ASA404, a flavone-8-acetic acid analogue, is a novel Tumor-Vascular Disrupting Agent (Tumor-VDA). The tumor vasculature is a validated target for selective cancer therapy.1 Unlike antiangiogenic agents, which predominantly inhibit neovascularization, Tumor-VDAs target the established tumor vasculature for cancer treatment.2 Tumor-VDAs inhibit tumor blood flow, which deprives tumors of the necessary nutrients, leading to tumor necrosis.
ASA404 is a Tumor-VDA with a unique mechanism of action which comprises direct and indirect anti-tumor activity.3 Direct tumor endothelial cell apoptosis results in a rapid reduction in tumor blood flow and increased tumor vascular permeability. In the second stage, ASA404 induces the release of Tumor Necrosis Factor-α (TNF-α) and nitric oxide. This intratumoral vasoactive cascade results in a sustained collapse of tumor blood flow and extensive tumor necrosis. Synergistic activity of ASA404 and chemotherapy has been demonstrated in preclinical models.4,5 There is a clear rationale for combining ASA404 with standard chemotherapy.4,5 In a randomized Phase II study, ASA404, in combination with paclitaxel/carboplatin, was well tolerated and demonstrated a survival advantage in first-line treatment of advanced squamous and non-squamous Non-Small Cell Lung Cancer (NSCLC).6,7
ASA404 is currently being investigated in a phase III development program in first-line NSCLC. It is also being evaluated as cancer treatment in other solid tumors.
References
1. Thorpe PE. Vascular targeting agents as cancer therapeutics. Clin Cancer Res. 2004;10:415-427.
2. Tozer GM, Kanthou C, Baguley BC. Disrupting tumour blood vessels. Nat Rev Cancer. 2005;5:423-435.
3. Baguley BC. Antivascular therapy of cancer: DMXAA. Lancet Oncol. 2003;4:141-148.
4. Kelland LR. Targeting established tumor vasculature: a novel approach to cancer treatment. Curr Cancer Ther Rev. 2005;1:1-9.
5. Siim BG, Lee AE, Shalal-Zwain S, et al. Marked potentiation of the antitumour activity of chemotherapeutic drugs by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Cancer Chemother Pharmacol. 2003;51:43-52.
6. von Pawel J, Reck M, McKeage M, AS1404-201 Study Group Investigators. Update on survival in a phase Ib/II study of DMXAA (AS1404) combined with carboplatin and paclitaxel in non-small cell lung cancer (NSCLC). Presented at AACR-NCI-EORTC. November 2006; Prague, Czech Republic.
7. M c Keage M, von Pawel J, ASA404-201 Study Group Investigators. Phase II study of DMXAA (ASA404) 1800mg/m2 combined with carboplatin and paclitaxel in non-small cell lung cancer. Presented at World Lung Cancer Conference. September 2007; Seoul, South Korea.
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