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.