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. 1999 May;80(5-6):716–723. doi: 10.1038/sj.bjc.6690415

Thalidomide increases both intra-tumoural tumour necrosis factor-α production and anti-tumour activity in response to 5,6-dimethylxanthenone-4-acetic acid

Z Cao 1, W R Joseph 1, W L Browne 1, K G Mountjoy 2, B D Palmer 1, B C Baguley 1, L-M Ching 1
PMCID: PMC2362281  PMID: 10360649

Abstract

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. Co-administration 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. © 1999 Cancer Research Campaign

Keywords: DMXAA, thalidomide, Colon 38, endotoxin, tumour necrosis factor

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Selected References

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