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Hematopoietic stem cell transplantation (HSCT) is an established treatment for multiple

Hematopoietic stem cell transplantation (HSCT) is an established treatment for multiple myeloma (MM) a plasma cell malignancy. might have resulted in nucleolar stress as reported previously and caused a p53-dependent cell death. A reduction by approximately 50% in the cytotoxicity of Gem and Clo was observed in the presence of pifithrin α a p53 inhibitor. Furthermore MM cell lines with mutant p53 exhibited greater resistance to Gem and Clo supporting a role for the p53 protein in these cytotoxic responses. Our results provide a rationale for clinical trials incorporating [Gem+Clo] combinations as part of conditioning therapy for high-risk patients with MM undergoing HSCT. Multiple myeloma (MM) is a malignancy of plasma cells that accumulate in the bone marrow and Ciluprevir interfere with the production of normal blood cells. The median age at diagnosis is approximately 70 years and the disease accounts for approximately 10% of hematologic malignancies [1]. Chemotherapeutic interventions for MM include proteasome inhibitor (bortezomib) and immunomodulatory therapy (thalidomide and lenalidomide). Recently advances in autologous and allogeneic hematopoietic stem cell transplantation (HSCT) have further improved the prognosis Ciluprevir for patients with MM; the differential application of different pretransplant regimens according to age has improved the survival rate [2-6]. However relapses continue to shorten survival and remain a big challenge for clinical investigators. Ciluprevir The efficacy of pretransplant regimens used with HSCT has a major role in the success of this form of treatment. Whether reduced-intensity conditioning or high-dose chemotherapy regimens are more efficacious for MM patients undergoing HSCT remains unresolved and requires further study. Reduced-intensity conditioning for allogeneic HSCT has not been generally associated with improved progression-free survival or overall survival [5] which suggests a need to revisit high-dose chemotherapy preparative regimens for high-risk patients with MM. The most commonly used preparative agents usually in combinations are melphalan busulfan and cyclophosphamide; however multiple other agents such as etoposide cytarabine fludarabine vincristine doxorubicin dexamethasone bortezomib thalidomide and lenalidomide have also been used [7]. Limited studies have been performed with the nucleoside analog gemcitabine (Gem) either as a single agent or as part of a combination with other drugs in a pretransplant conditioning regimens for patients with MM [8 9 However Gem has been shown to improve responses or survival when used as part of pretransplant regimens for leukemia and lymphoma patients [10-15]. In a nontransplant setting a favorable activity Ciluprevir of combined Gem and paclitaxel has been observed in relapsed Rabbit polyclonal to A1CF. or refractory multiple myeloma [16] suggesting the benefit of a Gem-containing regimen. Clofarabine (Clo) is another nucleoside analog with impressive antileukemia activity and it has been shown to significantly improve outcomes for patients with acute myelogenous leukemia (AML) myelodysplastic syndrome acute lymphocytic leukemia and lymphoma when used in a transplant setting [17-21]. Based on the efficacy of Gem and Clo in the aforementioned hematologic malignancies we hypothesized that their combination might provide synergistic cytotoxicity toward MM cells. We report in this preclinical study the cytotoxicity of Gem and Clo in both MM cell lines and patient-derived samples and we propose possible mechanisms of the observed synergism. The results provide a mechanistic framework for designing both conventional therapy and improved high-dose conditioning regimens for MM patients undergoing HSCT. Methods Cell lines and drugs The four cell lines used in this study were obtained from the American Type Culture Collection (Manassas VA USA) and cultured in RPMI 1640 (Mediatech Manassas VA USA) supplemented with 10% heat-inactivated fetal bovine serum (FBS; Atlanta Biologicals Lawrenceville GA USA) and 100 U/mL penicillin and 100 μg/mL streptomycin (Mediatech) at 37 C in a humidified atmosphere of 5% CO2. The cytogenetic characteristics of the four cell lines are listed in Table 1. Clofarabine (Clolar) was obtained from Genzyme Oncology (Cambridge MA; 1 mg/mL solution) and diluted in RPMI 1640 medium prior to use and gemcitabine (Eli Lilly Indianapolis IN) was dissolved in phosphate-buffered saline (PBS)..