? ? The effective treatment of cancer with designer drugs that target specific oncognes with little overall toxicity has become a reality in recent years. The kinase inhibitor imatinab was developed to suppress the enzyme activity of the ABL tyrosine kinase that becomes deregulated due to chromosomal translocation in chronic myeloid leukemia. High response rates has made the use of this compound the drug of choice for treating this disease, although therapeutic resistance usually develops with an approximately 5% annual progression rate. Resistance most often develops due to the appearance of secondary point mutations in the ABL gene or by gene amplification, rendering imatinab treatment ineffective. Recently, it has been shown that imatinab also inhibits the activating phosphorylation of the selenium-dependent enzyme glutathione peroxidase (GPx-1). Both human genetic studies and in vitro data have indicated that GPx-1 may have protective function against cancer development and do so via the reduction in DNA damage. These observations have led to the speculation that GPx-1 is the mediator of the chemoprotective properties of the essential trace element selenium and raise the possibility that imatinab therapy would have the unwanted side effect of inhibiting GPx-1 enzyme activity, and thus accelerating the time towards therapeutic failure. Were this true, than non-toxic strategies could be developed in which selenium supplementation would result in the restoration of GPx-1 levels and the extension of disease-free remission. Given the data on the chemopreventive and anti-mutagenic properties of selenium, supplementation with selenium may be effective in this regard even if the stimulation of GPx-1 levels is not the mechanism of protection. The purpose of this proposal therefore is to obtain preliminary data in support of the idea to use selenium as an adjuvant to imatinab therapy to extend the time of the drugs efficacy. This will be done by showing that patients receiving imatinab undergo a reduction in GPx-1 activity as measured in recovered lymphocytes and that selenium can counteract this suppression and reduce DNA damage in companion in vitro studies. Were these to occur, than larger clinical studies could be initiated to evaluate the potential benefits of selenium supplementation during imatinab treatment.New therapies for the treatment of cancer that target specific oncogenes have had a huge impact with regard to disease management, but face the challenge of acquired resistance due to secondary mutations in the genes that encode the target protein. This proposal is designed to begin to address the issue as to whether the essential trace element selenium could be an effective therapeutic adjuvant to the treatment of chronic myeloid leukemia by extending the time until resistance develops. This approach may be generally applicable as a non-invasive means of increasing the efficacy of existing cancer therapies. ? ? ?
| Reinke, Emily N; Bera, Soumen; Diamond, Alan M (2015) Exposure of chronic myelogenous leukemia cells to imatinib results in the post-transcriptional induction of manganese superoxide dismutase. Leuk Lymphoma 56:1096-9 |
| Reinke, Emily N; Ekoue, Dede N; Bera, Soumen et al. (2014) Translational regulation of GPx-1 and GPx-4 by the mTOR pathway. PLoS One 9:e93472 |
| Jerome-Morais, Anita; Wright, Margaret E; Liu, Rui et al. (2012) Inverse association between glutathione peroxidase activity and both selenium-binding protein 1 levels and Gleason score in human prostate tissue. Prostate 72:1006-12 |
| Terry, Emily N; Gann, Peter H; Molokie, Robert et al. (2011) Changes in the activity of the GPx-1 anti-oxidant selenoenzyme in mononuclear cells following imatinib treatment. Leuk Res 35:831-3 |
| Zhuo, Pin; Goldberg, Marci; Herman, Lauren et al. (2009) Molecular consequences of genetic variations in the glutathione peroxidase 1 selenoenzyme. Cancer Res 69:8183-90 |
