The prostate gland has among the highest level of polyamines in the body and prostate carcinomas have even greater elevated polyamine levels. These ubiquitous molecules synthesized by prostate epithelium are involved in many biochemical processes including cellular proliferation, cell cycle regulation, and protein synthesis. These properties have made polyamines a potential target for therapeutic intervention in diseases of excessive cell proliferation such as cancer. However, attempts to limit tumor growth by inhibition of polyamine synthesis have not been very successful since cells have the capacity to take up polyamines from the bloodstream. We report here studies utilizing polyamine depletion by means of a combination of blockade of polyamine synthesis with DFMO (a-di¯uoromethylornithine), an inhibitor of ornithine decarboxylase, the rate limiting enzyme in the polyamine synthetic pathway, and ORI 1202, a novel inhibitor of polyamine transport into the cell. This cytostatic combination, even in the presence of excess extracellular polyamines, signi®cantly slowed the growth of the human tumor cell line PC-3 grown in tissue culture with an EC 50 in the mM range. Other prostate cell lines were similarly growth inhibited including LNCaP.FGC and DU145. Growth of the PC-3 tumor cell line as a xenograft in nude mice was also slowed signi®cantly by this combination of compounds. Polyamine levels in the tumor were lowered from control tumor levels. This combination therapy could provide an effective and potentially non-toxic therapy for prostate tumors. Prostate Cancer and Prostatic Diseases (2000) 3, 275±279.
Costimulation blockade with the B7-CD28 pathway-specific agent belatacept is now used in clinical kidney transplantation, but its efficacy remains imperfect. Numerous alternate costimulatory pathways have been proposed as targets to synergize with belatacept, one of which being the inducible costimulator (ICOS)-ICOS ligand pathway. Combined ICOS-ICOS-L and CD28-B7 blockade has been shown to prevent rejection in mice, but has not been studied in primates. We therefore tested a novel ICOS-Ig human Fc-fusion protein in a nonhuman primate kidney transplant model alone and in combination with belatacept. ICOS-Ig did not prolong rejection-free survival as a monotherapy or in combination with belatacept. In ICOS-Ig alone treated animals, most graft-infiltrating CD4+ and CD8+ T cells expressed ICOS, and ICOS+ T cells were present in peripheral blood to a lesser degree. Adding belatacept reduced the proportion of graft-infiltrating ICOS+ T cells and virtually eliminated their presence in peripheral blood. Graft-infiltrating T cells in belatacept-resistant rejection were primarily CD8+CD28−, but importantly, very few CD8+CD28− T cells expressed ICOS. We conclude that ICOS-Ig, alone or combined with belatacept, does not prolong renal allograft survival in nonhuman primates. This may relate to selective loss of ICOS with CD28 loss.
Structure-activity relationships in the region of the phthalide ring of the inosine monophosphate dehydrogenase inhibitor mycophenolic acid have been explored. Replacement of the lactone ring with other cyclic moieties resulted in loss of potency, especially for larger groups. Replacement of the ring by acyclic substituents also indicated a strong sensitivity to steric bulk. A phenolic hydroxyl group, with an adjacent hydrogen bond acceptor, was found to be essential for high potency. The aromatic methyl group was essential for activity; the methoxyl group could be replaced by ethyl to give a compound with 2-4 times the potency of mycophenolic acid in vitro and in vivo.
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