Targeting the tumour vasculature is a powerful therapeutic approach, as destruction
of a single vessel can potentially kill thousands of tumour cells dependent upon
it for their supply of nutrients. DMXAA is a vascular disrupting agent that was
developed at the ACSRC and is currently in phase III clinical trials. In addition
to its direct effects on the tumour vascular endothelial cells (1,2), work by our
team showed that DMXAA activated both the cancer and the stromal cells to produce a
panel of cytokines within the tumour (3,4). These cytokines led to a subsequent
increase in anti-tumour immune responses (5,6), and alterations in the stromal cell
infiltrate (6,7).
Current efforts by our group are directed at identifying the signalling pathway(s) and molecular
target(s) involved in cytokine induction by
DMXAA. Results to date
indicate that the molecular mode
of action of DMXAA is complex and involves multiple pathways and targets. There is evidence for the involvement of NF-kB
(8,9), and the TBK1-IRF-3 signalling axis (10). Using a signalomics
approach to screen for changes in phosphorylation status of key signalling molecules,
DMXAA was found to inhibit phosphorylation of two translational regulators, eIF4E
and S6 kinase with resultant affects on protein translation in lymphoid cells (11).
Using an azido-analogue of DMXAA (12) in a photoaffinity labelling approach to
identify its receptor(s), oxidisable proteins were found to be preferentially labelled (13).
This observation has led to our current working hypothesis that DMXAA may be acting through
modulation of redox signalling.
References
1. Ching, L-M., Cao Z., Kieda, C., Zwain, S., Jameson, M.B. and Baguley, B.C. Induction
of endothelial cell apoptosis by the antivascular agent 5,6-dimethylxanthenone-4-acetic
acid. Br. J. Cancer ,86, 1937-1942, 2002.
2. Ching, L-M., Zwain, S, Baguley, B. C. Relationship between tumour endothelial
cell apoptosis and tumour blood flow shutdown following treatment with the antivascular
agent DMXAA in mice. Br J Cancer, 90, 906-910, 2004.
3. Joseph, W.R., Cao, Z., mountjoy, K.G., Marshall, E.S., Baguley, B.C., Ching,
L.-M. Stimulation of tumors to synthesize tumor necrosis factor-alpha in situ using
5,6-dimethylxanthenone-4-acetic acid: a novel approach to cancer therapy.'Cancer
Res 59, 633-638, 1999.
4. Ching, L-M., Goldsmith, D., Joseph, W.R., Korner, H., Sedgewick, J.D., Baguley,
B.C. 'Induction of intratumoral tumor necrosis factor (TNF) synthesis and hemorrhagic
necrosis by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF knockout mice.'
Cancer Res 59, 3304-3307, 1999.
5. Jassar, A.S., Suzuki, E., Kapoor, V., Sun, J., Silverberg, M.B., Cheung, L.,
Burdick, M.D., Streiter, R.M., Ching, L-M., Kaiser, L.R., Albelda, S.M. Activation
of tumor-associated macrophages by the vascular disrupting agent 5,6 dimethylxanthenone-4-acetic
acid (DMXAA) induces an effective CD8+ T-cell-mediated anti-tumor immune response
in immunogenic and non-immunogenic murine models of lung cancer and mesothelioma.
Cancer Res 65, 11752-11761, 2005.
6. Wallace, A, LaRosa, DF, Kapoor, V, Sun, J, Cheng, GJ, Jassar, A, Blouin, A,
Ching, L-M, Albelda, SM. The vascular disrupting agent 5,6-dimethylxanthenone-4-acetic
acid (DMXAA), directly activates dendritic cells through a MyD88-independent mechanism
and generates anti-tumor cytotoxic T-lymphocytes. Cancer Res, 67, 7011-7019, 2007.
7. Wang, L-CS, Thomsen, L, Sutherland, R, Reddy, C, Tijono, S, Chen, C-JJ, Angel,
KE, Dunbar, PR, Ching L-M. Neutrophil influx and chemokine production during the
early phases of the anti-tumor response to the vascular disrupting agent DMXAA (ASA404).
Neoplasia, 11, 793-803, 2009.
8. Woon, S-T, Zwain, S, Schooltink, M. A., Newth, A. L., Baguley, B. C., Ching,
L-M. NF-B activation in vivo in both host and tumour cells by the antivascular
agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), Eur J Cancer, 39, 1176-1183,
2003.
9. Wang, L-C.S., Woon S-T., Baguley, B.C., Ching, L-M. Inhibition of DMXAA-induced
tumor necrosis factor production in murine splenocyte cultures by NF-B inhibitors.
Oncology Research/Anti-cancer Drug Design, 16, 1-14, 2006.
10. Roberts, ZJ, Goutagny, N, Perera, P-Y, Fitzgerald, KA, Kato, H, Kumar, H, Kawai,
T, Akira, S, Savan, R, van Echo D, Young, HA, Ching, L-M, Vogel, SN. The Chemotherapeutic
agent 5,6-dimethylxanthenone-4-acetic acid, potently and specifically activates
the TBK1-IRF-3 signalling axis. J Exp Med 204, 1559-1569, 2007.
11. Kim, KK. A signalomics approachs to understanding the molecular action of DMXAA
on translational controls. University of Auckland Master of Science (Medical Science)
thesis, 2009. Supervisors: A/Prof Lai-Ming Ching and Prof Peter Shepherd
12. Palmer, BD, Henare, K, Woon, ST, Sutherland, R, Reddy, C, Wang, LC, Kieda, C,
Ching, L-M. Synthesis and biological activity of azido analogues of 5,6-dimethylxanthenone-4-acetic
acid for use in photoaffinity labeling. J Med Chem, 50, 3757-3764, 2007.
13. Brauer, R. Wang, L-CS, Woon, S-T, Bridewell, DJA, Henare, K, Malinger, D, Palmer
BD, Vogel, SN, Tijono, SM, Ching, L-M. Labeling of oxidizable proteins
with a photoactivatable analogue of the anti-tumor agent DMXAA: evidence for redox
signalling in its mode of action. Neoplasia, in press
