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Busulfan (Myleran, Busulfex)

Alias: Busulfex; Mitosan; Myleran; Mielucin; Misulban; Misulfan; BU; BUS; Myleran; Busulphan; Leucosulfan; Sulphabutin; Busulfex; Myelosan; CB2041; GT41; WR19508
Cat No.:V5078 Purity: ≥98%
Busulfan (Myleran; Busulfex IV) is a potent DNA alkylating agent with selective immunosuppressive effect on bone marrow.
Busulfan (Myleran, Busulfex)
Busulfan (Myleran, Busulfex) Chemical Structure CAS No.: 55-98-1
Product category: DNA alkylator
This product is for research use only, not for human use. We do not sell to patients.
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Other Forms of Busulfan (Myleran, Busulfex):

  • Treosulfan (NSC-39069; Treosulphan)
  • Thiotepa (STEPA; TESPA)
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Busulfan (Myleran; Busulfex IV) is a potent DNA alkylating agent with selective immunosuppressive effect on bone marrow. Since 1959, the approved cancer chemotherapy drug busulfan has been used in clinical settings. Within the alkyl sulfonate class of antineoplastics, busulfan is an alkylating agent that is non-specific to the cell cycle.

Biological Activity I Assay Protocols (From Reference)
Targets
DNA alkylator
ln Vitro
Busulfan suppresses the frequency of cobblestone area-forming cells but does not significantly raise the rate of apoptosis in hematopoietic stem cell progenitors and similar cells. By an apoptosis-independent mechanism, busulfan inhibits the hematopoietic function of HSC progenitors and cells alike. In a time-dependent manner, busulfan causes bone marrow hematopoietic cell senescence, which is linked to an upregulation of p16Ink4a and p19Arf expression.[1] Normal human diploid WI38 fibroblasts are exposed to busulfan, an alkylating agent that damages DNA by cross-linking DNAs and DNA and proteins. This agent causes senescence through the extracellular signal-regulated kinase (Erk) and p38 mitogen-activated protein kinase (p38 MAPK) cascade, which is independent of the p53-DNA damage pathway. Busulfan causes a temporary decrease in GSH but a persistent rise in ROS generation.[2] By reducing the expression of PCNA in testicular cells, busulfan-induced hypophosphorylation of Rb stops spermatogonial stem cells from undergoing apoptosis.[3]
ln Vivo
Busulfan-treated mice show a significant decrease in testis weight and an increase in apoptosis. In order to maximize the number of apoptotic cells and minimize the number of necrotic cells, 40 mg/kg body weight of busulfan is administered.[3] Using limiting dilution analysis, busulfan conditioning and radiation produce HSC detection sensitivity that is comparable in NOD/SCID mice.[4] Mice transplanted with busulfan exhibit incomplete and sluggish lymphoid engraftment. Mice that receive busulfan (20 mg/kg to 100 mg/kg) exhibit dose-dependent reconstitution of congenic lymphoid tissue.[5]
Enzyme Assay
Induction of cellular senescence is a common response of a normal cell to a DNA-damaging agent, which may contribute to cancer chemotherapy- and ionizing radiation-induced normal tissue injury. The induction has been largely attributed to the activation of p53. However, the results from the present study suggest that busulfan (BU), an alkylating agent that causes DNA damage by cross-linking DNAs and DNA and proteins, induces senescence in normal human diploid WI38 fibroblasts through the extracellular signal-regulated kinase (Erk) and p38 mitogen-activated protein kinase (p38 MAPK) cascade independent of the p53-DNA damage pathway. The induction of WI38 cell senescence is initiated by a transient depletion of intracellular glutathione (GSH) and followed by a continuous increase in reactive oxygen species (ROS) production via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which leads to the activation of the Erk and p38 MAPK pathway. Incubation of WI38 cells with N-acetylcysteine (NAC) replenishes intracellular GSH, abrogates the increased production of ROS, ameliorates Erk and p38 MAPK activation, and attenuates senescence induction by BU. Thus, inhibition of senescence induction using a potent antioxidant or specific inhibitor of the Erk and p38 MAPK pathway has the potential to be developed as a mechanism-based strategy to ameliorate cancer therapy-induced normal tissue damage.[2]
