Combined hyperthermia andcis-diamminedichloroplatinum in BD IX rats with transplanted BT4A tumours

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Abstract
Effects on tumour and toxicity of locally applied waterbath hyperthermia (44°C, 60 min) and cis-diamminedichloroplatinum (cis-DDP) were investigated in BD IX rats with transplanted BT4A tumours on the hind foot. The effect of cis-DDP at doses of 2, 3 and 4 mg/kg measured as tumour growth time, defined as time to reach five times the tumour volume at treatment, increased in a drug dose-dependent manner by using hyperthermia. Moderate systemic hyperthermia at a mean of 41°C during the second half of the treatment also increased the tumour regrowth delay of cis-DDP. Skin reactions after local hyperthermia did not increase in this cis-DDP dose range, but systemic toxicity of the drug was markedly enhanced by hyperthermia. At histological evaluation, hyperthermia at 44°C resulted in marked vasodilatation, red blood cell pooling and haemolysis, with a seemingly almost complete central tumour perfusion shutdown lasting up to five days after treatment. The combination of cis-DDP and hyperthermia resulted in additional cell death especially at the tumour periphery and at depth near the tendon and muscle. This in vivo study confirms in vitro data indicating cis-DDP as a candidate for clinical trials combined with hyperthermia. As both the tumour and systemic side effects of cis-DDP are enhanced by hyperthermia, caution is advocated when applying high drug doses with systemic hyperthermia.