Summary 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), synthesized in this laboratory and currently in phase I clinical trial, is a low molecular weight inducer of tumour necrosis factor-α (TNF-α). Administration of DMXAA to mice with established transplantable tumours elicits rapid vascular collapse selectively in the tumour, followed by extensive haemorrhagic necrosis mediated primarily through the production of TNF-α. In this report we have investigated the synthesis of TNF-α mRNA in hepatic, splenic and tumour tissue. Coadministration of thalidomide with DMXAA increased anti-tumour activity and increased intra-tumoural TNF-α production approximately tenfold over that obtained with DMXAA alone. Thalidomide increased splenic TNF-α production slightly but significantly decreased serum and hepatic levels of TNF-α induced with DMXAA. Lipopolysaccharide (LPS) induced 300-fold higher serum TNF-α than did DMXAA at the maximum tolerated dose, but induced similar amounts of TNF-α in spleen, liver and tumour. Splenic TNF-α activity induced with LPS was slightly increased with thalidomide, but serum and liver TNF-α levels were suppressed. Thalidomide did not increase intra-tumoural TNF-α production induced with LPS, in sharp contrast to that obtained with DMXAA. While thalidomide improved the anti-tumour response to DMXAA, it had no effect on the anti-tumour action of LPS that did not induce a significant growth delay or cures against the Colon 38 tumour. The increase in the anti-tumour action by thalidomide in combination with DMXAA corresponded to an increase in intra-tumoural TNF-α production. Co-administration of thalidomide may represent a novel approach to improving selective intra-tumoural TNF-α production and anti-tumour efficacy of DMXAA.Keywords: DMXAA; thalidomide; Colon 38; endotoxin; tumour necrosis factor 716British Journal of Cancer (1999) 80(5/6), 716-723 © 1999 Cancer Research Campaign Article no. bjoc.1998 Received 30 Silva et al, 1994), but was withdrawn from use as a sedative and anti-emetic in the 1960s because of its teratogenicity (Fabro et al, 1967). Recent studies indicate that its immunosuppressive and anti-inflammatory effects would be beneficial to the treatment of graft-versus-host disease (Vogelsang et al, 1992;Uthoff et al, 1995), rheumatoid arthritis (Gutierrez-Rodriguez et al, 1989), prevention of graft rejection (Vogelsang et al, 1988;Uthoff et al, 1995), HIV/AIDS (Makonkawkeyoon et al, 1993;Moreira et al, 1997), sarcoidosis (Carlesimo et al, 1995) and various other inflammatory diseases (Burroughs et al, 1995). In experiments to determine whether suppression of serum TNF-α production by thalidomide affected the antitumour response to DMXAA, we found that, while serum TNF-α levels decreased, anti-tumour activity was unexpectedly improved . Reduction of tumour blood flow induced by DMXAA, which is thought to be mediated by TNF-α, was not reversed by thalidomide . Thalidomide analogues that were more potent than thalidomide in inhibiting DMXAA-induced serum TNF-α were also more potent in...
The hyponatremic hypertensive syndrome is a rare but serious complication of reno-vascular disease. The syndrome is characterized by hypertension and profound natriuresis, leading to body sodium and water depletion. Hypertension is typically refractory to treatment. We report an 82-year-old patient with this syndrome and describe the results of an audit of the clinical records of patients admitted to a teaching hospital over a two-year period with confirmed renal artery stenosis and hyponatremia. The syndrome should be suspected in patients in whom severe hypertension is associated with hyponatremia without other apparent cause, especially in the presence of reno-vascular disease.
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