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PubMedDate not supplied

Biliary excretion of a glutathione conjugate of busulfan and 1,4-diiodobutane in the rat.

gamma-Glutamyl-beta-(S-tetrahydrothiophenium)alanyl-glycine, the glutathione-sulfonium conjugate of busulfan and 1,4-diiodobutane, was identified in the bile of rats following intravenous administration of equimolar doses of either compound. The glutathione-sulfonium conjugate was synthesized from 1-bromo-4-chlorobutane and characterized by 1H and 13C NMR and FAB/MS. An HPLC method was developed to identify the conjugate from rat bile by pre-column fluorescent derivatization with o-phthalaldehyde. The biliary excretion of cyclic sulfonium conjugates was quantitated indirectly by measuring the release of tetrahydrothiophene (THT) after treatment of the bile with base. THT release was quantitative and was measured by gas chromatography. With busulfan, peak biliary concentrations of THT-releasing metabolite(s) were reached after 90 min and 26% of the dose of busulfan was recovered in the bile after 8 hr. When diiodobutane was administered, 21% of the dose was recovered, and the peak concentration was reached in 30 min. The decline in THT releasing metabolite(s) was more rapid with 1,4-diiodobutane, and THT was no longer measurable after 3.5 hr compared to 7.5 hr after busulfan administration. These data confirm that busulfan and other 1,4-disubstituted butanes are conjugated with glutathione in vivo.

Animals↗
PubMed1988

Induction of sister chromatid exchanges and chromosomal aberrations by busulfan in Philadelphia chromosome-positive chronic myeloid leukemia and normal bone marrow.

Cytogenetic effects of busulfan in vitro were studied in normal bone marrow (nine cases) and Philadelphia chromosome (Ph)-positive cells (10 cases) of patients with chronic myeloid leukemia. The frequency of chromosome aberrations and sister chromatid exchange (SCE) increased dose dependently. While there were no significant differences between normal and leukemic cells with regard to the induction of chromosome aberrations, the frequency of SCE was significantly lower in Ph-positive cells than in normal bone marrow. This difference was not only apparent on the basis of the SCE frequency per cell, but also when the SCE frequency was correlated to the relative chromosome length as shown by the SCE rate per chromosome group. Longitudinal studies of three patients who received long term busulfan treatment did not show a significant change in the frequency of induced SCE. It can be suggested that the lower frequency of induced SCE in Ph-positive cells reveals less sensitivity of the leukemic cells to DNA damage by busulfan. Our data provide evidence for the inability of busulfan treatment to eradicate or even reduce Ph-positive cells in chronic myeloid leukemia. Evaluation of cell proliferation by sister chromatid differentiation shows longer cell cycle times for the Ph-positive cells. Busulfan affected the cell cycle duration of leukemia and normal cells very little.

Adolescent↗
PubMed1987

Long-term marrow cultures from mice with busulfan-induced chronic latent aplasia.

Mice treated with busulfan develop chronic latent marrow aplasia characterized by near-normal peripheral leukocyte counts, hematocrits, and marrow cellularity but very reduced stem cell (CFU-S) and progenitor cell (CFU-GM) populations. To determine whether the lesion is primarily in the stem cells or whether there is also a microenvironmental component we have used the Dexter-type long-term marrow cultures. Normal marrow maintains hemopoiesis for several weeks to months in such cultures, whereas "busulfan-marrow" will not support long-term growth. When normal marrow cells were transplanted onto an established adherent layer, whether derived from normal or busulfan marrow, normal hemopoiesis was established. However, busulfan-treated marrow cells would not establish hemopoiesis even when transplanted onto a normal stem cell-depleted adherent layer. It appears, therefore, that the primary lesion induced by busulfan is in the stem cells rather than in the microenvironment.

Animals↗
PubMed1985

[Randomized controlled study of methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU) in comparison with busulfan for chronic myelogenous leukemia].

