The effect of adrenalectomy and dexamethasone on interleukin-1α induced responses in RIF-1 tumours

Abstract

In the present studies the effect of bilateral adrenalectomy on the pathophysiologic responses to recombinant human interleukin-1 alpha (rHIL-1 alpha) was determined in RIF-1 tumour models. Acute vascular injury and haemorrhagic responses were quantitated by the intra-tumour accumulation of 59Fe radiolabelled erythrocytes. In vivo clonogenic tumour cell kill was determined by an excision assay. A single, intraperitoneal rHIL-1 alpha treatment (6.25 x 10(7) D10 units kg-1, 25 micrograms kg-1) resulted in acute tumour haemorrhage and approximately 55% clonogenic tumour cell kill (24 h). Bilateral adrenalectomy, 24 h before rHIL-1 alpha, significantly increased haemorrhagic responses, but haemodynamic toxicity was severe. This toxicity could be ameliorated by giving dexamethasone (5 mg kg-1) before or up to 3 h after rHIL-1 alpha. The effect of dexamethasone on rHIL-1 alpha induced tumour responses in adrenalectomised mice was sequence dependent. Given before rHIL-1 alpha, dexamethasone inhibited tumour haemorrhage. When dexamethasone was given up to 3 h after rHIL-1 alpha, tumour haemorrhage was directly related to sequence interval. Although adrenalectomy and dexamethasone alone had little effect on RIF-1 tumours, adrenalectomy increased rHIL-1 alpha mediated clonogenic tumour cell kill. The surviving fraction 24 h after rHIL-1 alpha (6.25 x 10(7) D10 units kg-1, 25 micrograms kg-1) and dexamethasone (5 mg kg-1, 2 h after rHIL-1 alpha) was 1.3 +/- 0.4%. The surviving fraction after this combination in intact mice (36.7 +/- 1.4%) was approximately 30-fold higher than that seen in adrenalectomised mice. The results indicate that adrenal responses secondary to rHIL-1 alpha treatment exert a negative feedback on rHIL-1 alpha mediated responses in solid tumours.