Differential cytotoxicity of clinically important camptothecin derivatives in P-glycoprotein overexpressing cell lines

被引:65
作者
Hoki, Y
Fujimori, A
Pommier, Y
机构
[1] NIH,MOL PHARMACOL LAB,BETHESDA,MD 20892
[2] NCI,DIV BASIC SCI,MOL PHARMACOL LAB,NIH,BETHESDA,MD 20892
关键词
topoisomerase I; camptothecin; multidrug resistance; P-glycoprotein(MDR); cancer chemotherapy;
D O I
10.1007/s002800050682
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Camptothecin and its derivatives are specific inhibitors of eukaryotic topoisomerase I (top1) and are active in cancer patients against a variety of refractory solid tumors and leukemia. Purpose: The present study further investigated the relationship between multidrug resistance (MDR) mediated by P-glycoprotein(MDR) and potential resistance to camptothecin derivatives using two experimental systems: (1) MDR KB-V1 cells selected for vinblastine resistance, and (2) NIH3T3 cells transfected with a plasmid expressing wildtype P-glycoprotein(MDR) multidrug transporter (NIH-MDR-G185). Results: We found that both KBV-1 and NIH-MDR-G185 cells were resistant to topotecan, and that topotecan-induced cleavable complexes were reduced in KB-V1 cells, consistent with a role of P-glycoprotein(MDR) in cellular resistance to topotecan. By contrast, no significant resistance to camptothecin, 9-aminocamptothecin, 10, 11-methylenedioxycamptothecin, or SN-38 (the active metabolite of CPT-I1) was observed in NIH-MDR-G185 cells, while KB-V1 cells were cross-resistant to these compounds but produced cleavable complexes similar to those produced by parental KB-3-1 cells. Conclusions: These results suggest that topotecan is the only camptothecin tested with significant susceptibility to MDR in cell culture, and that multidrug resistant cells such as KBV1 probably exhibit additional resistance mechanisms to camptothecins besides P-glycoprotein(MDR) overexpression.
引用
收藏
页码:433 / 438
页数:6
相关论文
共 48 条
[1]   ISOLATION AND GENETIC-CHARACTERIZATION OF HUMAN KB-CELL LINES RESISTANT TO MULTIPLE-DRUGS [J].
AKIYAMA, SI ;
FOJO, A ;
HANOVER, JA ;
PASTAN, I ;
GOTTESMAN, MM .
SOMATIC CELL AND MOLECULAR GENETICS, 1985, 11 (02) :117-126
[2]   PARTIAL-PURIFICATION AND RECONSTITUTION OF THE HUMAN MULTIDRUG-RESISTANCE PUMP - CHARACTERIZATION OF THE DRUG-STIMULATABLE ATP HYDROLYSIS [J].
AMBUDKAR, SV ;
LELONG, IH ;
ZHANG, JP ;
CARDARELLI, CO ;
GOTTESMAN, MM ;
PASTAN, I .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (18) :8472-8476
[3]   CHARACTERIZATION OF A MAMMALIAN MUTANT WITH A CAMPTOTHECIN-RESISTANT DNA TOPOISOMERASE-I [J].
ANDOH, T ;
ISHII, K ;
SUZUKI, Y ;
IKEGAMI, Y ;
KUSUNOKI, Y ;
TAKEMOTO, Y ;
OKADA, K .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1987, 84 (16) :5565-5569
[4]   CPT-II (IRINOTECAN) IN THE TREATMENT OF COLORECTAL-CANCER [J].
ARMAND, JP ;
DUCREUX, M ;
MAHJOUBI, M ;
ABIGERGES, D ;
BUGAT, R ;
CHABOT, G ;
HERAIT, P ;
DEFORNI, M ;
ROUGIER, P .
EUROPEAN JOURNAL OF CANCER, 1995, 31A (7-8) :1283-1287
[5]  
BERTRAND R, 1995, CELL GROWTH APOPTOSI, P96
[6]   Identification of a nucleolin binding site in human topoisomerase I [J].
Bharti, AK ;
Olson, MOJ ;
Kufe, DW ;
Rubin, EH .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (04) :1993-1997
[7]   Selected novel flavones inhibit the DNA binding or the DNA religation step of eukaryotic topoisomerase I [J].
Boege, F ;
Straub, T ;
Kehr, A ;
Boesenberg, C ;
Christiansen, K ;
Andersen, A ;
Jakob, F ;
Kohrle, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (04) :2262-2270
[8]  
CARDARELLI CO, 1995, CANCER RES, V55, P1086
[9]   CHARACTERIZATION OF CAMPTOTHECIN-RESISTANT CHINESE-HAMSTER LUNG-CELLS [J].
CHANG, JY ;
DETHLEFSEN, LA ;
BARLEY, LR ;
ZHOU, BS ;
CHENG, YC .
BIOCHEMICAL PHARMACOLOGY, 1992, 43 (11) :2443-2452
[10]  
CHEN AY, 1991, CANCER RES, V51, P6039