CADRALAZINE: A LESS TOXIC BUT EQUALLY EFFECTIVE ANALOGUE OF HYDRALAZINE IN VIVO

Horsman M.R., Chaplin D.J., Overgaard J.

Summary. A comparative assessment was undertaken into the ability of hydralazine and its less toxic analogue cadralazine to decrease tumour perfusion and enhance the anti-tumour activity of hypoxic cell cytotoxins. The tumours were the Lewis lung carcinoma grown on the backs of C57 mice and a C3H mammary carcinoma grown in the foot of CDF1 mice. Tumour perfusion, as measured using Hoechst 33342 fluorescent labelling (Lewis lung) and 86RbCI extraction (C3H mammary carcinoma), was reduced by 90% within 1 h after injecting both antihypertensive agents at a dose of 5 mg/kg. But, while the hydralazine effect had almost returned to normal by 12 h, with cadralazine there was still a 50% reduction at this time. These different perfusion changes did not appear to be related to the ability of these drugs to change mouse blood pressure, since while hydralazine produced a maximal 51% decrease in mean arterial blood pressure, with cadralazine only a 37% drop was seen. Injecting mice with hydralazine or cadralazine after injecting the bioreductive drug RSU-1069 or the alkylating agent melphalan increased the response to both chemotherapeutic drugs, as measured with an excision assay in the Lewis lung carcinoma. With RSU-1069 the enhancement ratios were 3.5 and 3.9 for hydralazine and cadralazine, respectively, and for melphalan the respective enhancement ratios were 2.6 and 2.8. Both hydralazine and cadralazine were able to enhance the tumour growth delay induced by hyperthermia (43.5°C) in the C3H mammary carcinoma when injected prior to heating, and did so to the same degree giving rise to an enhancement ratio of 1.5. Since cadralazine is as good as, if not better than, hydralazine at enhancing the anti-tumour activity of hypoxic cell cytotoxins and is known to be less toxic, it would suggest it to be a superior agent for use as a vascular modifier.

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