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Abstract
The investigational anti-tumour agent, 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA), an analogue of flavone acetic acid (FAA), has been scheduled for clinical evaluation. Like FAA, 5,6-MeXAA exhibits excellent experimental anti-tumour activity and is an efficient inducer of cytokines in mice. We have examined the effect of pharmacological suppression of tumour necrosis factor (TNF) production on the anti-tumour activity of 5,6-MeXAA, taking advantage of previous observations that TNF production in response to endotoxin in vitro is inhibited by thalidomide. Thalidomide at doses of between 8 and 250 mg kg-1 efficiently suppressed serum TNF activity in response to 5,6-MeXAA at its optimal TNF inducing dose of 55 mg kg-1. Suppression was achieved when thalidomide was administered at the same time as, or up to 4 h before, 5,6-MeXAA. Under conditions in which TNF activity was suppressed, the degree of tumour haemorrhagic necrosis and the proportion of cures in the subcutaneous Colon 38 tumour were increased. In mice administered thalidomide (100 mg kg-1) together with 5,6-MeXAA (30 mg kg-1), complete tumour regression was obtained in 100% of mice, as compared with 67% in mice receiving 5,6-MeXAA alone. The results suggest a possible new application for thalidomide and pose new questions about the action of 5,6-MeXAA and related compounds.
Highlights
We have shown that within 2 h of administration serum tumour necrosis factor (TNF) activity is elevated following treatment with 5,6-MeXAA or flavone acetic acid (FAA) but not with an inactive analogue, 8-methylxanthenone-4-acetic acid (8-MeXAA) (Philpott et al, 1995)
We have examined the effect of pharmacological suppression of TNF production on the anti-tumour activity of 5,6-MeXAA
Thalidomide is an effective inhibitor of LPS-induced TNF TNF is decreased, a greater number of 'armed' macrophages production (Sampaio et al, 1991), and we have shown here expressing cell-surface TNF are able to act against tumour that thalidomide inhibits TNF production in response to cells
Summary
Materials 5,6-MeXAA and 8-MeXAA were synthesised in this laboratory (Rewcastle et al, 1989, 1991), were freshly dissolved in 5% (v/w) sodium bicarbonate for each experiment and were protected from light (Rewcastle et al, 1990). (- )-Thalidomide was synthesised in this laboratory by a previously reported method (Casini and Ferappi, 1964) and freshly dissolved for each experiment in dimethyl sulphoxide (DMSO). Materials 5,6-MeXAA and 8-MeXAA were synthesised in this laboratory (Rewcastle et al, 1989, 1991), were freshly dissolved in 5% (v/w) sodium bicarbonate for each experiment and were protected from light (Rewcastle et al, 1990). (- )-Thalidomide was synthesised in this laboratory by a previously reported method (Casini and Ferappi, 1964) and freshly dissolved for each experiment in dimethyl sulphoxide (DMSO). Fragments of Colon 38 tumour (1 mm3) were implanted subcutaneously in the flank of anaesthetised (sodium pentobarbital, 90 mg kg-') animals. Serum preparation and TNF bioassay Blood was collected from mice anaesthetised with halothane, coagulated overnight at 4°C and centrifuged for 30 min at 2000 g. Effect of thalidomide on 5,6-MeXAA anti-tumour activity L-M Ching et al until assay for TNF. TNF activity was measured using the Results standard L929 cytotoxicity assay as previously described (Hogan and Vogel, 1990).
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