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Title:   Author  item
                                            Zunino, Susanitem
                                            Storms, Daviditem
                                            Newman, Johnitem
                                            Pedersen, Theresaitem
                                            KEEN, CARL - University Of Californiaitem
                                            DUCORE, JONATHAN - University Of California
  Submitted to: International Journal of Oncology
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 11/25/2011
                                    Publication  Date: 4/1/2012
                                    Citation: Zunino, S.J., Storms, D.H., Newman, J.W., Pedersen, T.L., Keen, C.L., Ducore, J.M. 2012. Resveratrol given intraperitoneally does not inhibit growth of high-risk t(4;11) acute lymphoblastic leukemia cells in NOD/SCID mouse model. International Journal of Oncology. 40(4):1277-84. DOI:10.3892/IJO.2011.1316.Interpretive Summary: Resveratrol is a well-known component of the skin of grapes, is present in high concentrations in red wine, and is also found in other fruits such as blueberries, mulberries, and cranberries.  Resveratrol has shown anti-cancer activity against high-risk acute lymphoblastic leukemia in a cell culture system.  Therefore, we determined whether resveratrol was also effective in killing high-risk leukemia cells in a mouse model for this disease.  Immunodeficient mice were injected with cells that were established from a patient with high-risk leukemia.  Mice were then treated with resveratrol at a concentration of 10 mg/kg body weight every other day for 4 weeks.  The resveratrol treated mice were compared with control mice (without treatment) and mice treated with vincristine, a chemotherapeutic agent used in the clinic to treat this disease.  Comparisons of the percent of human leukemia cells in mouse blood and survival curves showed that resveratrol did not inhibit the disease.  Analysis of resveratrol levels in the blood of the treated mice showed that resveratrol was modified by the additions of sugars and sulfur-containing molecules by the liver.  These data indicate that injected resveratrol does not have potential as a novel preventive agent against high-risk leukemia.
                                Technical Abstract: The efficacy of the phytochemical resveratrol as a preventive agent against the growth of t(4;11) acute lymphoblastic leukemia (ALL) was evaluated in NOD.CB17-Prkdcscid/J mice engrafted with the human t(4;11) ALL line SEM.  SEM cells were injected into the tail vein and engraftment was monitored by flow cytometry.  Once engraftment was observed, mice were injected intraperitoneally with dimethylsulfoxide (control) or resveratrol (10 mg/kg body weight)  every other day, or vincristine (0.5 mg/kg body weight) 3 times per week for 4 wk (n = 16 per group).  Comparisons of the percent of human leukemia cells in blood and survival curves showed resveratrol did not inhibit disease.  Liquid chromatography-mass spectrometry analyses of mouse sera showed resveratrol was rapidly metabolized to glucuronidated and sulfated forms 1h post-injection, but low levels or no resveratrol or metabolites were observed in sera by 24-48h. These data indicate that parenterally administered resveratrol does not have potential as a possible novel preventive agent against high-risk t(4;11) ALL.


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