HYPERTHERMIA ENHANCES THE CYTOTOXICITY AND PLATINUM-DNA ADDUCT FORMATION OF LOBAPLATIN AND OXALIPLATIN IN CULTURED SW-1573 CELLS

The cytotoxicity of cisplatin and cisplatin-DNA adduct formation in vi tro and in vivo is clearly enhanced by hyperthermia. We investigated w hether cytotoxicity and platinum-DNA adduct formation of two promising new third-generation platinum derivatives, lobaplatin [1,2-diamminome thylcyclobutane platinum(II) lactate] and oxaliplatin [oxalato-1,2-dia minocyclohexane platinum(II)], are also enhanced by hyperthermia. Cisp latin was used for comparison. SW 1573 cells were incubated with cispl atin, 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 detec tion of platinum-DNA adducts was performed with the rabbit antiserum N KI-A59. At 37 degrees C, cisplatin was the most cytotoxic, followed by oxaliplatin and lobaplatin. Hyperthermia clearly enhanced the cytotox icity of cisplatin, lobaplatin and oxaliplatin. There was no further i ncrease in cytotoxicity at 43 degrees C compared to 41 degrees C for c isplatin and oxaliplatin. A further increase in cytotoxicity at 43 deg rees C was observed for lobaplatin. At 43 degrees C thermal enhancemen t was higher for lobaplatin than for oxaliplatin, with the reverse pat tern at 41 degrees C. For both drugs, thermal enhancement of cytotoxic ity was lower than observed for cisplatin. Immunocytochemical detectio n of platinum-DNA adducts was feasible for all the drugs. Adduct forma tion was enhanced at 43 degrees C for cisplatin, lobaplatin and oxalip latin with a relative increase of 410%, 170% and 180%. These results s eem to confirm that an increase in platinum-DNA adduct formation is in volved in the in vitro thermal enhancement of cytotoxicity. The observ ed thermal enhancement of cytotoxicity of lobaplatin and oxaliplatin i n vitro warrants further in vivo investigations.