THE EFFECT OF ADRENALECTOMY AND DEXAMETHASONE ON INTERLEUKIN-1-ALPHA INDUCED RESPONSES IN RIF-1 TUMORS

In the present studies the effect of bilateral adrenalectomy on the pathophysiologic responses to recombinant human interleukin-l a(rHIL-1α) 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-lα treatment (6.25 × 107 D10 units kg-1, 25 μg kg-1) resulted in acute tumour haemorrhage and approximately 55% clonogenic tumour cell kill (24 h). Bilateral adrenalectomy, 24 h before rHIL-1α, significantly increased haemorrhagic responses, but haemodynamic toxicity was severe. This toxicity could be ameliorated by giving dexamethasone (5 mgkg-1) before or up to 3 h after rHIL-lα. The effect of dexamethasone on rHIL-1α induced tumour responses in adrenalectomised mice was sequence dependent. Given before rHIL-lα, dexamethasone inhibited tumour haemorrhage. When dexamethasone was given up to 3 h after rHIL-lα, tumour haemorrhage was directly related to sequence interval. Although adrenalectomy and dexamethasone alone had little effect on RIF-1 tumours, adrenalectomy increased rHIL-lα mediated clonogenic tumour cell kill. The surviving fraction 24 h after rHIL-lα (6.25 × 107 D10 units kg-1, 25 μg kg-1) and dexamethasone (5 mg kg-1, 2h after rHIL-lα) 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-lα treatment exert a negative feedback on rHIL-lα mediated responses in solid tumours. © Macmillan Press Ltd., 1990.