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 7/7 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 7/7 mice (4100 mg kg 71 ) than in wild-type mice (27.5 mg kg 71 ). The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (25 mg kg 71 ) was strongly attenuated in tumour necrosis factor receptor-1 7/7 mice. However, the reduced toxicity in tumour necrosis factor receptor-1 7/7 mice allowed the demonstration that at a higher dose (50 mg kg 71 ), 5,6-dimethylxanthenone-4-acetic acid was curative and comparable in effect to that of a lower dose (25 mg kg 71 ) 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 7/7 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.

Relationship between tumour endothelial cell apoptosis and tumour blood flow shutdown following treatment with the antivascular agent DMXAA in mice

“…TNF is induced following DMXAA administration to mice (Philpott et al, 1995), and the histology of tumours treated with DMXAA resembles that of TNF-treated tumours, suggesting that TNF participates in the antivascular action. Support for this hypothesis is provided by experiments where Colon 38 tumours were implanted in TNF À/À and TNFR À/À knockout mice, where the antitumour effects following administration of the same dose of DMXAA are substantially reduced (Ching et al, 1999;Zhao et al, 2002). In agreement with these findings, apoptosis induction and tumour blood flow inhibition following treatment with DMXAA (25 mg kg À1 ) were pronounced in tumours implanted in wild-type mice, but small in tumours implanted in TNF À/À and TNFR À/À knockout mice ( Table 2).…”

p38 Mitogen-Activated Protein Kinase Is Required for the Antitumor Activity of the Vascular Disrupting Agent 5,6-Dimethylxanthenone-4-acetic Acid

“…First, DMXAA induced rapid actin stress fiber formation and cytoskeleton reorganization in HUVECs through p38 MAPK activation. Second, previous investigations of the pharmacokinetics of DMXAA in colon 38 tumor-bearing mice (Zhao et al, 2002a) showed that after administration of DMXAA at a dose of 25 mg/kg, the maximal plasma concentration of DMXAA was 530 M, which is sufficient for DMXAA to induce rapid actin cytoskeleton reorganization in endothelial cells. Third, the rapid reduction in tumor flow induced by DMXAA occurred much earlier than the intratumoral production of TNF-␣, and the rapid blood flow reduction was evident as early as 30 min after DMXAA administration, a time at which TNF-␣ production could not be detected.…”

Vascular Targeting Agents as Cancer Therapeutics

“…The production of tumor necrosis factor ␣ is important for the mechanism of action of DMXAA, but it can induce vascular endothelial cell apoptosis in tumors, independent of tumor necrosis factor ␣ induction (76). The recent observation that DMXAA has activity in tumors growing in tumor necrosis factor receptor-1 knockout mice (77) suggests that the antitumor effects of DMXAA can be mediated via other cytokines or vasoactive factors. Circumstantial evidence suggests that DMXAA may stimulate phosphorylation of inhibitor of nuclear factor B, leading to a burst of nuclear factor B-mediated gene transcription (78).…”