Purpose Pre-clinical studies can help guide the selection of agents and

Purpose Pre-clinical studies can help guide the selection of agents and regimens for clinical testing. NOD/SCID/chainnull mice reconstituted with human hematopoietic cells and the impact of treatment on human hematopoiesis was evaluated. Results The dose-intensive regimen resulted in significant decreases in growth of human-glioblastoma xenografts. When this regimen was administered to mice made up of humanized bone marrow, flow cytometric analyses indicated that the human bone-marrow cells were significantly more sensitive to treatment than the murine bone-marrow cells, and that the regimen was highly toxic to human-derived hematopoietic cells of all lineages (progenitor, lymphoid, and myeloid). Conclusions The humanized bone-marrow xenograft model described has the potential to be used as a platform for monitoring the impact of anti-cancer therapies on human hematopoiesis and could lead to subsequent refinement of therapies prior to clinical evaluation. models to screen for potential toxicity to normal human Edivoxetine HCl cells in their appropriate microenvironment, early in the drug discovery, need development. Since bone-marrow toxicity can be a major life-threatening side effect of treatment, models to screen for the impact of treatment on human hematopoiesis would improve our ability to select compounds with decreased off-target toxicities. A humanized bone-marrow xenograft model was developed to assess toxicity to human hematopoietic cells hematotoxicity screening of new compounds and regimens. Furthermore, clonogenic assays have exhibited that human and mouse hematopoietic cells show a wide diversity in sensitivity to many anti-cancer drugs; mouse hematopoietic cells in many cases exhibit increased resistance to compound exposure compared to human hematopoietic cells (2-5). Masubuchi et al previously exhibited differential sensitivities of mice, doggie, and human bone-marrow cells uncovered to camptothecin derivatives. For example, camptothecin-like compounds-SN-38 and topotecan-exhibited differential inter-species resistance with mouse CFU being the Edivoxetine HCl most resistant to treatment (4). However, inter-species differences in sensitivity were not always observed. Three other compounds (DX-8951f, 9-aminocamptothecin, and camptothecin) exhibited fairly comparable sensitivities amongst all three species. Studies by Kurtzberg et al (3) indicated significant differences in sensitivities for tubulin-binding brokers; the IC90 values for vincristine and paclitaxel were 30 and 27 nM and for mouse CFU-GM and 3 and 9 nM for human CFU-GM respectively. In addition, IC90 values for tasidotin treatment were > 300 nM for mouse CFU-GM and 65 nM for human CFU-GM. Evaluation of human hematopoietic toxicity in immunodeficient mice could represent an additional benchmark in the final screening and selection of new therapeutics. This screening approach would take into account the influence of the bone-marrow microenvironment on damaged CD22 cells or the cycling kinetics of hematopoietic cells following treatment. An unexplored use of the NOD.Cg-treatment on human hematopoiesis (6). As a proof-of-concept, we selected to evaluate the impact of a combination therapy consisting of O6-benzylguanine and temozolomide (O6-BG/TMZ) on human hematopoiesis since it is usually currently being evaluated in clinical trials and the main dose-limiting toxicity in these patients is usually myelosuppression (7-10). We first developed Edivoxetine HCl a dosing regimen consisting of O6-benzylguanine Edivoxetine HCl and temozolomide (O6-BG/TMZ) followed by stem-cell rescue that would significantly inhibit the growth of TMZ-resistant human xenografts in NOD.Cg-and in xenograft studies with the addition of O6-BG, a direct inhibitor of MGMT activity (11, 13-14, 16). The down side of this approach is usually that both immature and mature hematopoietic cells can be extremely sensitive to this regimen due to low levels of endogenous DNA repair activity Edivoxetine HCl (17). In this study, the delivery of two cycles of a high-dose regimen of O6-BG/TMZ in combination with stem-cell rescue significantly inhibited the growth of a TMZ-resistant glioma. This course of therapy was then used to test the hypothesis that administration of the regimen would be toxic to human hematopoietic cells toxicity measure of human hematopoiesis following drug treatment and.

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