Busulfan

Background: Busulfan (BU) has a destructive effect on the male reproductive system. The goal of this study was to assess the effects of olive leaf extract (OLE) as a source of antioxidants and phenolic compounds, on BU-induced damages in rat testes.

Fludarabine with busulfan (FB) and fludarabine with melphalan (FM) are commonly used reduced-intensity conditioning (RIC) regimens. Pharmacokinetic dosing of busulfan (Bu) is frequently done for myeloablative conditioning, but evidence for its use is limited in RIC transplants. We compared transplant outcomes of FB versus FM using i.v. Bu targeted to the area under the curve (AUC). A total of 134 RIC transplants (47 FB and 87 FM) for acute myelogenous leukemia and myelodysplastic syndrome were identified, and median follow-up of the cohort was 40 months (range, 0 to 63.3). A significantly higher 2-year cumulative incidence of relapse (CIR) was associated with FB versus FM at 35.6% versus 17.3%, respectively (P = .0058). Furthermore, 2-year progression-free survival rates were higher for FM versus FB at 60.5% versus 48.7%, respectively (P = .04). However, 2-year rates of nonrelapse mortality (NRM) and overall survival (OS) were similar. The need for dose adjustment based on AUC did n...

Aims: Conditioned medium of mesenchymal stem cells have a positive effect on repairing damaged tissues because of having metabolites, growth factors and cytokines. The aim of current study was to investigate the healing effect of conditioned medium of adipose tissue-derived stem cells on histomorphometric changes of testis in treated mice with busulfan. Materials & Methods: In this experimental study, 18 adult male mice were divided into the three equal groups including control group (Without treatment), azoospermia sham and experimental groups. The sham and experimental groups were induced azoospermia by two injection of 10mg/kg busulfan intraperitoneally, with 21 days interval. 35 days after the second injection of busulfan, the experimental group treated with conditioned medium of adipose tissue-derived stem cells, and 60 days after conditioned medium injection, the testes of mice were removed and histomorphometric evaluation was done. The results were analyzed by SPSS 18 software using Mann-Whitney, ANOVA and Tukey's post hoc tests. Findings: The lumen diameter and area of the seminiferous tubules in the three groups did not have any significant difference; however, the total diameter, cellular diameter, cellular area, cross-sectional area and spermatogenesis index of the seminiferous tubules were significantly decreased in the experimental group compared to the control group (p<0.05), while they were significantly increased compared to the azoospermia sham group (p<0.001). Also, the number of tubules and numerical density of the seminiferous tubules were significantly increased in the azoospermia sham compared to the control and experimental groups (p<0.001). Conclusion: Secretory factors of conditioned medium from adipose tissuederived stem cells could be effective in the restoration of spermatogenesis in busulfan-induced infertile mice.

Retroviral gene therapy has proved efficacious for multiple genetic diseases of the hematopoietic system, but roughly half of clinical gene therapy trial protocols using gammaretroviral vectors have reported leukemias in some of the patients treated. In dramatic contrast, 39 adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) patients have been treated with 4 distinct gammaretroviral vectors without oncogenic consequence. We investigated clonal dynamics and diversity in a cohort of 15 ADA-SCID children treated with gammaretroviral vectors and found clear evidence of genotoxicity, indicated by numerous common integration sites near proto-oncogenes and by increased abundance of clones with integrations near MECOM and LMO2 These clones showed stable behavior over multiple years and never expanded to the point of dominance or dysplasia. One patient developed a benign clonal dominance that could not be attributed to insertional mutagenesis and instead likely resulte...

