School of Medical Sciences


Tumour vascular directed therapy

DMXAA_160px

DMXAA


The drug DMXAA (ASA404) was developed in the ACSRC and we have previously shown that it has effects on both inflammatory cells and on tumour blood flow. DMXAA is currently in Phase III clinical trial and it is evident that its clinical activity is observed in combination with cytotoxic drugs rather than in response to the drug alone. We are investigating the basis for this. 

The main focus for our current research is the ceramide pathway; ceramide is synthesised in the endoplasmic reticulum and transferred to the Golgi, where it is converted into sphingomyelin, eventually becoming part of the plasma membrane. We have found that DMXAA, as well as cytotoxic drugs used in clinical combination therapy with DMXAA, increase the cellular concentrations of ceramide. Since ceramide initiates a wide variety of signalling responses we are investigating how it might act on inflammatory cells, and on the cells lining tumour blood vessels and on the tumour cells themselves.

Selected recent publications


Baguley BC. ASA404 (DMXAA): New concepts in tumour vascular targeting therapy. In: Vascular Targeting Therapy for Cancer 2010; Part 3, 217-230. DOI: 10.1007/978-1-4419-6609-4_10

McKeage MJ, Baguley BC. Disrupting established tumor blood vessels: an emerging therapeutic strategy for cancer. Cancer 2010; 116(8), 1859-71. PMID: 20166210

Jameson MB, Sharp DM, Sissingh JI, Hogg CR, Thompson PI, McKeage MJ, Jeffery M, Waller S, Acton G, Green C, Baguley BC. Transient retinal effects of 5,6 dimethylxanthenone-4-acetic acid (DMXAA, ASA404), an antitumor vascular disrupting agent in phase I clinical trials. Invest Ophthal Vis Sci 2009; 50:2553-2559. PMID: 19387077

Wang SL-C, Ching L-M, Paxton JW, Kestell P, Sutherland R, Zhuang L, Baguley BC. Enhancement of the action of the antivascular drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by non-steroidal anti-inflammatory drugs. Invest New Drugs 2009; 27: 280-284. PMID: 18696010

Li J, Jameson MB, Baguley BC, Pili R, Baker SD. Population pharmacokinetic-pharmacodynamic (PK-PD) model of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in cancer patients. Clin Cancer Res 2008; 14: 2102-2010.PMID: 18381951

Zhao L, Marshall ES, Kelland LR, Baguley BC. Evidence for the involvement of p38 MAP kinase in the action of the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Invest New Drugs 2007; 25:271-276. PMID: 17203401