UNLABELLED: In a randomized controlled study, the efficacy of MCNU was compared with that of Busulfan in 95 patients with chronic myelogenous leukemia. Of the patients studied, 95 were entered among whom 77 were evaluable. These comprised 40 for an MCNU group (M) and 37 for a Busulfan group (B). No significant difference was found statistically between the two groups with regard to background factors, i.e., male-to-female ratio, age, white blood cell counts, platelet counts, splenomegaly or Ph1 chromosome. RESULTS: CR rate was 83% for M and 68% for B, and the number of days to CR was 88 for M and 155 for B. Blastic crisis was noted in 31% of M patients and 33% of B patients and the number of days to blastic crisis was 542.6 and 581.9, respectively for the two groups. Deaths accounted for 28% and 29% for each of M and B. Side effects were observed in 31% of M cases and 15% of B cases. A significant difference was observed only in the period to CR. MCNU showed almost equal efficacy to that of Busulfan but was superior to Busulfan in patients who required rapid response. Side effects were mild and transient. Despite its delivery by intravenous injection, the administration of MCNU is deemed convenient, considering the long interval possible between treatments, being comparable in this respect with oral Busulfan. MCNU therefore seems a very effective drug for chronic myelogenous leukemia.

Adult↗
PubMed1984

In vitro effect of captopril and three captopril metabolites on neutrophilic progenitor cells from normal mice and mice given busulfan.

Neutrophilic progenitor cells (CFU-NM) in mice with busulfan-induced latent bone marrow hypoplasia have been shown to be selectively suppressed by captopril in vivo. To study this further, marrow from mice given busulfan was used to test for myelotoxicity in vitro. It was found that myelotoxic agents, such as doxorubicin, cytarabine, 1,3-bis(2-chloroethyl)-1-nitrosourea, and chloramphenicol have the same suppressive effect in vitro on CFU-NM obtained from normal marrow as obtained from marrow of mice given busulfan. Our results suggest that in vitro, the CFU-NMs from mice given busulfan are not excessively sensitive to the action of at least these myelotoxic agents. It was also found that neither captopril nor three known captopril metabolites suppress CFU-NM from mice given busulfan. This result suggests either that the myelotoxicity induced in vivo by captopril is not caused by the parent compound or any of the three metabolites tested, or more likely, that the suppressive action of captopril on CFU-NM in vivo is caused by the suppression of an earlier myeloid progenitor cell.

Animals↗
PubMed1981

The effects of calusterone on hemopoiesis in mice after busulfan-induced suppression of hemopoietic stem cells.

Studies were undertaken in mice to determine the effect of calusterone (a weakly androgenic steroid) on hemopoiesis. Animals were myelosuppressed with a single injection of the alkylating agent busulfan and subsequently treated with varying courses of calusterone. Simultaneous injection of calusterone did not prevent the rapid decline in CFU-S or CFU-C. Daily administration of calusterone for 12 to 14 days after busulfan had little influence on bone marrow cellularity; however, a twofold increase in peripheral blood neutrophils was observed. Bone marrow CFU-S and CFU-C were twofold to threefold higher after 8 to 14 days of treatment with calusterone, but there were no progressive increments in these hemopoietic stem cells during this time interval. In contrast to the granulocyte series, erythroid recovery was rapid after busulfan. Marrow erythroid precursors and CFU-E returned to normal levels by day 8. Daily treatment with calusterone accelerated recovery and led to an overshoot in these parameters of marrow erythropoiesis. Although an early course of calusterone treatment had only modest effects on CFU-S and CFU-C, delayed treatment was clearly stimulatory. A 10-day course of calusterone from days 14 to 24 after busulfan increased bone marrow CFU-S and CFU-C from 5% to 23% of controls to near normal values. Thus calusterone appears to stimulate all classes of hemopoietic progenitor cells. Its effects after busulfan are highly time-dependent, with greatest activity observed in those cellular compartments undergoing proliferative expansion.

Animals↗
PubMed1995

Busulfan concentration in relation to permanent alopecia in recipients of bone marrow transplants.

Alopecia is an important long-term complication after bone marrow transplantation (BMT). The aim of this study was to analyze the influence of busulfan concentration on the development of permanent alopecia. Sixty five patients who survived for at least 6 months after BMT were studied. The median follow-up was 2.1 years (range 0.5-5.7 years). Thirty one patients (47%) had some degree of alopecia and 19 of these patients had extensive alopecia. The mean minimum busulfan concentration was 656 +/- 222 ng/ml in patients who developed alopecia compared with 507 +/- 224 ng/ml in those who did not (P = 0.005). Patients with more extensive alopecia had higher busulfan concentrations than patients with less significant abnormalities. In multivariate analysis, alopecia was associated with busulfan concentrations higher than the median (OR 3.43; 95% CI 3.04-3.88), allogeneic transplantation (OR 2.56; 95% CI 2.28-2.88) and female sex (OR 1.96; 95% CI 1.73-2.88). There was no association between alopecia and chronic graft-versus-host disease. High busulfan concentrations may contribute to the development of permanent alopecia and the risk for alopecia should be considered when choosing the conditioning regimen before BMT.

