Mechanism of hyperthermic potentiation of cisplatin action in cisplatin-sensitive and -resistant tumour cells

被引:44
|
作者
Hettinga, JVE
Lemstra, W
Meijer, C
Dam, WA
Uges, DRA
Konings, AWT
DeVries, EGE
Kampinga, HH
机构
[1] UNIV GRONINGEN,DEPT RADIOBIOL,NL-9713 BZ GRONINGEN,NETHERLANDS
[2] UNIV GRONINGEN,DEPT MED ONCOL,NL-9713 BZ GRONINGEN,NETHERLANDS
[3] UNIV GRONINGEN,DEPT HOSP PHARM,NL-9713 BZ GRONINGEN,NETHERLANDS
关键词
thermochemosensitization; cisplatin resistance; cisplatin accumulation; cisplatin-DNA adducts; adduct repair;
D O I
10.1038/bjc.1997.297
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
In this study, the mechanism(s) by which heat increases cis-diamminedichloroplatinum (cisplatin, cDDP) sensitivity in cDDP-sensitive and -resistant cell lines of murine as well as human origin were investigated. Heating cells at 43 degrees C during cDDP exposure was found to increase drug accumulation significantly in the cDDP-resisiant cell lines but had little effect on drug accumulation in the cDDP-sensitive cell lines. DNA adduct formation, however, was significantly increased in all cell lines studied. Furthermore, ongoing formation of platinum (Pt)-DNA adducts after the end of cDDP treatment was enhanced and/or adduct removal was decreased in heated cells, resulting in relatively more DNA damage remaining at 24 h after the end of cDDP exposure. Correlation plots with survival revealed weak correlations with cellular Pi accumulation (r(2) = 0.59) and initial Pt-DNA adduct formation (r(2) = 0.64). Strong correlations, however, were found with Pt-DNA adducts at 6 h (r(2) = 0.97) and 24 h (r(2) = 0.89) after the incubation with the drug. In conclusion, the mechanism by which heat sensitizes cells for cDDP action seems to be the sum of multiple factors, which comprise heat effects on accumulation, adduct formation and adduct processing. This mechanism did not seem to differ between cDDP-sensitive and -resistant cells, emphasizing the potential of hyperthemia to reduce cDDP resistance.
引用
收藏
页码:1735 / 1743
页数:9
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