The arachidonic acid (AA) lipoxygenase (LOX) pathway plays a potential role in regulating tumor cell survival and apoptosis. Prostate cancer (PCa) is the most commonly diagnosed neoplasm and second leading cause of male death in the United States. Human PCa cells express increased 12- LOX which may serve as a survival factor for their growth. We (Biomide) have synthesized approximately 300 12-LOX inhibitors designated hydroxamic acids (HA). Since the resubmission of this SBIR grant last August, we've finished the primary, secondary and tertiary screening of all HA compounds on androgen-independent PCa PC3 cells. The results have revealed that: l) approximately 30% of the HAs induce the apoptotic death of PC3 and other prostate cancer cells, with one subclass showing LD50 values at 5-20 mu M; 2) The HA lead compounds demonstrate stronger apoptotic effects than several chemotherapeutic drugs tested; 3) The HA lead compounds demonstrate lower cytotoxicity to several types of normal cells; 4) The HA lead compound 188 delivered by i.p. injection or oral gavage inhibited the primary growth and local invasion of Du145 PCa cells orthotopically implanted into the SCID mice; 5) The HA lead compound 188 demonstrated low acute toxicity in rats and mice; and 6) PC3 cells overexpressing 12-LOX are more resistant to HA-induced apoptosis. In the current revised Phase I proposal, we plan to: l) synthesize large quantities of HA 188 compound; 2) perform two sets of large scale SCID mice experiment to confirm the in vivo anti-tumor activity of the HA lead compound; and 3) determine the role of 12-LOX in HA188-mediated PC3 cell apoptosis. The long term objective of this project is to develop clinically useful drugs or adjuvants that could be used to treat PCa. PROPOSED COMMERCIAL APPLICATIONS: The current project will substantiate the in vivo anti-tumor efficacy of the HA compound. It will also partially characterize the molecular mechanisms of action for these compounds. Results obtained from the Phase I study will provide guidance for the development of improved chemical entities that can be used for animal studies, preclinical trial, and potentially clinical treatment of human PCa (Phase II project).
