The inflammatory cells in the tumour
infiltrate release numerous growth and survival
factors that are essential for tumour progression. A promising approach to cancer
therapy targets the inflammatory cells to suppress their production of survival
factors. The power of this approach is exemplified by the success of the IMiDs,
thalidomide and its second generation analogue, lenalidomide, for treating multiple myeloma.
Interactions between the myeloma cells and the bone marrow stromal cells,
stimulate
the release of factors that include IL-6, VEGF and TNF. The IMiDs
disrupt the interactions between the myeloma cells and the bone marrow cells, and attenuate
the production of the factors required for the myeloma cells to grow.
Previous work from our group investigated whether
it was thalidomide or its metabolites
that was the active agent. Of the three metabolites that could be detected in myeloma
patients responding to thalidomide therapy (1,2), only one of the metabolites, known as CGI for short,
showed an ability to modulate TNF and IL-6 production by cells
in culture. Analogues of
CGI have been synthesised at the ACSRC to develop compounds that are
more active than thalidomide but with fewer side-effects. Promising new analogues will
be evaluated in a transgenic murine model of myeloma.
Earlier work from our group demonstrated that thalidomide could potentiate the anti-tumour effects of DMXAA in a murine colon carcinoma model (3-5). Recent studies indicated that
the second generation IMiDs also possess this activity. Since DMXAA and the IMiDs
cross the blood brain barrier, we are currently investigating the activity of these
drugs in combination for the treatment of brain cancers and brain metastases.
References
1. Chung, F., Lu, J., Palmer,B. D., Kestell, P., Browett, Baguley, B, C., Tingle,
M., Ching, L-M. Thalidomide pharmacokinetics and metabolite formation in mice, rabbits
and multiple myeloma patients. Clinical Cancer Res. 10, 5949-5956, 2004.
2. Lu, J., Palmer B.D., Kestell, P., Browett, P., Baguley, B.C., Muller, G.,
Ching, L-M. Thalidomide metabolites in mice and patients with multiple myeloma. Clinical
Cancer Res. 9, 1680-1688,
2003.
3. Cao, Z., Joseph, W.R., Browne, W.L., Mountjoy, K.G., Palmer, B.D., Baguley, B.C.,
Ching, L-M. Thalidomide increases both intra-tumoural tumour necrosis factor-alpha
production and anti-tumour activity in response to 5,6-dimethylxanthenone-4-acetic
acid. Br J Cancer 80, 716-723, 1999.
4. Ching, L-M., Browne, W.L., Tchernegovski, R., Gregory, T., Baguley, B.C., Palmer,
B.D. Interaction of thalidomide, phthalimide analogues of thalidomide and pentoxifylline
with the antitumour agent
5,6-dimethylxanthenone-4-acetic acid: concomitant reduction
of serum tumour necrosis factor-alpha and enhancement of antitumour activity. Br
J Cancer 78, 336-343, 1998.
5. Ching, L-M., Xu, Z.-F., Gummer, B.H., Palmer, B.D., Joseph, W.R., Baguley, B.C.
'Effect of thalidomide on tumour necrosis factor production and anti-tumour activity
induced by 5,6-dimethylxanthenone-4-acetic acid.' Br J Cancer 72, 339-343, 1995.
