Use of tetrahydraindazolone dicarboxylic acid (HIDA) to improve the therapeutic effect in vivo of combined cisplatin, heat and radiation treatment.

The effect of tetrahydraindazolone dicarboxylic acid (HIDA) on tumour response and mouse lethality after treatment with cisplatin given either alone or combined with hyperthermia (43.5 degrees C/60 min) with or without radiation, was studied in the CDF1 mouse bearing a foot transplanted C3H mouse mammary carcinoma. The tumour response to a combined heat, cisplatin and HIDA treatment was assessed by tumour growth time, while local tumour control was used when irradiation was added to that treatment scheme. Toxicity was estimated as lethality within 14 days. Cisplatin and heat exerted the highest antitumour effect when given simultaneously, but at the same time there was a substantial increase in lethality. No sensitization of the tumour response or enhanced toxicity to cisplatin was observed if heat was given sequentially (i.e. 4 h) after cisplatin. The effect of this sequential schedule being only additive. When HIDA (100 mg/kg) was given 150 min before cisplatin and tumours heated 15 min later, the lethal toxicity was significantly reduced. HIDA did not, however, influence tumour growth time results. In tumour control studies combining radiation, drug and heat, cisplatin (6 mg/kg) and heat (43.5 degrees C/60 min) were given simultaneously 4 h after local irradiating the leg of tumour-bearing mice. The lethality of this regime was more than 55%, but when HIDA was added to the protocol, the toxicity fell to 5% without affecting local tumour control. In conclusion, HIDA administered before cisplatin protects against drug-induced toxicity without reducing the drug's antitumour activity when used alone or in combination with hyperthermia and/or radiation, and thus results in a significantly improved therapeutic benefit.

Reduction of cis-dichlorodiammineplatinum(II) caused nephrotoxicity by indazolone carboxylic acid.

To reduce the nephrotoxicity of cis-dichlorodiammineplatinum (cis-DDP) we have used tetrahydroindazolonedicarboxylic acid (HIDA) in doses of 200, 100 or 50 mg/kg 4, 2 and 1 h before or 1, 2 and 4 h after cis-DDP treatment (10 mg/kg). At any dose, given 2 or 1 h before or 1 h after cis-DDP, HIDA reduced the kidney damage as judged by the blood urea nitrogen (BUN) levels in blood. No protective effect was seen when HIDA was given 4 h before cis-DDP injection. Studies in vitro on L1210 cells have revealed that HIDA does not directly interact with cis-DDP.