Male germ cell apoptosis has been extensively explored in rodents. In contrast, very little is known about the susceptibility of developing germ cells to apoptosis in response to busulfan treatment. Spontaneous apoptosis of germ cells is rarely observed in the adult mouse testis, but under the experimental conditions described here, busulfan-treated mice exhibited a marked increase in apoptosis and a decrease in testis weight. TdT-mediated dUTP-X nicked end labeling analysis indicates that at one week following busulfan treatment, apoptosis was confined mainly to spermatogonia, with lesser effects on spermatocytes. The percentage of apoptosis-positive tubules and the apoptotic cell index increased in a time-dependent manner. An immediate effect was observed in spermatogonia within one week of treatment, and in the following week, secondary effects were observed in spermatocytes. RT-PCR analysis showed that expression of the spermatogonia-specific markers c-kit and Stra 8 was reduced but that Gli I gene expression remained constant, which is indicative of primary apoptosis of differentiating type A spermatogonia. Three and four weeks after busulfan treatment, RAD51 and FasL expression decreased to nearly undetectable levels, indicating that meiotic spermatocytes and post-meiotic cells, respectively, were lost. The period of germ cell depletion did not coincide with increased p53 or Fas/FasL expression in the busulfan-treated testis, although p110Rb phosphorylation and PCNA expression were inhibited. These data suggest that increased depletion of male germ cells in the busulfan-treated mouse is mediated by loss of c-kit/SCF signaling but not by p53- or Fas/FasL-dependent mechanisms. Spermatogonial stem cells may be protected from cell death by modulating cell cycle signaling such that E2F-dependent protein expression, which is critical for G1 phase progression, is inhibited[3].
Cell Assay
Cell Line: WI38 cells
Concentration: 120 μM
Incubation Time: 24 hours
Result: Incited a moderate p53 activation, but strong Erk, p38, and JNK phosphorylation, in a time-dependent manner. Elicited an immediate up-regulation of p21 expression, which subsided by day 11.
Exposure of murine bone marrow (BM) cells to ionizing radiation (IR; 4 Gy) resulted in >95% inhibition of the frequency of various day types of cobblestone area-forming cells in association with the induction of apoptosis in hematopoietic stem cell alike cells (Lin(-) ScaI(+) c-kit(+) cells; IR: 64.8 +/- 0.4% versus control: 20.4 +/- 0.5%; P < 0.001) and progenitors (Lin(-) ScaI(-) c-kit(+) cells; IR: 46.2 +/- 1.4% versus control: 7.8 +/- 0.5%; P < 0.001). Incubation of murine BM cells with busulfan (BU; 30 micro M) for 6 h also inhibited the cobblestone area-forming cell frequency but failed to cause a significant increase in apoptosis in these two types of hematopoietic cells. After 5 weeks of long-term BM cell culture, 33% and 72% of hematopoietic cells survived IR- and BU-induced damage, respectively, as compared with control cells, but they could not form colony forming units-granulocyte macrophages. Moreover, these surviving cells expressed an increased level of senescence-associated beta-galactosidase, p16(Ink4a), and p19(Arf). These findings suggest that IR inhibits the function of hematopoietic stem cell alike cells and progenitors