Objective:
The goal of these studies is to determine whether the antioxidant phytochemicals resveratrol and curcumin can increase survival of individuals with high-risk leukemia. The specific aims are to determine if these plant-derived compounds can kill this leukemia and prevent relapse in vivo by using a mouse model for this disease, and to also analyze the mechanisms of actions, as well as bioavailability of these antioxidants in serum and tissues.

Approach:
Non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice will be engrafted with leukemic cells by tail vein injection. Engraftment will be positively established when the proportion of human leukemia cells in the peripheral blood reaches 1%, as determined by flow cytometric analysis using anti-human CD45 antibody. Both the SEM cell line and underived leukemic cells from patients with t(4;11) leukemia will be used. Cancer preventive efficacy will be determined by two approaches. Leukemic mice will be treated with the chemotherapeutic agent vincristine to induce remission and then fed diets containing either 0.2% w/w resveratrol or 0.5% w/w curcumin to determine if dietary intervention can prevent relapse. Leukemic mice will also be given the phytochemicals intraperitoneally to determine if these phytochemicals can prevent leukemia growth. Minimal residual disease and re-engraftment will be monitored by PCR and flow cytometry, respectively. Sixteen mice will be used in each group. Efficacy of resveratrol and curcumin in the prevention of leukemia will be measured in all experiments by length of survival of the mice compared to control animals and results from necropsy of bone marrow, blood, spleen, and liver. Survival data will be analyzed by Kaplan-Meier survival curves and differences between curves evaluated with the log-rank test. Cell cycle, caspase activation, Bcl-2 levels, and mitochondrial membrane depolarization will be analyzed in the leukemic cells by flow cytometry to determine in vivo mechanisms of cell death induced by resveratrol and curcumin. Bioavailability of parent compounds and metabolites will be measured in serum and tissues for all animals by UPLC-mass spectrometry. Documents Reimbursble with NIH. Log 29934.