Antivascular therapy of cancer: DMXAA

Baguley, Bruce C.

doi:10.1016/s1470-2045(03)01018-0

Cited by 172 publications

(142 citation statements)

References 58 publications

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“…The degree of significance suggests that tumour blood flow inhibition is a consequence of endothelial cell apoptosis. Damage to the endothelium and subsequent loss of the structural integrity of the vessels leading to increase in vascular permeability would result in a reduction in blood flow (Baguley, 2003). 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.…”

Section: Discussionmentioning

confidence: 99%

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

Zwain

2004

Br J Cancer

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5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is currently undergoing clinical evaluation as an antivascular agent for the treatment of cancer. We have previously demonstrated that DMXAA induces apoptosis of vascular endothelial cells in murine tumour sections and in a breast carcinoma biopsy from one patient in a Phase I trial. We wished to determine the tissue selectivity of this effect and its relationship to induced blood flow changes. Mice with Colon 38 tumours were treated with DMXAA and tissues were examined for apoptosis by TdT-mediated dUTP nick-end labelling (TUNEL). Hoechst 33342 was used to stain functional vessels, with the loss of stained vessels used as a measure of tumour vascular collapse. Treatment with DMXAA at 25 mg kg À1 , its maximum tolerated dose (MTD), showed, after 3 h, a 12-fold increase in TUNEL staining of tumour vascular endothelial cells. In contrast, tissue from the heart, brain, liver and spleen showed no increase. Induction of apoptosis in tumour tissue was both dose-dependent, observable at doses as low as 5 mg kg À1 , and time-dependent. Apoptosis was significantly lower in Colon 38 tumours of mice, with a targeted disruption in the TNF gene (TNF À/À ), or in the TNF receptor 1 gene (TNFR À/À ), as compared with that in wild-type mice. Increasing the DMXAA dose to 50 mg kg À1 in these knockout mice raised tumour apoptosis to a level comparable to that induced in wild-type mice given DMXAA at the MTD. For all the data, a significant correlation (r ¼ 0.94; Po0.001) was found between logarithmic percentage apoptosis induction and the logarithmic density of Hoechst-stained vessels. These results suggest that blood flow inhibition caused by DMXAA is tumour tissue-specific and is a consequence of induction of apoptosis in tumour vascular endothelial cells.

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Section: Discussionmentioning

confidence: 99%

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

Zwain

2004

Br J Cancer

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“…The tumour-VDA, ASA404, induces apoptosis of tumour vascular endothelial cells and cytokine production, leading to tumour vascular collapse (Ching et al, 2002;Baguley, 2003;Tozer et al, 2005). In animal models, this culminates in extensive tumour necrosis predominantly within the tumour core (Zwi et al, 1994;Laws et al, 1995;Ching et al, 1999Ching et al, , 2004Joseph et al, 1999).…”

mentioning

confidence: 99%

Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer

et al. 2008

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ASA404 (5,6-dimethylxanthenone-4-acetic acid or DMXAA) is a small-molecule tumour-vascular disrupting agent (Tumour-VDA). This randomised phase II study evaluated ASA404 plus standard therapy of carboplatin and paclitaxel in patients with histologically confirmed stage IIIb or IV non-small cell lung cancer (NSCLC) not previously treated with chemotherapy. Patients were randomised to receive p6 cycles of carboplatin area under the plasma concentration -time curve 6 mg ml À1 min and paclitaxel 175 mg m À2 (CP, n ¼ 36) or standard therapy plus ASA404 1200 mg m À2 (ASA404-CP, n ¼ 37). There was little change in the systemic exposure of either total or free carboplatin or paclitaxel on addition of ASA404. Safety profiles were similar and manageable in both groups, with most adverse effects attributed to standard therapy. Tumour response rate (31 vs 22%), median time to tumour progression (5.4 vs 4.4 months) and median survival (14.0 vs 8.8 months, hazard ratio 0.73, 95% CI 0.39, 1.38) were improved in the ASA404 combination group compared with the standard therapy group. In conclusion, this study establishes the feasibility of combining ASA404 with carboplatin and paclitaxel in patients with previously untreated, advanced NSCLC, demonstrating a manageable safety profile and lack of adverse pharmacokinetic interactions. The results indicate that there may be a benefit associated with ASA404, but this needs to be evaluated in a larger trial.

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“…In contrast, DMXAA is a vascular disrupting agent that induces apoptosis in tumour endothelial cells, resulting in collapse of the tumour vasculature and thus tumour hypoxia and necrosis [177]. With DMXAA treatment at 1800mg/m 2 , the dose used in phase III clinical trials in combination with chemotherapy [178], a phase I trial of single agent DMXAA reported an estimated plasma C max of 1000µM [179].…”

Section: Vascular Disrupting Agentmentioning

confidence: 99%

“…The precise methods by which DMXAA exerts its anti-vascular effect are unknown, however it has been postulated that DMXAA stimulates apoptosis in endothelial cells via nuclear factor kappa B (NF-κB) and induces tumour expression of tumour necrosis factor α (TNFα) within 24 hours of exposure [177].…”

Section: Dmxaa Drug Mechanismsmentioning

confidence: 99%