primarily by inducing apoptosis, whereas BU does so mainly by inducing premature senescence. In addition, induction of premature senescence in BM hematopoietic cells also contributes to IR-induced inhibition of their hematopoietic function. Interestingly, the induction of hematopoietic cell senescence by IR, but not by BU, was associated with an elevation in p53 and p21(Cip1/Waf1) expression. This suggests that IR induces hematopoietic cell senescence in a p53-p21(Cip1/Waf1)-dependent manner, whereas the induction of senescence by BU bypasses the p53-p21(Cip1/Waf1) pathway.[1]
Animal Protocol
ICR male mice ranging in age from 8 to 12 weeks (30-40 g)
40 mg/kg (in sesame oil)
IP; single dose
Human hematopoietic stem cell (HSC) xenotransplantation in NOD/SCID mice requires recipient conditioning, classically achieved by sublethal irradiation. Pretreatment with immunosuppressive and alkylating agents has been reported, but has not been rigorously tested against standard irradiation protocols. Here, we report that treatment of mice with a single dose (35 mg/kg) of Busilvex, an injectable form of busulfan, enables equivalent engraftment compared to 3.5 Gy irradiation. Mice treated with two doses of 25 mg/kg to reduce busulfan toxicity showed increased chimerism. Busulfan conditioning and irradiation resulted in comparable sensitivity of HSC detection as evaluated by limiting dilution analysis.[4]
ADME/Pharmacokinetics
Absorption, Distribution and Excretion
Completely absorbed from the gastrointestinal tract. Busulfan is a small, highly lipophilic molecule that crosses the blood-brain-barrier. The absolute bioavailability, if a single 2 mg IV bolus injection is given to adult patients, is 80% ± 20%. In children (1.5 - 6 years old), the absolute bioavailability was 68% ± 31%. When a single oral dose is given to patients, the area under the curve (AUC) was 130 ng•hr/mL. The peak plasma concentration when given orally is 30 ng/mL (after dose normalization to 2 mg). It takes 0.9 hours to reach peak plasma concentration after dose normalization to 4 mg.
Following administration of 14C- labeled busulfan to humans, approximately 30% of the radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in feces. Less than 2% of the administered dose is excreted in the urine unchanged within 24 hours. Elimination of busulfan is independent of renal function.
2.52 ml/min/kg [Following an infusion of dose of 0.8 mg/kg every six hours, for a total of 16 doses over four days]
The pharmacokinetic disposition of busulfan differs in children versus adults. The mean bioavailability of busulfan is lower in children than in adults; the interindividual variation in bioavailability for oral busulfan is large, particularly in children. In a pharmacokinetic study in children receiving IV busulfan (0.8 or 1 mg/kg based on actual body weight), an estimated volume of distribution of 0.64 L/kg (with an interpatient variability of 11%) was reported.
Busulfan, a small and highly lipophilic molecule, easily crosses the blood-brain barrier. Busulfan concentrations in the cerebrospinal fluid (CSF) are approximately equal to concurrent busulfan plasma concentrations. It is not known whether the drug is distributed into milk.
For adults receiving busulfan 2, 4, or 6 mg orally as a single dose on consecutive days, the drug exhibits linear kinetics for both the maximum plasma concentration and the area under the concentration-time curve (AUC); a mean peak plasma concentration (normalized to a dose of 2 mg) of about 30 ng/mL was observed. In a study of 12 patients receiving single oral busulfan doses of 4-8 mg, a mean peak plasma concentration (normalized to a dose of 4 mg) of about 68 ng/mL was reported; the time to peak plasma concentration was about 0.9 hours.
