INHIBITION OF LYMPHOCYTE AND TUMOR-INDUCED ANGIOGENESIS BY THE ADMINISTRATION OF DIFLUOROMETHYLORNITHINE

Background - Alpha-Difluoromethylornithine (DFMO), an irreversible inh ibitor of polyamine biosynthesis, has been widely used to decrease tum or growth and metastasis in a variety of experimental models. In order to study some of the mechanisms involved in tumor inhibition we have investigated the effects of DFMO in the angiogenic response evoked by tumor cells and lymphocytes from tumor bearing mice (TBM). Methods - A ngiogenesis assay - 4.10(6) spleen cells or 10(5) tumor cells from mic e were injected intradermically (i.d.) into syngeneic mice (recipient mice). Each animal received two injections in the thoracolumbar region of the trunk. Five days later the skin was carefully separated from u nderlying tissues. The quantification of vascularization was determine d by measuring the density of vessels. Ceruloplasmin activity assay - The spectrophotometric measurements of ceruloplasmin activities were p erformed using o-dianisidine as substrate. Results - Our results indic ate that while lymphocytes from TBM were able to induce angiogenesis, lymphocytes from DFMO treated TBM did not evoke this host response. Fu rthermore, when normal recipient mice were submitted to DFMO treatment prior to angiogenesis assay, the neovascularization induced either by tumor cells or lymphocytes from TBM was also suppressed. Positive ang iogenesis was correlated with high serum levels of ceruloplasmin. Conc lusions - DFMO can inhibit tumor growth and metastasis occurrence not ly by affecting cell proliferation, but also by suppression of the ang iogenesis initiated by tumor cells and activated lymphocytes. The anti polyamine drug also reduces significantly the serum levels of cerulopl asmin.