Colorectal cancer is the second leading cause of cancer deaths accounting for 10% of all cancer-related deaths in the United States. Despite a relative decline in colorectal cancer death rates in recent years, colorectal cancer remains a serious public health issue. Effective colorectal cancer prevention strategies and agents would therefore provide substantial health and societal benefits. Recent attempts at using conventional drugs as chemoprevention agents have been hampered because of serious systemic side effects. In particular, concerns about the cardiovascular toxicity of COX-2 inhibitors have prompted the cancellation of the """"""""APPROVe"""""""" and """"""""ARC"""""""" cancer prevention trials and will likely impact future prevention studies with conventional drugs. Clearly there is a need for identifying effective cancer prevention agents with a wider safety margin. Many cancer prevention agents isolated from foods have wide safety margins such as curcumin, sulforaphane, and perillyl alcohol. Theoretically, the systemic exposure to a colorectal cancer preventive agent may not be required since an orally administered compound will achieve its highest concentration at the desired site of action, i.e., the lumen of the gastrointestinal tract. Therefore, since systemic toxicity is intimately associated with the blood levels in the general circulation, i.e., pharmacokinetics or toxicokinetics, an ideal colorectal cancer prevention agent would attain high local concentrations in the target gastrointestinal tissues but exhibit limited to no systemic exposure. This localized delivery concept is a key component to the observed preventive effects and lack of toxicity of curcumin, which attains high concentrations in the gastrointestinal tract but has negligible oral bioavailability based on the parent compound. Identifying other compounds with curcumin-like properties would provide alternatives or potential combination agents for colorectal cancer prevention modalities. One potential candidate is farnesol, an isoprenoid phytochemical with observed preclinical chemopreventive activity in several cancer models including colorectal cancer. In particular, farnesol exhibited impressive preclinical in vivo chemopreventive activity in the azoxymethane - aberrant crypt foci (AOM-ACF) model in Fisher F344 rats by two independent research groups, one of which was co-authored by the two consultants on this grant. Furthermore, preliminary pharmacokinetic studies from our laboratory demonstrate that farnesol is rapidly and extensively metabolized upon oral administration of 14C-farnesol to Sprague-Dawley rats suggesting negligible systemic bioavailability. Therefore, the goals of this proposal are to further delineate the pharmacokinetics of farnesol, to characterize the gastrointestinal tissue disposition of the compound, and to determine the intestinal permeability and metabolism of farnesol in Fisher F344 rats, the strain used in AOM:ACF studies. Our hypothesis is that the pharmacokinetics and intestinal/colonic disposition of farnesol will ultimately determine its in vivo activity as a colorectal cancer prevention agent. To test this hypothesis and pursue the project goals, we propose to pursue the following Specific Aims: SA1: Determine the pharmacokinetics, oral bioavailability and gene expression effects of farnesol after acute administration and after 28 days of dosing in Fisher F344 rats. SA2: Determine the intestinal disposition and intestinal tissue kinetics of farnesol in Fisher F344 rats. ? ? ?
| Xu, Y; Agrawal, S; Cook, T J et al. (2008) Maternal di-(2-ethylhexyl)-phthalate exposure influences essential fatty acid homeostasis in rat placenta. Placenta 29:962-9 |