Busulfan is rapidly and completely absorbed from the GI tract after oral administration of the drug. The effect of food on the bioavailability of busulfan is not known.
For more Absorption, Distribution and Excretion (Complete) data for BUSULFAN (11 total), please visit the HSDB record page.
Metabolism / Metabolites
Busulfan is extensively metabolizes in the hepatic. Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. GSTA1 is the primary GST isoform that facilitates the the metabolism of busulfan. Other GST isoforms that are also involved are GSTM1 and GSTP1. At least 12 metabolites have been identified among which tetrahydrothiophene, tetrahydrothiophene 12-oxide, sulfolane, and 3-hydroxysulfolane were identified. These metabolites do not have cytotoxic activity.
After IP injections of 2:3-(14)C-Myleran in the rat, rabbit and mouse, 60% of the urinary radioactivity was found to be in the form of the 3-hydroxy tetrahydrothiophene-1,1-dioxide, a sulphone. It is suggested that in vivo Myleran undergoes a reaction with cysteine or a cysteinyl moiety to form a cyclic sulphonium ion, which in turn undergoes cleavage to the tetrahydrothiophene, oxidation to the 1,1-dioxide and biological hydroxylation to the 3-hydroxy compound.
In the rat and mouse 50-60% of a single dose of Myleran-(35)S (10 mg/kg bw) injected intraperitoneally in arachis oil was excreted within 24 to 48 hours, mainly as methane sulphonic acid; a small amount of unchanged Myleran and two unidentified components were present. In the rabbit, methane sulphonic acid was the only metabolite found in the urine.
The metabolic fate of busulfan has been studied in rats and humans using (14)C- and (35)S-labeled materials. In humans, as in the rat, almost all of the radioactivity in (35)S-labeled busulfan is excreted in the urine in the form of (35)S-methanesulfonic acid. /It was/ demonstrated that the formation of methanesulfonic acid in vivo in the rat is not due to a simple hydrolysis of busulfan to 1,4-butanediol, since only about 4% of 2,3-(14)C-busulfan was excreted as carbon dioxide, whereas 2,3-(14)C-1,4-butanediol was converted almost exclusively to carbon dioxide. The predominant reaction of busulfan in the rat is the alkylation of sulfhydryl groups (particularly cysteine and cysteine-containing compounds) to produce a cyclic sulfonium compound which is the precursor of the major urinary metabolite of the 4-carbon portion of the molecule, 3-hydroxytetrahydrothiophene-1,1-dioxide. This has been termed a "sulfur-stripping" action of busulfan and it may modify the function of certain sulfur-containing amino acids, polypeptides, and proteins; whether this action makes an important contribution to the cytotoxicity of busulfan is unknown.
(14)C busulfan was administered ip (15 mg/kg) to 5 male Sprague-Dawley rats. For 72 hours, the urinary recovery of (14)C was approximately 70% of the total dose, while the fecal excretion was within the range 1.5-2%. The pattern of the urinary metabolites of busulfan was studied by HPLC in combination with radioactivity detection of the pooled urine. At least eight radioactive fractions could be separated. Three major metabolite peaks were identified by GC/MS and NMR spectroscopy: 3-hydroxysulfolane (39% of total urine radioactivity), tetrahydrothiophene 1- oxide (20%), and sulfolane (13%). Busulfan (6%) and tetrahydrofuran (2%) were also identified. A sulfonium ion glutathione conjugate was hypothesised as another metabolite, but was not isolated because it was very unstable. However, another compound was observed. This metabolite co-eluted with the sulfonium ion obtained of the reaction of busulfan with N-acetyl-L-cysteine and produced tetrahydrothiophene when hydrolyzed. Finally, busulfan and the three main metabolites were tested for cytotoxicity on Chinese V79 hamster cells in vitro. Cell toxicity was induced only by busulfan, which indicates that the cytotoxicity in vivo is mediated by the parent compound, as expected.