Adolescent↗
PubMed1986

Degradation of busulfan in aqueous solution.

The influence of pH, phosphate buffer components and temperature on the degradation rate of busulfan was studied. The analysis was performed using gas chromatography with electron capture detection and reversed-phase liquid chromatography with radioactivity monitoring. The degradation rate of busulfan showed no pH dependence in the range pH 1.5-11 and increased at higher pH values. The degradation rate constant was 0.034 +/- 0.001 h(-1) (S.E.M.) for the degradation of busulfan in pure water and 0.45 +/- 0.01 h(-1)M(-1) (S.E.M.) for the reaction of busulfan with the hydroxide ion at 37 degrees C. The reactivity of HPO(4)(-2) was six times higher than the reactivity of H(2)PO(4)(-1) towards busulfan. The hydrolysis products were identified as tetrahydrofuran and methanesulphonic acid by nuclear magnetic resonance spectroscopy.

Journal Article↗
PubMed2000

Hematopoietic stem cell transplantation (HSCT) with a conditioning regimen of busulfan, cyclophosphamide, and etoposide for children with acute myelogenous leukemia (AML): a phase I study of the Pediatric Blood and Marrow Transplant Consortium.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an important treatment modality for children with AML. The optimal conditioning regimen is unknown. The aim of this study was to determine the appropriate dosing of etoposide in combination with busulfan and cyclophosphamide in this setting. PROCEDURE: Twenty patients with a diagnosis of AML in first or second remission, or myelodysplasia scheduled for bone marrow transplantation, were included in this study. Patients received busulfan 640 mg/m(2) in 16 doses, cyclophosphamide 120 to 150 mg/kg in two doses, and etoposide from 40-60 mg/kg as a single dose. Extensive toxicity data was collected. RESULTS: Nineteen patients were evaluable for toxicity. Mucositis was seen in all patients. Four patients developed bacteremia and one patient died from overwhelming sepsis on day +3. Four patients developed moderate to severe skin toxicity. The major dose-limiting +3 toxicity was hepatic toxicity, which occurred in 14 of 19 patients. Eight patients developed clinical veno-occlusive disease, including three patients at dose level 4, two of whom had life-threatening disease. This hepatic toxicity defined the MTD of 640 mg/m(2) busulfan, 120 mg/kg of cyclophosphamide, and 60 mg/kg of etoposide. Overall, 9 of 20 patients enrolled in the study survive in remission, 8/14 allogeneic (median follow-up 44 months), and one of six autologous patients (follow-up, 54 months). CONCLUSIONS: We conclude that the combination of busulfan, cyclophosphamide, and etoposide at the doses defined above has activity in the treatment of children with high-risk AML/MDS undergoing allogeneic HSCT. Whether it offers an advantage over other conditioning regimens will require a randomized trial with a larger cohort of patients.

Adolescent↗
PubMed1984

Effects of thymocytes on marrow cells from normal and busulfan-treated mice.

To study the effects of thymocytes on hemopoiesis, we 1) cocultured marrow cells with and without thymocytes in an erythroid burst (BFU-E) culture system, 2) injected marrow cells with and without thymocytes into supralethally irradiated mice to assay CFU-S, and 3) assessed the survival of supralethally irradiated mice transplanted with marrow cells with or without thymocytes. The marrow cells used were either from mice given six injections of busulfan and then permitted to rest for 2, 5, or 10 weeks or from mice treated similarly with the busulfan vehicle alone. Thymocytes did not alter spleen surface colony counts or survivorship in any of the test groups. Thymocytes did effect an increase in BFU-E cultured from marrow obtained from the vehicle-treated mice but not from marrow of busulfan-treated mice. Thus, in addition to decreasing the population of hemopoietic precursors in the marrow, busulfan alters the nature of the remaining early erythroid precursor cell population rendering it unresponsive to thymocytes in vitro.

Animals↗
PubMed1986

Granulopoiesis in long-term culture by marrow from mice with busulfan-induced chronic latent aplasia.

