A role for Danazol in chronic lymphocytic leukemia

Abstract

The clinical management of chronic lymphocytic leukemia (CLL) patients with fludarabine-resistant disease or tumor cells with 17p deletions remains problematic. 1 High-dose glucocorticoids (HDGCs) are among the most effective treatment approaches for such patients, as well as elderly patients who cannot tolerate conventional chemotherapy. However, HDGCs are not without significant side effects and are only palliative in nature. 2 Identification of nontoxic agents that could improve the therapeutic efficacy of HDGCs would help significantly in managing these patients. We report a case that suggests the weak androgen Danazol 3 may be such an agent. A 61-year-old female with slowly

Danazol induces apoptosis and cytotoxicity of leukemic cells alone and in combination with purine nucleoside analogs in chronic lymphocytic leukemia

“…Based on these properties of danazol, we assessed its effects on leukemic cells derived from CLL patients. Consistently with the observations of Tung et al [ 19 ], we showed that danazol-induced caspase-dependent apoptosis and cytotoxicity of CLL cells in the peripheral blood and bone marrow. Danazol-induced apoptosis appears to involve both mitochondrial and membrane cascades because of similar levels of active caspase-9 and active caspase-8 expressions detected in leukemic cells.…”

“…However, the role and the mechanism of action of danazol in these cases are unclear. Danazol-induced apoptosis of CLL cells was first described by Tung et al [ 19 ]. The authors studied patients receiving danazol in combination with glucocorticoids and showed a significant decrease in the leukocyte count, which increased after withdrawal of this drug.…”

“…The authors studied patients receiving danazol in combination with glucocorticoids and showed a significant decrease in the leukocyte count, which increased after withdrawal of this drug. Based on these observations, pre-clinical laboratory tests with CLL cells were performed, and these cells showed toxicity of danazol against CD19+/CD5+ cells at concentrations above 3 μM, and the optimal concentration was 10 μM [ 19 ]. The mechanism of danazol activity in CLL is unknown.…”

“…The mechanism of danazol activity in CLL is unknown. Tung et al [ 19 ] proposed that a reduction in blood CD23 level by danazol observed during endometriosis treatment suggested a direct effect on activated B cells in CLL [ 25 , 26 ]. Similarly, danazol can decrease production of inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha, which probably can restrict their ability to induce proliferation of CLL cells in vivo [ 10 , 27 ].…”

“…4 μg/ml cladribine, 20 μM bendamustine, or a mixture of danazol and one of these drugs. We selected a danazol concentration of 10 μM based on preliminary experiments in CLL performed by Tung et al [ 19 ]. To obtain stock solutions, danazol was dissolved in ethanol.…”