title: Hyperthermia enhances the cytotoxicity and platinum-DNA adduct formation of lobaplatin and oxaliplatin in cultured SW 1573 cells.
abstract: The cytotoxicity of cisplatin and cisplatin-DNA adduct formation in vitro and in vivo is clearly enhanced by hyperthermia. We investigated whether cytotoxicity and platinum-DNA adduct formation of two promising new third-generation platinum derivatives, lobaplatin [1,2-diamminomethylcyclobutane platinum(II) lactate] and oxaliplatin [oxalato-1,2-diaminocyclohexane platinum(II)], are also enhanced by hyperthermia. Cisplatin was used for comparison. SW 1573 cells were incubated with cisplatin, lobaplatin or oxaliplatin at different concentrations for 1 h at 37 degrees, 41 degrees and 43 degrees C. The reproductive capacity of cells was determined by cloning experiments. Immunocytochemical detection of platinum-DNA adducts was performed with the rabbit antiserum NKI-A59. At 37 degrees C, cisplatin was the most cytotoxic, followed by oxaliplatin and lobaplatin. Hyperthermia clearly enhanced the cytotoxicity of cisplatin, lobaplatin and oxaliplatin. There was no further increase in cytotoxicity at 43 degrees C compared to 41 degrees C for cisplatin and oxaliplatin. A further increase in cytotoxicity at 43 degrees C was observed for lobaplatin. At 43 degrees C thermal enhancement was higher for lobaplatin than for oxaliplatin, with the reverse pattern at 41 degrees C. For both drugs, thermal enhancement of cytotoxicity was lower than observed for cisplatin. Immunocytochemical detection of platinum-DNA adducts was feasible for all the drugs. Adduct formation was enhanced at 43 degrees C for cisplatin, lobaplatin and oxaliplatin with a relative increase of 410%, 170% and 180%. These results seem to confirm that an increase in platinum-DNA adduct formation is involved in the in vitro thermal enhancement of cytotoxicity. The observed thermal enhancement of cytotoxicity of lobaplatin and oxaliplatin in vitro warrants further in vivo investigations.
authors.affiliation: Department of Medical Oncology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: R C
authors.initials: RC
authors.lastname: Rietbroek
authors.forename: P J
authors.initials: PJ
authors.lastname: van de Vaart
authors.forename: J
authors.initials: J
authors.lastname: Haveman
authors.forename: F A
authors.initials: FA
authors.lastname: Blommaert
authors.forename: A
authors.initials: A
authors.lastname: Geerdink
authors.forename: P J
authors.initials: PJ
authors.lastname: Bakker
authors.forename: C H
authors.initials: CH
authors.lastname: Veenhof
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology; D003503:Cyclobutanes / Q000378:metabolism / Q000494:pharmacology; D018736:DNA Adducts / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism*; D006801:Humans; D006979:Hyperthermia, Induced; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000378:metabolism* / Q000494:pharmacology*; D000077150:Oxaliplatin; D010984:Platinum / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D003503:Cyclobutanes; D018736:DNA Adducts; D004273:DNA, Neoplasm; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010984:Platinum; C066228:lobaplatin; D002945:Cisplatin