Related Experiment Video
Updated: Sep 30, 2026
Determination of the Relative Potency of an Anti-TNF Monoclonal Antibody (mAb) by Neutralizing TNF Using an In Vitro Bioanalytical Method
Published on: September 16, 2017
The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF receptor-1 knockout mice
1Auckland 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.
Insights
Tumor necrosis factor (TNF) signaling is crucial for the anticancer effects and toxicity of 5,6-dimethylxanthenone-4-acetic acid. However, alternative pathways can mediate its antitumour activity, suggesting potential for clinical application.
Area of Science:
- Pharmacology
- Oncology
- Immunology
Background:
- 5,6-dimethylxanthenone-4-acetic acid is a novel antivascular anticancer drug that has completed Phase I clinical trials.
- Its known mechanisms include TNF induction, serotonin release, and inhibition of tumor blood flow, leading to necrosis and regression.
Purpose of the Study:
- To investigate the role of TNF signaling in the efficacy and toxicity of 5,6-dimethylxanthenone-4-acetic acid.
- To determine if TNF signaling is essential for the drug's antitumour activity.
Main Methods:
- Utilized mice with targeted disruption of the tumor necrosis factor receptor-1 (TNFR1) gene.
- Administered colon 38 carcinoma to TNFR1(-/-) and wild-type mice.
- Assessed pharmacokinetics, TNF induction, maximum tolerated dose, antitumour activity, and serotonin release (5-hydroxyindoleacetic acid levels).
Main Results:
- Pharmacokinetics and TNF induction were similar between TNFR1(-/-) and wild-type mice.
- Maximum tolerated dose was significantly higher in TNFR1(-/-) mice (>100 mg kg(-1)) compared to wild-type mice (27.5 mg kg(-1)).
- Antitumour activity was reduced in TNFR1(-/-) mice at 25 mg kg(-1), but higher doses (50 mg kg(-1)) showed curative effects comparable to lower doses in wild-type mice. Serotonin release was diminished in TNFR1(-/-) mice.
Conclusions:
- TNF signaling plays a significant role in mediating both the toxicity and antitumour activity of 5,6-dimethylxanthenone-4-acetic acid.
- Antitumour action can be mediated by factors other than TNF, suggesting therapeutic potential even in the absence of robust TNF signaling.
