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

Abstract

5,6-dimethylxanthenone-4-acetic acid, a novel antivascular anticancer drug, has completed Phase I clinical trial. Its actions in mice include tumour necrosis factor induction, serotonin release, tumour blood flow inhibition, and the induction of tumour haemorrhagic necrosis and regression. We have used mice with a targeted disruption of the tumour necrosis factor receptor-1 gene as recipients for the colon 38 carcinoma to determine the role of tumour necrosis factor signalling in the action of 5,6-dimethylxanthenone-4-acetic acid. The pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid, as well as the degree of induced plasma and tissue tumour necrosis factor, were similar in tumour necrosis factor receptor-1(-/-) and wild-type mice. However, the maximum tolerated dose of 5,6-dimethylxanthenone-4-acetic acid was considerably higher in tumour necrosis factor receptor-1(-/-) mice (>100 mg kg(-1)) than in wild-type mice (27.5 mg kg(-1)). The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (25 mg kg(-1)) was strongly attenuated in tumour necrosis factor receptor-1(-/-) mice. However, the reduced toxicity in tumour necrosis factor receptor-1(-/-) mice allowed the demonstration that at a higher dose (50 mg kg(-1)), 5,6-dimethylxanthenone-4-acetic acid was curative and comparable in effect to that of a lower dose (25 mg kg(-1)) in wild-type mice. The 5,6-dimethylxanthenone-4-acetic acid -induced rise in plasma 5-hydroxyindoleacetic acid, used to reflect serotonin production in a vascular response, was larger in colon 38 tumour bearing than in non-tumour bearing tumour necrosis factor receptor-1(-/-) mice, but in each case the response was smaller than the corresponding response in wild-type mice. The results suggest an important role for tumour necrosis factor in mediating both the host toxicity and antitumour activity of 5,6-dimethylxanthenone-4-acetic acid, but also suggest that tumour necrosis factor can be replaced by other vasoactive factors in its antitumour action, an observation of relevance to current clinical studies.

Figure 1

Dose response for TNF induction by DMXAA. TNF activity in serum, colon 38 tumour, spleen, and liver of WT and TNFR1^−/− mice, untreated or 2 h after treatment with a range of DMXAA doses, was measured by ELISA assay and expressed as the mean±s.e. (n=3).

Figure 2

Growth of colon 38 tumours in WT (A) and TNFR1^−/− (B) mice. Tumor volumes in mice without treatment, or following treatment with DMXAA at doses of 25, 27.5 and 50 mg kg⁻¹ were expressed as the mean±s.e. (n=5).

Figure 3

Plasma 5HIAA responses following administration of DMXAA. (A) Time course of 5HIAA response of non-tumour bearing WT mice treated with DMXAA (30 mg kg⁻¹) and non-tumour bearing TNFR1^−/− mice treated with DMXAA (25 mg kg⁻¹). (B) Time course of 5HIAA response of colon 38-tumour bearing TNFR1^−/− mice treated with DMXAA (25 mg kg⁻¹). Previously published data (Zhao et al, 2002) for tumour bearing WT mice treated with DMXAA (25 mg kg⁻¹) is shown for comparison. (C) Dose dependence of 5HIAA response (24 h after administration of DMXAA) for TNFR1^−/− mice without or with colon 38 tumours. Each point represents the mean±s.e. (n⩾3).

Figure 4

Plasma DMXAA concentration-time profiles in WT and TNFR1^−/− colon 38-bearing mice. Concentrations were measured up to 8 h after administration of DMXAA (25 mg kg⁻¹) and expressed as the mean±s.e. (n=3).