Polyamine depletion therapy in prostate cancer

The prostate gland has among the highest level of polyamines in the body an d prostate carcinomas have even greater elevated polyamine levels. These ub iquitous molecules synthesized by prostate epithelium are involved in many biochemical processes including cellular proliferation, cell cycle regulati on, and protein synthesis. These properties have made polyamines a potentia l target for therapeutic intervention in diseases of excessive cell prolife ration such as cancer. However, attempts to limit tumor growth by inhibitio n of polyamine synthesis have not been very successful since cells have the capacity to take up polyamines from the bloodstream. We report here studie s utilizing polyamine depletion by means of a combination of blockade of po lyamine synthesis with DFMO (alpha -difluoromethylornithine), an inhibitor of ornithine decarboxylase, the rate limiting enzyme in the polyamine synth etic pathway, and ORI 1202, a novel inhibitor of polyamine transport into t he cell. This cytostatic combination, even in the presence of excess extrac ellular polyamines, significantly slowed the growth of the human tumor cell line PC-3 grown in tissue culture with an EC50 in the muM range. Other pro state cell lines were similarly growth inhibited including LNCaP.FGC and DU 145. Growth of the PC-3 tumor cell line as a xenograft in nude mice was als o slowed significantly by this combination of compounds. Polyamine levels i n the tumor were lowered from control tumor levels. This combination therap y could provide an effective and potentially non-toxic therapy for prostate tumors.