DNA Alkylator

Carmustine is a chemotherapy drug used to treat cancer. Neuronal cell proliferation, tumor cytoplasm, and intact N-benzoyltransferase (NAT) activity of 2-aminobenzoic acid (AF) and p-aminobenzoic acid (PABA) are all reduced by carmustine (8, 80, and 800 μM). The DNA-AF addition complex rises with the development of tumor nerve growth cells, while carmustine lowers it [1].

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Carmustine and lomustine are nitrosourea antitumor chemotherapeutic agents which were used to determine whether or not they could affect arylamine N-acetyltransferase (NAT) activity and DNA-2-aminofluorene adducts in rat glial tumor cell line (C6 glioma). The NAT activity was measured by high preformance liquid chromatography (HPLC) assaying for the amounts of N-acetyl-2-aminofluorene (AAF) and N-acetyl-p-aminobenzoic acid (N-Ac-PABA) and remaining 2-aminofluorene (AF) and p-aminobenzoic acid (PABA). The results indicate that NAT activity in glial tumor cell cytosols and intact tumor cells were decreased by carmustine and lomustine in a dose-dependent manner. The apparent values of Km and Vmax of NAT from rat glial tumor cell also decreased after co-treatment of carmustine and lomustine in both examined cytosols and intact cells. Following exposure of glial tumor cells to the various concentrations of AF with or without co-treatment with carmustine and lomustine, DNA-AF adducts were determined by using gamma-[32p]-dATP and HPLC. The DNA-AF adducts in rat glial tumor cells were decreased by co-treatment with carmustine and lomustine. This report is the first demonstration to show carmustine and lomustine did inhibit rat glial tumor cells NAT activity and DNA-AF adduct formation.[1]

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Carmustine inhibited arylamine N-acetyltransferase (NAT) activity in rat glial tumor cell (C6 glioma) cytosols and intact cells in a dose-dependent manner, using both 2-aminofluorene (AF) and p-aminobenzoic acid (PABA) as substrates. At concentrations of 8, 80, and 800 µM, NAT activity decreased by 0.20–0.78-fold for AF and 0.17–0.79-fold for PABA in cytosols, compared to controls. [1]
In intact rat glial tumor cells co-treated with 80 µM Carmustine, NAT activity (measured as production of acetylated products from AF and PABA) decreased by 43–48% for AF and 45–52% for PABA over incubation periods of 6 to 24 hours. [1]
Carmustine (80 µM) decreased the formation of DNA-2-aminofluorene (AF) adducts in rat glial tumor cells by 40% when co-incubated with 30 µM AF and by 40% when co-incubated with 60 µM AF. [1]
Carmustine (80 µM) altered the kinetic constants of NAT in rat glial tumor cells. In cytosols, the apparent Km for AF decreased from 1.28 ± 0.28 mM (control) to 0.56 ± 0.12 mM, and Vmax decreased from 4.17 ± 0.66 to 2.49 ± 0.48 nmol/min/mg protein. In intact cells, Km for AF decreased from 1.12 ± 0.17 mM to 0.68 ± 0.14 mM, and Vmax decreased from 3.88 ± 0.53 to 2.49 ± 0.44 nmol/min/mg protein. [1]

In comparison to stents level (GSSG) and reduced glutathione (GSH)/GSSG value, carmustine (BCNU; 25 mg/kg, ip) led to greater levels of death to body weight, the ratio of bound bilirubin, external bile flow, and oxidized glutathione [2].

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This study investigated the effect of trimetazidine (TMZ), known as an anti-oxidant agent, on intrahepatic cholestasis caused by Carmustine (BCNU) in rats. Rats were assigned into four groups. The first group (Saline) consisted of 12 rats, which were injected with 2 ml/kg of saline intraperitoneally (IP) 48 h before the study. The second group (corn oil group, n=15), which were injected with 2 ml/kg of corn oil IP 48 h before the study. The third group (BCNU group, n=16), which were injected with 2 ml/kg of corn oil+25 mg/kg BCNU IP 48 h before the study. The fourth group (TMZ group, n=12), which were injected with 2.5 mg/kg per day of TMZ IP, administered at the same hour of the day as a single-dose. Twelve hour after the first dose of TMZ, corn oil 2 ml/kg+BCNU 25 mg/kg IP were injected, and the rats were included in the study 48 h after the administration of corn oil+BCNU. Following a pentobarbital anaesthesia, abdomen was opened with incision, a cannula was placed into the channel of choledocus, and the amount of bile was measured per hour. Then intracardiac blood sample was taken, and consequently centrifuged to obtain the plasma. Finally, the rats were killed with cervical dislocation, and their livers were removed and weighted. In addition to histopathological examination of liver, the levels of malon dialdehyde (MDA), oxidised glutation (GSSG), and reduced glutation (GSH) were detected. Also the osmolality of bile and plasma was estimated in mOsm/kg. As a result, the biliary flow was seen to decrease in BCNU group (P<0.005), but to be normal in TMZ group. The serum level of conjugated biluribin was higher in BCNU group compared to other groups (P<0.05 for each). Although the level of total glutation was lower (P<0.005) in TMZ group, GSH/GSSG ratio was normal. These findings suggest that TMZ has a protective effect on intrahepatic cholestasis caused by BCNU.[2]

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A single intraperitoneal dose of Carmustine (BCNU) (25 mg/kg) administered to Wistar Albino rats induced intrahepatic cholestasis. This was evidenced by significantly reduced biliary flow, increased plasma conjugated bilirubin levels, decreased glutathione levels, and increased liver malondialdehyde (MDA) levels compared to control groups. Histopathological examination of the liver in the BCNU-treated group showed mild cellular edema and mononuclear cellular infiltrations. [2]

