脱氧胞苷（吉西他滨，dFdC）和1-β-D-阿拉伯呋喃糖基胞苷（ara-C）表现出附带敏感性。H69/DAU，一种具有P-gP过表达的H69的柔红霉素（DAU）抗性变体，和NYH/VM，一种具有at-MDR的NYH的VM-26（替尼泊苷）抗性变体，两者均对吉西他滨敏感2倍，对阿糖胞苷敏感7倍和2倍。MDR变体的脱氧胞苷激酶（dCK）活性分别增加了4.3倍和2.0倍，dCK催化吉西他滨和阿糖胞苷的第一个限速活化步骤。此外，负责dFdC和ara-C失活的脱氧胞苷脱氨酶在H69/DAU细胞中低9.0倍。胸苷激酶2（一种也可以磷酸化脱氧胞苷和吉西他滨的线粒体酶）的水平在变体之间没有显著差异。这些差异很可能导致活性代谢物（dFdCTP，在NYH/VM和H69/DAU细胞中分别为2.1倍和1.6倍）和ara-CTP（在NYH/VM细胞中为1.3倍）的蓄积增加。在任一H69变体中均未检测到Ara-CTP积累。与H69变体相比，NYH变体中所有核糖核苷和脱氧核糖核苷三磷酸的库至少高3至4倍;对于dCTP和dGTP，这种差异甚至更大。较高的核糖核苷酸库可以解释与H69变体相比，NYH中dFdCTP的累积高> 10倍。由于dCTP低，H69细胞可能不需要高ara-CTP积累来抑制DNA聚合酶。这可能与H69变体中缺乏ara-CTP有关。此外，MDR变体中CTP、ATP和UTP池的增加可能解释了ara-CTP和dFdCTP蓄积的增加。总之，人SCLC细胞系的MDR变体由于增加的dCK活性以及因此增加的ara-CTP和dFdCTP积累而具有间接敏感性。(C)2001 Elsevier Science Inc. All rights reserved.
Multidrug resistance (MDR), characterized by a cross-resistance to many natural toxin-related compounds, may be caused either by overexpression of a drug efflux pump such as P-glycoprotein, (P-gP), multidrug resistance proteins MRP1-3, or BCRP/MXR or, in the case of DNA topoisomerase II active drugs, by a decrease in the enzymatic activity of the target molecule termed altered topoisomerase MDR (at-MDR). However, human small cell lung carcinoma (SCLC) cell lines showed a collateral sensitivity to 2',2'-difluorodeoxycytidine (gemcitabine, dFdC) and1-beta -D-arabinofuranosylcytosine (ara-C). H69/DAU, a daunorubicin (DAU)-resistant variant of H69 with a P-gP overexpression, and NYH/VM, a VM-26 (teniposide)-resistant variant of NYH with an at-MDR, were both 2-fold more sensitive to,gemcitabine and 7- and 2-fold more sensitive to ara-C, respectively. MDR variants had a 4.3- and 2.0-fold increased activity of deoxycytidine kinase (dCK), respectively, dCK catalyzes the first rate-limiting activation step of both gemcitabine and ara-C. In addition, deoxycytidine deaminase, responsible for inactivation of dFdC and ara-C, was 9.0-fold lower in H69/DAU cells. The level of thymidine kinase 2, a mitochondrial enzyme that can also phosphorylate deoxycytidine and gemcitabine, was not significantly different between the variants. These differences most likely caused an increased accumulation of the active metabolites (dFdCTP, 2.1- and 1.6-fold in NYH/VM and H69/DAU cells, respectively) and of ara-CTP (1.3-fold in NYH/VM cells). Ara-CTP accumulation was not detectable in either H69 variant. The pools of all ribonucleoside and deoxyribonucleoside triphosphates were at least 3- to 4-fold higher in the NYH variants compared to the H69 variants; for dCTP and dGTP this difference was even larger. The higher ribonucleotide pools might explain the > 10-fold higher accumulation of dFdCTP in NYH compared to H69 variants. Since dCTP is low, H69 cells might not need a high ara-CTP accumulation to inhibit DNA polymerase. This might be related to the lack of ara-CTP in H69 variants. In addition, the increased CTP, ATP, and UTP pools in the MDR variants might explain the increased ara-CTP and dFdCTP accumulation. In conclusion, the MDR variants of the human SCLC cell lines were collaterally sensitive due to an increased dCK activity, and consequently an increased ara-CTP and dFdCTP accumulation. (C) 2001 Elsevier Science Inc. All rights reserved.