DMXAA (5,6-dimethylxanthenone-4-acetic acid), a novel anti-tumour agent currently undergoing clinical evaluation, appears to mediate its anti-tumour effects through immune modulation and the production of the
cytokine tumour
necrosis factor-alpha (TNF). Our previous studies have shown that
thalidomide, a potent inhibitor of TNF biosynthesis that has numerous
biological effects, including inhibition of tumour angiogenesis, unexpectedly augments the anti-tumour response in mice to
DMXAA. We show here that
thalidomide (100 mg kg(-1)) has no effect when administered with inactive doses of
DMXAA, and that it must be given simultaneously with an active dose of
DMXAA to have its maximum potentiating effect on the growth of the murine Colon 38
adenocarcinoma. To address the issue of whether inhibition of serum TNF production is important for potentiation of anti-tumour activity, we have tested three potent analogues of
thalidomide. All three analogues, when co-administered with
DMXAA to mice at doses lower than those used with
thalidomide, inhibited TNF production and were effective in potentiating the anti-tumour activity of
DMXAA against transplanted Colon 38 tumours. One of the analogues, N-phenethyltetrafluorophthalimide, was 1000-fold more potent than
thalidomide and at a dose of 0.1 mg kg(-1) in combination with
DMXAA (30 mg kg(-1)) cured 100% of mice, compared with 67% for the group treated with
DMXAA alone. We also tested
pentoxifylline and found it to suppress TNF production in response to
DMXAA and to potentiate the anti-tumour effect of
DMXAA. The results are compatible with the hypothesis that pharmacological reduction of serum TNF levels might benefit the anti-tumour effects of
DMXAA and suggest new strategies for
therapy using this agent.