title: The chemopreventive agent oltipraz possesses potent antiangiogenic activity in vitro, ex vivo, and in vivo and inhibits tumor xenograft growth.
abstract: Angiogenesis plays a pivotal role in tumor growth and represents a key target for chemopreventive intervention. On the basis of the structural features and lack of target organ specificity of the synthetic dithiolethione oltipraz, inhibition of angiogenesis was assessed as a potential mechanism for its broad-based chemopreventive activity. The effects of oltipraz on the development and maturation of a vascular network was determined in vitro using two-dimensional capillary tube formation assays with human umbilical vein endothelial cells plated on Matrigel and ex vivo using primary rat aortic ring explant cultures in three-dimensional collagen gels, respectively. The antiangiogenic and antitumor efficacy of oltipraz administration in vivo in nude mice was evaluated by determining its effects on neovascularization in s.c. Matrigel implants seeded with vascular endothelial growth factor and basic fibroblast growth factor-stimulated porcine aortic endothelial cells and on tumor growth and angiogenesis in SVR murine angiosarcoma xenografts implanted s.c. A dose-dependent reduction (0.4-100 microM) in microvessel formation was observed in both human and rodent bioassays after oltipraz exposure, with inhibition approaching 100% in the rat aortic ring assay at the highest concentration (P < 0.01). Similarly, oltipraz (40 microM) inhibited complete capillary tube formation by human umbilical vein endothelial cells by 62% (P < 0.05) relative to control cultures. p.o. administration of oltipraz (250 mg/kg/day for 6 days) to nude mice implanted with porcine aortic endothelial cell-Matrigel plugs resulted in a 42% reduction in neovascularization (P < 0.05) relative to vehicle-treated control mice. Administration of the same dose of oltipraz to athymic mice bearing established s.c. SVR angiosarcoma xenografts for 10 days resulted in a significant inhibition of tumor growth as early as day 4 of dosing (P < 0.005), with a maximum inhibition of tumor growth (81%, P < 0.001) relative vehicle-treated mice by day 10. The observed efficacy of oltipraz in this model is comparable with that of SU 5416 and TNP-470, known antiangiogenic agents currently under clinical development. Plasma levels of oltipraz at the termination of in vivo efficacy studies were 66.4 +/- 7 microM as determined by reversed phase high-performance liquid chromatography, a concentration range associated with significant antiangiogenic activity of oltipraz in vitro and ex vivo. These data suggest that the chemopreventive agent oltipraz may be effective in the treatment of advanced stage cancers and metastases, in part, because of its antiangiogenic activity in vivo.
authors.affiliation: Division of Oncology, Cephalon, Inc., West Chester, Pennsylvania 19380, USA. bruggeri@cephalon.com
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ruggeri
authors.forename: Candy
authors.initials: C
authors.lastname: Robinson
authors.forename: Thelma
authors.initials: T
authors.lastname: Angeles
authors.forename: John
authors.initials: J
authors.lastname: Wilkinson
authors.forename: Margie L
authors.initials: ML
authors.lastname: Clapper
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D006394:Hemangiosarcoma / Q000098:blood supply* / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011719:Pyrazines / Q000627:therapeutic use*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D013871:Thiones; D013876:Thiophenes; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D020533:Angiogenesis Inhibitors; D016588:Anticarcinogenic Agents; D011719:Pyrazines; D017468:Receptors, Fibroblast Growth Factor; D017978:Receptors, Growth Factor; D013871:Thiones; D013876:Thiophenes; D007334:Insulin-Like Growth Factor I; C026209:oltipraz; C496371:FGFR4 protein, human; C496372:Fgfr4 protein, mouse; C496373:Fgfr4 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051499:Receptor, Fibroblast Growth Factor, Type 4; D040262:Receptors, Vascular Endothelial Growth Factor; C046366:angiogenin; D012259:Ribonuclease, Pancreatic