INTERACTION OF THALIDOMIDE, PHTHALIMIDE ANALOGS OF THALIDOMIDE AND PENTOXIFYLLINE WITH THE ANTITUMOR AGENT 5,6-DIMETHYLXANTHENONE-4-ACETIC ACID - CONCOMITANT REDUCTION OF SERUM TUMOR-NECROSIS-FACTOR-ALPHA AND ENHANCEMENT OF ANTITUMOR-ACTIVITY

DMXAA (5,6-dimethylxanthenone-4-acetic acid), a novel anti-tumour agen t currently undergoing clinical evaluation, appears to mediate its ant i-tumour effects through immune modulation and the production of the c ytokine tumour necrosis factor-alpha (TNF). Our previous studies have shown that thalidomide, a potent inhibitor of TNF biosynthesis that ha s numerous biological effects, including inhibition of tumour angiogen esis, unexpectedly augments the anti-tumour response in mice to DMXAA. We show here that thalidomide (100 mg kg(-1)) has no effect when admi nistered with inactive doses of DMXAA, and that it must be given simul taneously with an active dose of DMXAA to have its maximum potentiatin g effect on the growth of the murine Colon 38 adenocarcinoma. To addre ss the issue of whether inhibition of serum TNF production is importan t for potentiation of anti-tumour activity, we have tested three poten t analogues of thalidomide. All three analogues, when cc-administered with DMXAA to mice at doses lower than those used with thalidomide, in hibited TNF production and were effective in potentiating the anti-tum our activity of DMXAA against transplanted Colon 38 tumours. One of th e analogues, N-phenethyltetrafluorophthalimide, was 1000-fold more pot ent than thalidomide and at a dose of 0.1 mg kg(-1) in combination wit h DMXAA (30 mg kg(-1)) cured 100% of mice, compared with 67% for the g roup 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 h ypothesis that pharmacological reduction of serum TNF levels might ben efit the anti-tumour effects of DMXAA and suggest new strategies for t herapy using this agent.