title: Mechanism of hyperthermic potentiation of cisplatin action in cisplatin-sensitive and -resistant tumour cells.
abstract: 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-resistant 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 Pt accumulation (r2 = 0.59) and initial Pt-DNA adduct formation (r2 = 0.64). Strong correlations, however, were found with Pt-DNA adducts at 6 h (r2 = 0.97) and 24 h (r2 = 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 hyperthermia to reduce cDDP resistance.
authors.affiliation: Department of Radiobiology, University of Groningen, The Netherlands.
authors.forename: J V
authors.initials: JV
authors.lastname: Hettinga
authors.forename: W
authors.initials: W
authors.lastname: Lemstra
authors.forename: C
authors.initials: C
authors.lastname: Meijer
authors.forename: W A
authors.initials: WA
authors.lastname: Dam
authors.forename: D R
authors.initials: DR
authors.lastname: Uges
authors.forename: A W
authors.initials: AW
authors.lastname: Konings
authors.forename: E G
authors.initials: EG
authors.lastname: De Vries
authors.forename: H H
authors.initials: HH
authors.lastname: Kampinga
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy*; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D002470:Cell Survival; D002945:Cisplatin / Q000378:metabolism / Q000627:therapeutic use*; D018736:DNA Adducts; D003627:Data Interpretation, Statistical; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D006979:Hyperthermia, Induced; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D002945:Cisplatin