We investigated the long-term safety and disease control data obtained with i.v. busulfan (Bu) combined with clofarabine (Clo) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). A total of 107 patients, median age 38 years (range, 19 to 64 years) received a matched sibling donor (n = 52) or matched unrelated donor (n = 55) transplant for ALL in first complete remission (n = 62), second complete remission (n = 28), or more advanced disease (n = 17). Nearly one-half of the patients had a high-risk cytogenetic profile as defined by the presence of t(9;22) (n = 34), t(4;11) (n = 4), or complex cytogenetics (n = 7). Clo 40 mg/m(2) was given once daily, with each dose followed by pharmacokinetically dosed Bu infused over 3 hours daily for 4 days, followed by hematopoietic cell infusion after 2 days of rest. The Bu dose was based on the drug clearance as determined by a test Bu dose of 32 mg/m(2). The target daily area ...

A 38-year-old woman developed chronic myeloid leukaemia after 2 years of lithium carbonate therapy. A peculiar feature of her leukaemia, as well as of the 5 patients previously reported in whom CML has developed in the course of lithium therapy, was the unusually high degree of granulocyte maturation manifested in normal leucocyte alkaline phosphatase (LAP) score and, in 1 case, selective increase of transcobalamin III. Although a cause and effect relation between lithium therapy and CML has not yet been established, in view of the stimulatory effect of lithium on granulocyte proliferation, such treatment should be avoided in patients with established myeloproliferative disorders, or in patients at high risk of developing leukaemia.

Busulfan is a bifunctional alkylating agent that appears to be cytotoxic to slowly proliferating or non-proliferating stem cell compartments, although its specific molecular and cellular mechanisms are unknown. It is the drug of preference in treatment of chronic myelogenous or granulocytic leukemia because its cytotoxic activity results in primary damage or destruction of hematopoietic cells. Additional effects resulting from the cytotoxicity of busulfan in hematological and other tissues, as documented by both human and animal model studies, include lethality, sterility, teratogenicity, and alteration of immune function. Busulfan has been shown to be mutagenic to microorganisms, mammalian cells in culture, Drosophila, and rodents. This agent is also considered potentially carcinogenic to humans. Various tissue hyperplasia and preneoplastic cells have been observed in animal model studies with busulfan, and case reports on human patients implicate busulfan as the causative agent in...

Heptanediol distilt&#x27;amato (liopsiilfani. NSC 329680) is a new anti- cancer agent which is currently undergoing phase I clinical trials. The mechanism of action of this compound is not clear at this time. We have recently shown that hepsulfam was more toxic to I.I 210 leukemia cells than was busulfan. Consistent with the difference in toxicity, we found that hepsulfam induced DNA interstrand cross-links in I 1210 mouse leukemia cells, whereas busulfan did not. In the present study, we have found that hepsulfam was more cytotoxic to two human leukemia cell lines (111-60 and K562) and to two human colon carcinoma cell lines (BE and HT-29) than was busulfan. As in 11210 cells, hepsulfam induced a higher level of DNA interstrand cross-links than busulfan. Both com pounds induced DNA-protein cross-links. Hepsulfam was also more cytotoxic to the human leukemia cell lines when the concentrations were reduced 10-fold and the duration of drug exposure was increased to 12 h. This more acc...

Chemotherapy and radiation therapy result in increased free radical formation and depletion of tissue antioxidants. It is not known whether parenteral nutrition (PN) administered during bone marrow transplantation (BMT) supports systemic antioxidant status. The aims of the study were to determine 1) whether high-dose chemotherapy decreases concentrations of major circulating antioxidants in patients undergoing BMT and 2) whether administration of standard PN maintains systemic antioxidant concentrations compared with PN containing micronutrients and minimal lipids alone. Twenty-four BMT patients were randomly assigned to receive either standard PN containing conventional amounts of dextrose, amino acids, micronutrients, and lipid (120 kJ/d) or a solution containing only micronutrients (identical to those in standard PN) and a small amount of lipid (12 kJ/d). Plasma antioxidant status was measured before conditioning therapy and serially at days 1, 3, 7, 10, and 14 after BMT. Plasma ...

