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

Zhao L, Ching LM, Kestell P, Baguley BC - Br. J. Cancer (2002)

Bottom Line: 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)).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 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.

View Article: PubMed Central - PubMed

Affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.

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.

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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).
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fig1: 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).

Mentions: The maximum tolerated doses (MTD) of DMXAA in TNFR1−/− mice was determined and found to be much higher in TNFR1−/− mice than in WT mice (Table 1Table 1Maximum tolerated dose (MTD) of DMXAA). The capacity of DMXAA to induce TNF was compared 2 h after treatment with DMXAA at doses of up to 100 mg kg−1. The maximal dose was considerably greater than the MTD in WT mice (Table 1), but could be used because it has been shown previously (Philpott et al, 1995) that no signs of distress occur within the time period of the experiment. DMXAA induced similar TNF activity in WT and TNFR1−/− mice, with maximal activity at 75 mg kg−1 (Figure 1Figure 1


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

Zhao L, Ching LM, Kestell P, Baguley BC - Br. J. Cancer (2002)

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).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2376130&req=5

fig1: 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).
Mentions: The maximum tolerated doses (MTD) of DMXAA in TNFR1−/− mice was determined and found to be much higher in TNFR1−/− mice than in WT mice (Table 1Table 1Maximum tolerated dose (MTD) of DMXAA). The capacity of DMXAA to induce TNF was compared 2 h after treatment with DMXAA at doses of up to 100 mg kg−1. The maximal dose was considerably greater than the MTD in WT mice (Table 1), but could be used because it has been shown previously (Philpott et al, 1995) that no signs of distress occur within the time period of the experiment. DMXAA induced similar TNF activity in WT and TNFR1−/− mice, with maximal activity at 75 mg kg−1 (Figure 1Figure 1

Bottom Line: 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)).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 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.

View Article: PubMed Central - PubMed

Affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.

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.

Show MeSH
Related in: MedlinePlus