Mice given high-dose busulfan therapy develop a chronic latent marrow aplasia characterized by normal peripheral blood neutrophil numbers, hematocrits and marrow cellularity but reduced numbers of pluripotent hemopoietic stem cells (CFU-s) and granulocyte-monocyte progenitor cells (CFU-gm). To study the pathogenesis of this lesion, bone marrow was propagated in long-term marrow cultures (LTMC). Small amounts of normal marrow readily established and sustained long-term granulopoiesis in vitro. In contrast, inocula of marrow from busulfan-treated animals containing three to five times as many stem and progenitor cells failed to establish long-term granulopoiesis in vitro. These results suggest that high-dose busulfan therapy produces a qualitative defect in either the hemopoietic stem cells, the stromal-forming elements, or both, rendering them incapable of establishing long-term granulopoiesis in vitro. Furthermore, mixing experiments employing normal and busulfan-damaged marrow demonstrate that this qualitative defect is not due to the emergence of a suppressor cell population. LTMC can show types of marrow damage not detectable by other techniques currently available and represent a powerful tool for studying latent bone marrow failure.

Anemia↗
PubMed1989

Pharmacokinetics of high-dose busulfan in children.

The pharmacokinetics of high-dose busulfan given orally at 1 mg/kg every 6 h over 4 days (total dose, 16 mg/kg) in combined chemotherapy followed by autologous bone marrow transplantation was studied in 12 children with a mean age of 7 years (range, 4-14 years). Busulfan levels in biological fluids were measured by a gas chromatographic assay with mass fragmentographic detection, using a deuterated analogue as the internal standard. In a high-dose regimen, busulfan followed one-compartment model kinetics with zero-order absorption. A mean maximal concentration of 803 +/- 228 ng/ml was achieved at 92-255 min after dosing. The mean elimination half-life was 2.33 h, and the mean total clearance was 119 +/- 54 ml/min per m2, with an apparent distribution volume of 27.10 +/- 11.50 l/m2. A mean trough level of 370 ng/ml was found throughout the 4 days of the chemotherapy course. There were no significant variations in pharmacokinetic parameters measured after the first and last doses. Busulfan was monitored in the CSF of nine children at 3.25-7 h after the last dose and was detected in all patients, with a mean CSF-to-plasma concentration ratio of 0.95 (range, 0.5-1.4).

Adolescent↗
PubMed1988

Randomized study on the treatment of chronic myeloid leukemia (CML) in chronic phase with busulfan versus hydroxyurea versus interferon-alpha.

For palliative therapy during the chronic phase of CML busulfan has proved to be the drug of choice. During the past years hydroxyurea and also interferon-alpha have gained increasing significance since they might prolong the duration of the chronic phase. In a multicenter study it is being determined, whether the use of hydroxyurea or of interferon-alpha instead of busulfan prolongs the duration of the chronic phase of Philadelphia positive CML. Additional goals are the examination of whether the types of disease evolution and the terminal phases differ between the treatment groups, and the prospective recognition of prognostic criteria for the duration of the chronic phase of CML. By December 31, 1987, 326 CML-patients had been randomized, 150 for busulfan, 150 for hydroxyurea and 26 for interferon-alpha. The average age is 50 years. 59 patients reached the end of the chronic phase, 55 died. The mean observation time of all patients is 1.34 years. At present no significant difference in survival is recognizable between the busulfan and hydroxyurea groups. Fewer adverse effects have been observed in the hydroxyurea group. Philadelphia chromosome negative patients show a higher average age and tend to have lower white blood cell and platelet counts. The number of patients having received interferon-alpha is still too small to allow evaluation. This report intends to document organization and progress of this study which to our knowledge is, at present, the largest ongoing prospective multicenter study on the therapy of CML.

Busulfan↗
PubMed1991

Induction of specific-locus and dominant lethal mutations in male mice by busulfan.

The chemotherapeutic agent busulfan was tested for the induction of dominant lethal and specific-locus mutations in male mice. A dose of 5 mg/kg b.w. of busulfan induces dominant lethal mutations in spermatozoa. A dose of 20 mg/kg b.w. induces dominant lethal mutations in spermatozoa and spermatids. A total of 83,196 offspring were scored in the specific-locus experiments. Busulfan-induced specific-locus mutations were recovered in spermatozoa and spermatids, but not in spermatogonia. The sensitivity patterns for the induction of dominant lethal and specific-locus mutations by busulfan in germ cells of male mice are similar but not identical.

Alleles↗
PubMed2005

Low dose busulfan facilitates chimerism and tolerance in a murine model.

