The combined cytotoxicity of cisplatin (DDP) and caffeine (CA) against DDP-sensitive (O-342) and -resistant (O-342/DDP) rat ovarian tumor cell lines in vitro was investigated. 0-342/DDP cells showed a similar sensitivity to CA as O-342 cells did. Simultaneous administration of DDP and CA resulted in infra-additive to additive cytotoxicity in O-342 cells, whereas in O-342/DDP cells, combination of DDP with CA produced effects from infra-additivity to synergism. The strength of this enhancement of DDP cytotoxicity by CA in both cell lines varied in a CA-dose dependent manner but inversely with DDP concentrations. ADP-ribosyl transferase (ADPRT) activity was 2.6-fold in O-342/DDP cells compared to that in O-342 cells. CA (2.5 mM) caused 53.4% and 28.9% inhibition of ADPRT activity in control and DDP-treated O-342/DDP cells, respectively. This inhibitory effect, however, was not observed in 0-342 cells. Our results suggest that CA may have some potential in combination with DDP for treatment of DDP-resistant malignancies in the clinic. One of the possible mechanisms involved in this process might be that CA inhibits ADPRT-associated DNA repair in the resistant cells.

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