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.
Highlights
A single intraperitoneal recombinant human interleukin-la (rHIL-la) (6.25 x 1O' units kg-'; 25 gig kg-') resulted in acute haemorrhagic responses that were visually obvious within 3-6 h after treatment
The haemodynamic shock and systemic toxicity of rHIL-la in ADX C3H/HeJ mice was ameliorated by giving dexamethasone (5.0 mg kg-') within 3 h after rHIL-lx treatment
At 24 h after rHIL-lx treatment, the haemorrhagic response in RIF-1 tumours in ADX mice was qualitatively greater than that seen in intact mice treated with rHIL-lI alone (Figure 1)
Summary
The RIF-1 fibrosarcoma tumour model was maintained according to the protocol described by Twentyman et al (1980). RIF-1 cells were propagated in RPMI 1640 medium (Mediatech, Washington DC) supplemented with 10% fetal bovine serum (FBS) (Irvine Scientific, Santa Ana, CA) and 2 mM glutamine (Gibco, Grand Island, NY), as described. Received 15 March 1989; and in revised form 17 July 1989. Previously (Braunschweiger et al, 1982; Braunschweiger & Schiffer, 1986). RIF-1 tumours were routinely produced in 6-10 week old (- 20 g), endotoxin hyposensitive, female C3H/HeJ mice (Jackson Laboratories, Bar Harbor, ME) by inoculating 5 x 105 tissue culture cells, subcutaneously, on the right flank. Studies were initiated 14 days later when tumours weighed approximately 0.5 g
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