T cell depletion, sirolimus and "mega" dose donor specific bone marrow (DSBM) infusion promotes stable multilineage chimerism and indefinite survival of skin allografts in completely mismatched mice. The purpose of this study is to determine whether the addition of low dose busulfan can reduce the amount of DSBM required while preserving efficacy. C57BL/6 recipients of BALB/c skin allografts were treated with alphaCD4 and alphaCD8 monoclonal antibodies, DSBM, sirolimus and various doses of busulfan. The kinetics and phenotype of chimerism and the presence of clonal deletion of alloreactive T-cells were defined using flow cytometry. In vitro reactivity was determined using mixed lymphocyte culture. Second skin grafts confirmed the presence of tolerance. All doses of busulfan resulted in engraftment when combined with this regimen using a reduced dose of donor marrow. The level, kinetics and character of chimerism observed were dose related. Chimerism was associated with indefinite allograft acceptance (>200 days). Tolerance was documented both in vitro/in vivo and was associated with clonal deletion. Addition of a single low dose of busulfan to an established tolerance protocol reduced the required DSBM dose by over 80% while still promoting comparable levels of donor chimerism and donor-specific tolerance.

Animals↗
PubMedDate not supplied

[Interstitial pneumopathies caused by busulfan. Histologic, developmental and bronchoalveolar lavage analysis of 3 cases].

Busulfan-induced diffuse interstitial pneumonia is a rare but serious disease attributed to a direct toxic effect of busulfan (an alkylating antimitotic drug) on alveolar cells. We report three new cases explored by repeated bronchoalveolar lavages and lung biopsies. All patients had circulating immune complexes, abnormalities at capillaroscopy and above all lymphocytic or mixed alveolitis at bronchoalveolar lavage. The clinical outcome was favourable with regression of the alveolar lesions in the patient with pure lymphocytic alveolitis. It was unfavourable in patients showing severe alveolitis with polymorphonuclear cells. Histology revealed constant abnormalities of type I pneumocytes and rarefaction of type II pneumocytes, together with interstitial oedema and pulmonary fibrosis in which tissue mast cells could not be identified. The immunological disturbances observed in busulfan lung might enhance an initial toxic reaction and account for the often unfavourable outcome, even after withdrawal of busulfan.

Bronchoalveolar Lavage Fluid↗
PubMed2004

High-performance thin-layer chromatography with a derivatization procedure, a suitable method for the identification and the quantitation of busulfan in various pharmaceutical products.

Busulfan is an alkylating agent widely used in combination chemotherapy regimens followed by allogeneic or autologous hematopoietic stem cell transplantation (HSCT). We present a rapid method for assaying busulfan in pharmaceutical preparations using high-performance thin-layer chromatography (HPTLC) and derivatization with 4-nitrobenzylpyridine. The method is accurate and precise and allows quantitation of busulfan in aqueous solutions from 100 to 500 microg/ml. It is suitable for identification. quantitation and stability studies of busulfan in pharmaceutical products, i.e. capsules or infusion bags prepared in a hospital pharmacy.

Busulfan↗
PubMed2003

Plasma pharmacokinetics of high-dose oral busulfan in children and adults undergoing bone marrow transplantation.

We have analyzed the plasma pharmacokinetics of busulfan in 272 patients receiving high-dose oral busulfan and intravenous cyclophosphamide in conjunction with allogeneic or autologous bone marrow transplantation. The patients ranged in age from 2 months to 59 yr (mean 10, median 12 yr) and had the following diagnoses: thalassemia or sickle cell anemia (n = 74); leukemia or myelodysplasia (n = 112); inborn errors of metabolism (n = 41) or immunodeficiency (n = 45). Plasma specimens were collected following the first dose for each patient which ranged from 1 to 4 mg/kg (mean +/- SD, 1.21 +/- 0.41, median 1.15). Busulfan was quantitated using ultraviolet absorbance detection after derivatization and HPLC separation. Pharmacokinetic parameters were derived by modeling the raw data to fit first-order single compartment kinetics. The kinetic parameters showed wide interpatient variability independent of age and diagnosis. There was a statistically significant correlation of age with the following parameters: area under the curve (AUC); maximal concentration; minimum concentration; clearance; volume of distribution and absorption half-time. The coefficients of determination (i.e. correlation coefficient squared) were low ranging from 0.04 to 0.12 implying only a small part (i.e. 4-12%) of the variance was explained by age. Although busulfan pharmacokinetics are age-related most of the variability is not explained by age or diagnosis.

Adolescent↗