Heim M M, Eberhardt W, Seeber S, Müller M R
Department of Internal Medicine (Cancer Research), University of Essen Medical School, West German Cancer Centre Essen, Germany.
J Cancer Res Clin Oncol. 2000 Apr;126(4):198-204. doi: 10.1007/s004320050033.
Modulation of DNA repair represents one strategy to overcome cellular drug resistance to alkylating agents and platinum compounds. The effects of different known DNA repair modulators such as O6-benzylguanine (6 microg/ml), fludarabine (25 ng/ml), aphidicolin (8.5 ng/ml), pentoxifylline (1.4 microg/ml) and methoxamine (12.4 microg/ml) on the cytotoxicity of mafosfamide, chlorambucil, 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), cisplatin and carboplatin were tested in human lung cancer cell lines.
Chemosensitivity of the human adenocarcinoma cell line MOR/P and the cisplatin-resistant subline MOR/CPR as well as the large-cell lung cancer cell line L23/P and its cisplatin-resistant counterpart L23/CPR were evaluated by the MTT colorimetric assay.
O6-benzylguanine, an inhibitor of O6-alkylguanine-DNA alkyltransferase, significantly sensitised MOR/P and MOR/CPR cells to the cytotoxic effect of BCNU. Fludarabine, methoxamine and aphidicolin did not change the chemosensitivity of the parental and cisplatin-resistant cell lines to any cytotoxic drug tested. Interestingly, O6-benzylguanine enhanced the chemoresistance of parental and cisplatin-resistant cell lines to platinum compounds. Also, pentoxifylline increased resistance of the MOR cell lines to mafosfamide.
Modulation of DNA repair elicits not only chemosensitisation but may also enhance cellular resistance to DNA-affine drugs.
调节DNA修复是克服细胞对烷化剂和铂类化合物耐药性的一种策略。测试了不同的已知DNA修复调节剂，如O6-苄基鸟嘌呤（6微克/毫升）、氟达拉滨（25纳克/毫升）、阿非科林（8.5纳克/毫升）、己酮可可碱（1.4微克/毫升）和甲氧明（12.4微克/毫升）对人肺癌细胞系中马磷酰胺、苯丁酸氮芥、1,3-双（2-氯乙基）-1-亚硝基脲（卡莫司汀）、顺铂和卡铂细胞毒性的影响。
通过MTT比色法评估人腺癌细胞系MOR/P和顺铂耐药亚系MOR/CPR以及大细胞肺癌细胞系L23/P及其顺铂耐药对应物L23/CPR的化学敏感性。
O6-烷基鸟嘌呤-DNA烷基转移酶抑制剂O6-苄基鸟嘌呤显著增强了MOR/P和MOR/CPR细胞对卡莫司汀细胞毒性的敏感性。氟达拉滨、甲氧明和阿非科林未改变亲代和顺铂耐药细胞系对任何测试细胞毒性药物的化学敏感性。有趣的是，O6-苄基鸟嘌呤增强了亲代和顺铂耐药细胞系对铂类化合物的化学抗性。此外，己酮可可碱增加了MOR细胞系对马磷酰胺的抗性。
DNA修复的调节不仅会引起化学增敏，还可能增强细胞对DNA亲和性药物的抗性。