Chronic granulomatous disease (CGD) can be cured by allogeneic haemopoietic stem-cell transplantation (HSCT). Complications include graft failure, graft-versus-host disease (GvHD), infection and transplant-related mortality (TRM); therefore, reduced-intensity conditioning (RIC) regimens are being used to improve outcomes. In this retrospective study, the aim was to determine the outcome of Treosulfan-based conditioning in HSCT for paediatric patients with CGD. The following data were collected: risk features pre-HSCT, additional conditioning agents, donor type and stem cell source, toxicity, engraftment, GvHD, chimerism, viral reactivation, post-HSCT complications, length of follow up and outcome. Seventy patients (median age 107 months; IQR 46-232) from 16 centres worldwide were transplanted between 2006 and 2015. Ninety-one % had high-risk features. Fifty-seven HLA-matched donor, 12 HLA-mismatched donor and 1 CD3+TCR alpha beta/CD19 depleted parental haploidentical transplants wer...

We prospectively studied the pharmacokinetics (PK) and clinical outcomes of intravenous busulfan (Bu) in 71 children with preexisting liver damage who underwent hematopoietic stem cell transplantation for thalassemia. Intravenous Bu was administered every 6 hours as part of a conditioning regimen with PK-based dose adjustment to target a conservative area under the concentration-versus-time curve (AUC) range (900-1350 μMol*min). The first-dose Bu clearance (CL) was significantly higher than the subsequent daily CL that remained unchanged in the ensuing days. One-third of patients required dose escalation based on dose 1 AUC, whereas dose reduction was needed in the subsequent days. At doses 5, 9, and 13, 78%, 81%, and 87% of patients, respectively, achieved the target range of AUC. A population PK analysis confirmed that the first-dose CL was 20% higher and that body weight was the most important covariate to explain PK variability. Patients with variant GSTA1*B had a 10% lower Bu C...

Thirty-one consecutive patients with chronic myelogenous leukemia were treated in the chronic phase with immunotherapy in addition to chemotherapy. Immunotherapy consisted of Bacillus Calmette-Guérin and allogeneic myeloblasts given by vaccination, and chemotherapy comprised busulfan p.o. in most patients. No randomly allocated control group was designated, but patient characteristics appear to be typical of those of other published groups. Twenty-eight of 31 patients were followed from diagnosis to death, and the three remaining patients were followed for over 5 years. The median survival of the patients in our group was 37 months. There was a constant rate of decline in survival with time, with a mean annual death rate of 30% per year. Twenty-five of the 31 patients terminated in blast crisis. One of 21 patients achieved complete remission in blast crisis of myeloid or indeterminate type, and three of four patients achieved complete remission for blast crisis of lymphoid type. The...

Aplastic anaemia (AA) is characterized by hypocellular marrow, pancytopenia, and risk of severe anaemia, haemorrhage and infection. AA is often idiopathic, but frequently occurs after exposure to drugs/chemicals. However, the pathogenesis of AA is not clearly understood, and there ...

Intensive chemotherapy frequently results in gut toxicity, indicated by oral and intestinal mucositis, resulting in poor treatment outcomes and increased mortality. There are no effective preventive strategies against gut toxicity and the role of diet is unknown. We hypothesized that the severity of chemotherapy-induced gut toxicity in early life is diet-dependent, and that intake of bovine colostrum (BC) provides better gut protection than an artificial milk replacer (MR). A total of 37 3-d-old pigs received 6 d of either intravenous saline control or myeloablative treatment with busulfan and cyclophosphamide, and were fed either BC or MR, resulting in the following 4 treatments: bovine colostrum plus saline control (Ctr-BC), milk replacer plus saline control (Ctr-MR), bovine colostrum plus busulfan and cyclophosphamide chemotherapy (BUCY-BC), and milk replacer plus busulfan and cyclophosphamide chemotherapy (BUCY-MR); n = 8-10 per group. The gut was collected for analysis 11 d aft...