The evaluation of thioridazine as a hematopoietic progenitor cell mobilizing agent in healthy human subjects

Abstract

Adhesion molecules comprise a large class of proteins that control the trafficking of hematopoietic progenitor cells between the bone marrow compartment and peripheral blood. The normal trafficking of blood-forming cells is dependent upon the controlled regulation of CXCR4, LFA-1 and VLA-4-mediated binding and unbinding events involving stromal elements.1, 2 The mobilization of hematopoietic progenitor cells has been exploited for numerous medical conditions, including the use of erythropoietin for the harvest of autologous red cells transfusions, granulocyte colony stimulating factor (G-CSF) for the release of granulocytes to treat chemotherapy-induced myelosuppression, and plerixafor for the mobilization of CD34 + HPCs cells in autologous stem cell transplantation.3 Autologous and allogeneic stem cell transplantation remains an important therapeutic option for patients who require intensified chemotherapy for a variety of indications. Autologous stem cells were initially directly harvested from the bone marrow compartments of patients prior to receiving cytotoxic therapies. Advances in clinical therapy have allowed hematopoietic progenitor cells (HPCs) to be harvested from the peripheral blood. In human subjects, HPCs comprise a very small faction of peripheral blood mononuclear cells (1 cell/1,000; or 0.1%). Such efforts have become vastly more efficient with the utilization of HPC chemical stimulants, termed mobilizing agents, which enhance the release of CD34+ HPCs from the bone marrow compartment into the peripheral blood for harvest.3-5 However, a number of problems related to the failure to mobilize sufficient numbers of CD34+ HPCs in donors or patients still exist,3, 5 necessitating further efforts to improve stem cell mobilization regimens to be short and maximally efficient. Repurposing (repositioning) of existing drugs can potentially provide one of the approaches to achieve this goal.6 Multiple hematological side effects have been reported to result from treatment with psychoactive phenothiazines. These reported toxicities include leucopenia, granulocytopenia, thrombocytopenia, agranulocytosis, and bone marrow aplasia.7-9 Until recently, the physiological mechanism causing these potentially life-threatening blood dyscrasias was unknown. However, recently we discovered that phenothiazines can almost instantaneously antagonize VLA-4 dependent cell adhesion and, after administration of thioridazine, HPCs could be rapidly mobilized into the peripheral blood in a murine model.10 We proposed that by interfering with VLA-4-mediated cell-cell adhesion involving HPCs in the bone marrow, phenothiazines might mobilize cells from the bone marrow niche. This phenomenon might help to explain the cellular mechanisms behind the frequent observation of dyserthropoeisis in patients who underwent treatment with thioridazine for psychosis.11, 12 Because the time-course for thioridazine-induced stem cell mobilization in human remains unknown, we hypothesized that thioridazine could be employed as a chemical means to mobilize CD34+ progenitor cells for peripheral blood collection. We thus designed an open-label, prospective, non-randomized feasibility clinical trial to assess the mobilizing capacity of thioridazine in healthy individuals.