Busulfan is extensively metabolizes in the hepatic. Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. GSTA1 is the primary GST isoform that facilitates the the metabolism of busulfan. Other GST isoforms that are also involved are GSTM1 and GSTP1. At least 12 metabolites have been identified among which tetrahydrothiophene, tetrahydrothiophene 12-oxide, sulfolane, and 3-hydroxysulfolane were identified. These metabolites do not have cytotoxic activity.
Route of Elimination: Following administration of 14C- labeled busulfan to humans, approximately 30% of the radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in feces. Less than 2% of the administered dose is excreted in the urine unchanged within 24 hours. Elimination of busulfan is independent of renal function.
Half Life: 2.6 hours
Biological Half-Life
2.6 hours
The terminal half life /in children from < 6 months up to 17 years old/ ranged from 2.26 to 2.52 hr.
The elimination half-life is about 2.6 hours in adults receiving oral busulfan.
Following intravenous administration, the mean half life of busulfan ranged from 2.83 hours to 3.90 hours ... . Oral busulfan had a mean half life of 3.87 hours.
Toxicity/Toxicokinetics
Toxicity Summary
Busulfan is an alkylating agent that contains 2 labile methanesulfonate groups attached to opposite ends of a 4-carbon alkyl chain. Once busulfan is hydrolyzed, the methanesulfonate groups are released and carbonium ions are produced. These carbonium ions alkylate DNA, which results in the interference of DNA replication and RNA transcription, ultimately leading to the disruption of nucleic acid function. Specifically, its mechanism of action through alkylation produces guanine-adenine intrastrand crosslinks. This occurs through an SN2 reaction in which the relatively nucleophilic guanine N7 attacks the carbon adjacent to the mesylate leaving group. This kind of damage cannot be repaired by cellular machinery and thus the cell undergoes apoptosis.
Interactions
Itraconazole reduced busulfan clearance by up to 25% in patients receiving itraconazole compared to patients who did not receive itraconazole. Higher busulfan exposure due to concomitant itraconazole could lead to toxic plasma levels in some patients. Fluconazole had no effect on the clearance of busulfan. Patients treated with concomitant cyclophosphamide and busulfan with phenytoin pretreatment have increased cyclophosphamide and busulfan clearance, which may lead to decreased concentrations of both cyclophosphamide and busulfan. However, busulfan clearance may be reduced in the presence of cyclophosphamide alone, presumably due to competition for glutathione.
Busulfan-induced pulmonary toxicity may be additive to the effects produced by other cytotoxic agents.
In one study, 12 of approximately 330 patients receiving continuous busulfan and thioguanine therapy for treatment of chronic myelogenous leukemia were found to have portal hypertension and esophageal varices associated with abnormal liver function tests. Subsequent liver biopsies were performed in 4 of these patients, all of which showed evidence of nodular regenerative hyperplasia. Duration of combination therapy prior to the appearance of esophageal varices ranged from 6 to 45 months. With the present analysis of the data, no cases of hepatotoxicity have appeared in the busulfan-alone arm of the study. Long-term continuous therapy with thioguanine and busulfan should be used with caution.
Busulfan may cause additive myelosuppression when used with other myelosuppressive drugs.
For more Interactions (Complete) data for BUSULFAN (8 total), please visit the HSDB record page.
Non-Human Toxicity Values
LD50 Rat iv 14-25 mg/kg
LD50 Mouse oral 120 mg/kg
References

