Anti-tumor activity of antizyme which targets the ornithine decarboxylase (ODC) required for cell growth and transformation

Cell proliferation and transformation induced by growth factor stimulation or by carcinogens, viruses, or oncogenes are characterized by an associated increase in polyamine levels, which is mediated by increased polyamine bio synthesis and enhanced uptake of polyamines, Polyamine biosynthesis is cata lyzed particularly, in the level of ornithine decarboxylase (ODC), The elev ation of cellular polyamine levels on the other hand accelerates the induct ion of ornithine decarboxylase antizyme (antizyme), which is involved not o nly in ODC-degradation, but in the negative regulation of polyamine transpo rt. Taking advantage of these characteristics of antizyme, the potential of antizyme as a factor having anti-cell growth and anti-tumor activity was i nvestigated. We show that antizyme can induce cell death associated with a rapid decline of intracellular polyamine contents. The possible anti-tumor activities of ectopically expressed antizyme were tested in p21H-ras (Val 1 2)-transformed NIH3T3 cells and several human malignant cell lines includin g a line with loss of p53 expression, and they were shown to be as sensitiv e as nontransformed NIH3T3 cells in vitro. The in vivo antitumor activity w as also tested using nude mice inoculated with H-vas transformed NIH3T3 cel ls that had been transfected with inducible antizyme expression vector and the results showed that antizyme expression in vivo blocks tumor formation in these mice. These results suggest that ectopic antizyme expression is of possible therapeutic benefit in the treatment of cancer, which is mediated by ODC inactivation and intracellular polyamine depletion.