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

Abstract

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 bjoc.1998 Received 30 Silva et al, 1994), but was withdrawn from use as a sedative and anti-emetic in the 1960s because of its teratogenicity (Fabro et al, 1967).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...

Induction of endothelial cell apoptosis by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid

“…The results also provide a possible mechanism for the DMXAA-induced extravasation of erythrocytes in murine tumours (Zwi et al, 1994b). Although a number of studies have implicated TNF in the antitumour response of DMXAA (Browne et al, 1998;Cao et al, 1999), three observations in this study support a TNF-independent action of DMXAA on the vascular endothelium. Firstly, apoptosis of endothelial cells was observed in Colon 38 tumour sections within 30 min after administration, well before the time at which TNF is detectable in plasma or tumour tissue .…”

The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF receptor-1 knockout mice

“…One of the most unusual properties of DMXAA is its ability, as a low molecular weight drug, to induce the cytokine TNF in both plasma and tumour tissue (Philpott et al, 1995;Cao et al, 1999). The results described here provide two novel findings on the role of TNF in this action.…”

“…An administration schedule of DMXAA (two doses, 3 days apart) that increases TNF production also improves antitumour activity (Philpott et al, 1995). Co-administration of thalidomide with DMXAA increases intratumoural TNF synthesis and concomitantly increases cure rate Browne et al, 1998;Cao et al, 1999).…”

5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent: phase I clinical and pharmacokinetic study

“…In this study, as in the parallel phase I study of DMXAA (Jameson et al, submitted), only a single unconfirmed tumour response was seen. Synergistic activity of DMXAA in combination with bioreductive cytotoxic drugs (Cliffe et al, 1994;Lash et al, 1998), chemotherapy (notably taxanes) (Pruijn et al, 1997;Horsman et al, 1999;Wilson and Baguley, 2000), thalidomide (Cao et al, 1999), immunotherapy (Kanwar et al, 2001), radiotherapy , and radioimmunotherapy (Pedley et al, 1999) has been demonstrated in animal models, and the potential of DMXAA in cancer treatment with its novel mechanism of action is likely to lie in combination therapy with other treatment modalities.…”