[1]. Cancer Res . 2003 Sep 1;63(17):5414-9.

[2]. Free Radic Biol Med . 2007 Jun 15;42(12):1858-65.

[3]. FEBS Lett . 2004 Sep 24;575(1-3):41-51.

[4]. Haematologica . 2006 Oct;91(10):1384.

[5]. Blood . 1991 Dec 15;78(12):3312-6.

[6]. Eur J Clin Pharmacol . 2012 Jun;68(6):923-35.

Additional Infomation
Therapeutic Uses
Busulfan is used in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation in patients with chronic myelogenous leukemia (CML) and is designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this disease.
/VET/ Antineoplastic agent used in adjunct therapy of acute granulocytic leukemias in small animals.
Busulfan is an alkylating agent with myeloablative properties and activity against non-dividing marrow cells and, possibly, non-dividing malignant cells. Its use has been well established in the treatment of hematological malignancies, particularly in patients with chronic myeloid leukemia and other myeloproliferative syndromes.
Busilvex followed by cyclophosphamide (BuCy4) or melphalan (BuMel) is indicated as conditioning treatment prior to conventional hematopoietic progenitor cell transplantation in pediatric patients.
Drug Warnings
Myleran is a potent drug. It should not be used unless a diagnosis of chronic myelogenous leukemia has been adequately established and the responsible physician is knowledgeable in assessing response to chemotherapy. Myleran can induce severe bone marrow hypoplasia. Reduce or discontinue the dosage immediately at the first sign of any unusual depression of bone marrow function as reflected by an abnormal decrease in any of the formed elements of the blood. A bone marrow examination should be performed if the bone marrow status is uncertain.
Life-threatening hepatic veno-occlusive disease has occurred in patients receiving busulfan (usually in combination with cyclophosphamide or other antineoplastic agents as a component of marrow-ablative therapy prior to bone marrow transplantation). The manufacturer states that a clear causal relationship to busulfan has not been demonstrated. Hepatic veno-occlusive disease diagnosed by clinical examination and laboratory findings occurred in 8% (5/61) of patients receiving IV busulfan in the allogeneic transplant clinical trial and was fatal in 40% (2/5) of cases. Overall mortality from hepatic veno-occlusive disease was 3% for the entire study population. Retrospectively, 3 of the 5 patients diagnosed with hepatic veno-occlusive disease were found to meet the Jones' criteria for this condition. In patients receiving high-dose oral busulfan as a component of a conditioning regimen prior to bone marrow transplant in randomized, controlled studies, the incidence of hepatic veno-occlusive disease was 7.7-12%.
Interstitial pneumonitis and pulmonary fibrosis, which rarely were fatal, also have been reported in patients receiving high oral doses of busulfan as a component of a conditioning regimen prior to allogeneic bone marrow transplantation. Nonspecific interstitial fibrosis was diagnosed by lung biopsy in one patient receiving IV busulfan who subsequently died from respiratory failure.
In patients receiving oral busulfan, pancytopenia generally occurs with failure to adequately monitor hematologic status and promptly discontinue the drug in response to a large or rapid decrease in leukocyte or platelet counts. Although individual variation in response to the drug does not appear to be an important contributing factor, some patients may be especially sensitive to busulfan and experience abrupt onset of neutropenia or thrombocytopenia. Busulfan-induced pancytopenia may be more prolonged than that induced by other alkylating agents; although recovery may take 1 month to 2 years, the toxicity is potentially reversible and patients should be vigorously supported through any period of severe pancytopenia. Some patients develop bone marrow fibrosis or chronic aplasia which is probably due to busulfan toxicity. Aplastic anemia, sometimes irreversible, has been reported rarely in patients receiving oral busulfan; aplastic anemia usually has occurred following high doses of the drug or long-term administration of conventional doses.
For more Drug Warnings (Complete) data for BUSULFAN (42 total), please visit the HSDB record page.
Pharmacodynamics
Busulfan is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn leads to a miscoding of DNA. Alkylating agents are cell cycle-nonspecific and work by three different mechanisms, all of which achieve the same end result - disruption of DNA function and cell death. Overexpression of MGST2, a glutathione s-transferase, is thought to confer resistance to busulfan. The role of MGST2 in the metabolism of busulfan is unknown however.
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C6H14O6S2
Molecular Weight
246.3018
Exact Mass
246.023
Elemental Analysis
C, 29.26; H, 5.73; O, 38.98; S, 26.04
CAS #
55-98-1
Related CAS #
55-98-1 (Busulfan); 299-75-2 (Treosulfan); 52-24-4 (Thiotepa; Girostan; AI3-24916; NSC-6396)
PubChem CID
2478
Appearance
White to khaki solid powder
Density
1.4±0.1 g/cm3
Boiling Point
464.0±28.0 °C at 760 mmHg
Melting Point
114-117 °C(lit.)
Flash Point
234.4±24.0 °C
Vapour Pressure
0.0±1.1 mmHg at 25°C
Index of Refraction
1.471
LogP
-0.52
Hydrogen Bond Donor Count
0
Hydrogen Bond Acceptor Count
6
Rotatable Bond Count
7
Heavy Atom Count
14
Complexity
294
Defined Atom Stereocenter Count
0
SMILES
S(C([H])([H])[H])(=O)(=O)OC([H])([H])C([H])([H])C([H])([H])C([H])([H])OS(C([H])([H])[H])(=O)=O
InChi Key
COVZYZSDYWQREU-UHFFFAOYSA-N
InChi Code
InChI=1S/C6H14O6S2/c1-13(7,8)11-5-3-4-6-12-14(2,9)10/h3-6H2,1-2H3
Chemical Name
4-methylsulfonyloxybutyl methanesulfonate
Synonyms
Busulfex; Mitosan; Myleran; Mielucin; Misulban; Misulfan; BU; BUS; Myleran; Busulphan; Leucosulfan; Sulphabutin; Busulfex; Myelosan; CB2041; GT41; WR19508
HS Tariff Code
2905591000
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: 63~125 mg/mL (255.8~507.5 mM)
Methanol: ~1 mg/mL (~4.1 mM)
H2O: ~1 mg/mL (~4.1 mM)
Solubility (In Vivo)
Solubility in Formulation 1: 6.25 mg/mL (25.38 mM) in 15% Cremophor EL + 85% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

