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An In Vitro Evaluation of the Anti-Cancer Potential of Novel 1, 2, 4, 5-Tetraoxanes for Chronic Lymphocytic Leukemia at Physiologically Relevant Oxygen Tension

Alma O Reilly, Sarah Rawe, Robert Redmond, Elaine Meade, James Murphy and Mary Garvey

Chronic Lymphocytic Leukemia (CLL) is the most prevalent leukemia amongst adults in Europe and North America with a median age of diagnosis of 72 years. Risk factors for this disease include sex, ethnicity, age, hereditary influences and xenobiotic exposure. CLL is characterized by clonal proliferation with progressive accretion of B-cell lymphocytes expressing CD19+, CD5+ and CD23+ typically infiltrating the lymph system, spleen and bone marrow of susceptible persons. Treatment of CLL is via monotherapy with alkylating agents such as chlorambucil for elderly patients. As a relatively cheap chemotherapeutic with low toxicity chlorambucil has the disadvantage of having a low response and risk of side effects including myelodysplasia. Monoclonal antibodies such as Alemtuzumab have emerged as an alternative/combination therapy however; such therapy is typically more expensive and less convenient as an IV injection. This study reports on an investigation into novel drug therapy options for treatment of CLL and provides a comparative toxicity profile against non-tumour cells to determine selectivity. Five synthetic 1, 2, 4, 5-tetraoxanes, the semi-synthetic artemisinin derivative dihydroartemisinin (DHA) and clinically used chlorambucil were evaluated for their antiproliferative activity in two leukemic cell lines at physiologically relevant oxygen tension (5% v/v). All five tetraoxanes and DHA performed significantly better that chlorambucil against HL-60 cells with single digit micromolar antiproliferative IC50 values. Three tetraoxanes and DHA also displayed higher selectivity for tumour over non-tumour cells. Against the hard-to-treat MEC-1 cell line, all compounds showed less antiproliferative activity than against the HL-60 cell line. Only one of these compounds, a synthetic tetraoxane, had a selectivity index greater than 1, outperforming both chlorambucil and DHA and demonstrating that 1, 2, 4, 5-tetraoxanes have potential as a new class of anti-leukemia therapeutics.