Differential modulation of chemosensitivity to alkylating agents and platinum compounds by DNA repair modulators in human lung cancer cell lines

被引:23
作者
Heim, MM [1 ]
Eberhardt, W [1 ]
Seeber, S [1 ]
Müller, MR [1 ]
机构
[1] Univ Essen Gesamthsch, Sch Med, W German Canc Ctr, Dept Internal Med Canc Res, D-45122 Essen, Germany
关键词
DNA repair; resistance modifier; drug resistance;
D O I
10.1007/s004320050033
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 O-6-benzylguanine (6 mu g/ml), fludarabine (25 ng/ml), aphidicolin (8.5 ng/ml), pentoxifylline (1.4 mu g/ml) and methoxamine (12.4 mu g/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. Methods: 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. Results: O-6-benzylguanine, an inhibitor of O-6-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, O-6-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. Conclusions: Modulation of DNA repair elicits not only chemosensitisation but may also enhance cellular resistance to DNA-affine drugs.
引用
收藏
页码:198 / 204
页数:7
相关论文
共 28 条
[1]  
Aebi S, 1996, CANCER RES, V56, P3087
[2]   KINETICS OF INTRAVENOUS AND ORAL PENTOXIFYLLINE IN HEALTHY-SUBJECTS [J].
BEERMANN, B ;
INGS, R ;
MANSBY, J ;
CHAMBERLAIN, J ;
MCDONALD, A .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1985, 37 (01) :25-28
[3]   Combination effects of poly(ADP-ribose) polymerase inhibitors and DNA-damaging agents in ovarian tumor cell lines - With special reference to cisplatin [J].
Bernges, F ;
Zeller, WJ .
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, 1996, 122 (11) :665-670
[4]  
Buschfort C, 1997, CANCER RES, V57, P651
[5]   DNA repair: Enzymatic mechanisms and relevance to drug response [J].
Chaney, SG ;
Sancar, A .
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1996, 88 (19) :1346-1360
[6]   THE ARRHYTHMOGENIC EFFECTS OF CAFFEINE IN HUMAN-BEINGS [J].
DOBMEYER, DJ ;
STINE, RA ;
LEIER, CV ;
GREENBERG, R ;
SCHAAL, SF .
NEW ENGLAND JOURNAL OF MEDICINE, 1983, 308 (14) :814-816
[7]   DEPLETION OF MAMMALIAN OXYGEN-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE ACTIVITY BY OXYGEN-6-BENZYLGUANINE PROVIDES A MEANS TO EVALUATE THE ROLE OF THIS PROTEIN IN PROTECTION AGAINST CARCINOGENIC AND THERAPEUTIC ALKYLATING-AGENTS [J].
DOLAN, ME ;
MOSCHEL, RC ;
PEGG, AE .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (14) :5368-5372
[8]   EFFECTS OF CAFFEINE ON ULTRAVIOLET-IRRADIATED MOUSE L CELLS [J].
DOMON, M ;
RAUTH, AM .
RADIATION RESEARCH, 1969, 39 (01) :207-+
[9]  
FINGERT HJ, 1986, CANCER RES, V46, P2463
[10]   Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma [J].
Friedman, HS ;
Kokkinakis, DM ;
Pluda, J ;
Friedman, AH ;
Cokgor, I ;
Haglund, MM ;
Ashley, DM ;
Rich, J ;
Dolan, ME ;
Pegg, AE ;
Moschel, RC ;
McLendon, RE ;
Kerby, T ;
Herndon, JE ;
Bigner, DD ;
Schold, SC .
JOURNAL OF CLINICAL ONCOLOGY, 1998, 16 (11) :3570-3575