Studies of the chemopreventive efficacy and pharmacokinetics of curcumin in a murine model of colorectal cancer
thesisposted on 15.12.2014, 10:33 by Sarah. Perkins
Curcumin, the major yellow pigment in turmeric, prevents the development of adenomas in the intestinal tract of the C57BI/6J Min/+ mouse, a model of human colorectal cancer with an Apc gene mutation. In order to aid the rational development of curcumin as a colorectal cancer preventive agent, and the link between its chemopreventive potency in the Min/+ mouse and levels of drug and metabolites in target tissue and plasma was explored.;Curcumin was administered in the diet at a variety of dose levels and time periods to assess the effect of this phytochemical on tumour burden in Min/+ mice. The growth, survival and haematocrit of the mice were investigated. The effect of a combination of aspirin and curcumin was also explored as well as the effect of altering the dietary matrix. Long-term administration of curcumin (0.2%) was efficacious at reducing tumour multiplicity in the small intestine by 39%. This dosing regime was utilised to study the effect of curcumin on potential markers of carcinogenesis. These included cyclooxygenase-2 (COX-2) expression, malondialdehyde (MDA), and deoxyguanosine adducts, M1G and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG). The studies tested the potential application of these markers to carcinogenesis and investigated the antioxidant properties of curcumin. Potential markers of carcinogenesis and mechanisms of action of curcumin were also studied using cDNA microarray. The results highlighted significant gene changes in 420 genes, many of which are germane to chemoprevention, most notably genes involved in antioxidation. Pharmacokinetics of dietary administration of curcumin suggests that this phytochemical is poorly bioavailable with the majority of the agent excreted unchanged in the faeces.;Curcumin reduces tumour in Min/+ mouse, at least in part through reduction in oxidative DNA damage and suppression of COX-2 activity. In conclusion the results support the clinical evaluation of curcumin as a colorectal cancer chemopreventive agent.