Solubility in Formulation 2: ≥ 2.08 mg/mL (8.44 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (8.44 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C,1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.


Solubility in Formulation 4: ≥ 2.08 mg/mL (8.44 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL corn oil and mix evenly.

Solubility in Formulation 5: 5%DMSO+ 40%PEG300+ 5%Tween 80+ 50%ddH2O: 3.15mg/ml (12.79mM)

Solubility in Formulation 6: 3.12 mg/mL (12.67 mM) in Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.

 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 4.0601 mL 20.3004 mL 40.6009 mL
5 mM 0.8120 mL 4.0601 mL 8.1202 mL
10 mM 0.4060 mL 2.0300 mL 4.0601 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Reconstitution Calculator allows you to calculate the volume of solvent required to reconstitute your vial.

  • Enter the mass of the reagent and the desired reconstitution concentration as well as the correct units
  • Click the “Calculate” button
  • The answer appears in the Volume (to add to vial) box
In vivo Formulation Calculator (Clear solution)
Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)
Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)
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Calculation results

Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
             (2) Be sure to add the solvent(s) in order.

Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT00534469 Active
Recruiting
Drug: busulfan
Drug: cytarabine
Leukemia City of Hope Medical Center February 8, 2000 Phase 2
NCT00638898 Active
Recruiting
Drug: busulfan
Drug: melphalan
Solid Tumor
Ewing Sarcoma
City of Hope Medical Center February 26, 2007 Phase 1
NCT01798004 Active
Recruiting
Drug: Busulfan
Drug: Cisplatin
Ganglioneuroblastoma
Stage 1 Neuroblastoma
Children's Oncology Group April 8, 2013 Phase 1
NCT00534430 Active
Recruiting
Drug: busulfan
Drug: etoposide
Myelodysplastic Syndromes
Leukemia
City of Hope Medical Center February 29, 2000 Phase 2
NCT02250937 Active
Recruiting
Drug: Busulfan
Drug: Cladribine
Acute Myeloid Leukemia
Myelodysplastic Syndrome
M.D. Anderson Cancer Center October 27, 2014 Phase 2
Biological Data
  • Monitoring of male germ cell apoptosis following busulfan treatment by the TUNEL and annexin V assays. FEBS Lett . 2004 Sep 24;575(1-3):41-51.
  • Male germ cell-specific gene expression levels in busulfan-treated adult testis. FEBS Lett . 2004 Sep 24;575(1-3):41-51.
  • Engraftment of Ly-5.1 donor lymphocytes in (A) peripheral blood, (B) lymph nodes, and (C) spleens of C57BL/6 Ly-5.2 mice transplanted after graded doses (10 mg/kg to 100 mg/kg) of busulfan or TBI (900 rad). Blood . 1991 Dec 15;78(12):3312-6.
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