Hyperthermia and platinum complexes: Time between treatments and synergyin vitroandin vivo

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Abstract
To investigate the greatest therapeutic efficacy, we investigated the effect of scheduling on the cytotoxic interaction between hyperthermia and seven different platinum complexes in vitro and in vivo using the FSaII murine fibrosarcoma cells. Hyperthermia treatment (43°C, 1 h) was administered at various times relative to exposure of the cells to the IC90 (at 37°C, 1 h) of each platinum complex. Greater-than-additive killing of FSaII cells was obtained with cis-diamminedichloroplatinum (II) (CDDP) and hyperthermia when the drug and heat exposure were overlapping or simultaneous. The same cell killing effect with carboplatin and hyperthermia resulted from heat exposure up to 5 h prior to, simultaneous with, or immediately after the drug exposure. D-Tetraplatin and K2PtCl4 were synergistic with hyperthermia only if the drug and heat exposure were simultaneous. PtCl4(Nile Blue)2 and hyperthermia produced greater-than-additive cell killing if the heat and drug exposure occurred in immediate sequence, simultaneously, or with drug exposure up to 5 h prior to heat exposure. PtCl4(Rh-123)2 and hyperthermia produced greater-than-additive cell killing if the drug and heat occurred in immediate sequence, overlapping, or simultaneously. PtCl4(Fast Black)2 and hyperthermia were additive over a wide range of scheduling from heat exposure 2 h prior to 5 h after drug exposure. When animals bearing FSaIIC tumours were treated with single doses of CDDP (10 mg/kg), carboplatin/PtCl4(Nile Blue)2 (50 mg/kg), PtCl4(Rh-123)2/PtCl4(Fast Black)2 (100 mg/kg) under various combined schedules with hyperthermia treatment (43°C, 30 min), similar cytotoxicity patterns were observed. To administer hyperthermia at a time when the drug concentration in the tumour tissue is at peak level, careful scheduling of systemically administered anticancer drugs with hyperthermia is needed. Modelling studies can identify the stringency/flexibility of drug/heat scheduling to achieve synergistic tumour cell killing.