2-Aminofluorene (AF) and p-Aminobenzoic acid (PABA) N-acetylation is determined in an Acetyl-CoAdependent manner. The assay system's incubation mixtures have a total volume of 90 μL and include glial tumor cells cytosols, diluted as needed, in 50 μL of lysis buffer (20 mM Tris/HCl, pH 7.5, 1 mM DTT and 1 mM EDTA), 20 μL of an Acetyl-CoA recycling mixture of 50 mM Tris-HCl (pH7.5), 0.2 mM EDTA, 2 mM DTT, 15 mM acetylcamitine, 2U/mL carnitine acetyltransferase, and AF or PABA at designated concentrations. Addition of 20 μL of acetyl-CoA initiates the reactions. Acetyl-CoA is replaced in the control reactions with 20 μL of distilled water. The final concentrations of AcCoA and PABA for the single point activity measurements are 0.5 mM and 0.1 mM, respectively. 50 μL of 20% trichloroacetic acid is used to stop the PABA reactions and 100 μL of acetonitrile is used to stop the AF reactions after the reaction mixtures, either with or without specific concentrations of carmustine and lomustine, are incubated for 10 minutes at 37°C. Every reaction, including controls and experiments, is carried out in triplicate[1].

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Arylamine N-Acetyltransferase (NAT) Activity Assay: The assay measured Acetyl-CoA-dependent N-acetylation of substrates (AF or PABA). Reaction mixtures (total volume 90 µL) contained rat glial tumor cell cytosol or intact cells, lysis buffer (Tris/HCl, DTT, EDTA), an Acetyl-CoA recycling mixture (containing acetylcarnitine and carnitine acetyltransferase), specific concentrations of AF or PABA, and Acetyl-CoA to initiate the reaction. Reactions were incubated at 37°C for 10 minutes and stopped with trichloroacetic acid (for PABA) or acetonitrile (for AF). Acetylated products (N-acetyl-2-aminofluorene, AAF; or N-acetyl-p-aminobenzoic acid, N-Ac-PABA) and remaining substrate were quantified by HPLC using C18 reversed-phase columns with specific mobile phases and UV detection. NAT activity was expressed as nmol acetylated product formed per minute per mg of cytosolic protein. [1]

Intact Cell NAT Activity Assay: Rat glial tumor cells (C6 glioma) were seeded at 1×10⁶ cells/ml in 24-well plates with RPMI 1640 medium containing glutamine and 10% fetal calf serum. Cells were co-incubated with AF or PABA and various concentrations of Carmustine at 37°C in a 5% CO₂ atmosphere for specified times (e.g., 6, 12, 18, 24 hours). After incubation, cells and media were centrifuged. For AF experiments, the supernatant was extracted with ethyl acetate/methanol (95:5), evaporated, redissolved in methanol, and analyzed for AAF by HPLC. For PABA experiments, aliquots of the supernatant were directly analyzed for N-Ac-PABA by HPLC. [1]
DNA Adduct Formation Assay: Rat glial tumor cells were incubated with AF with or without Carmustine (80 µM) for 18 hours. Cells were harvested, and DNA was isolated using a commercial DNA isolation kit. Isolated DNA was hydrolyzed to nucleotides, and adducted nucleotides were labeled with [γ-³²P]ATP using polynucleotide kinase. Labeled adducted nucleotides were separated by HPLC using a C18 reversed-phase ion-pairing column with a gradient elution of potassium phosphate buffer (pH 6.0) and acetonitrile. Radioactivity in collected fractions was quantified by scintillation counting. DNA adduct levels were calculated as pmol adduct per mg DNA. [1]

Rats: Rats are randomly assigned to four groups after being weighted individually before beginning the study and having their weights recorded. There are twelve rats in Group I (the saline group). The study includes the rats 48 hours after they receive an intraperitoneal (IP) injection of 2 mL/kg of saline 48 hours prior to the study. Fifteen rats make up Group II (corn oil group). The rats receive a 2 mL/kg injection of corn oil (vehicle) IP 48 hours prior to the investigation. Sixteen rats make up Group III (Carmustine group). For three days, the same hour of the day, a single-dose of 1 mL of saline IP is injected into these rats. The rats are added to the study 48 hours after the first dose of saline is administered, and twelve hours later, they receive injections of corn oil (2 mL/kg) and carmustine (25 mg/kg IP). There are twelve rats in Group IV (the trimetazidine group). For three days, these rats receive a single-dose injection of 2.5 mg/kg of trimetazidine (TMZ) IP at the same hour every day. Corn oil (2 mL/kg) and carmustine (25 mg/kg IP) are injected 12 hours after the first dose of TMZ, and the rats are added to the study 48 hours later[2].

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Wistar Albino rats weighing 200-350 g were used. Carmustine (BCNU) was dissolved in corn oil and administered via a single intraperitoneal injection at a dose of 25 mg/kg. Rats in the BCNU group received saline injections (1 ml/day) for 3 days prior to BCNU administration. Twelve hours after the first saline dose, a single dose of corn oil (2 ml/kg) plus BCNU (25 mg/kg) was injected intraperitoneally. Animals were included in the study 48 hours after BCNU administration. Prior to terminal procedures, rats were anesthetized with phenobarbital (60 mg/kg, i.p.), the bile duct was cannulated, and bile flow was collected and measured for 60 minutes. Blood samples were taken intracardially, and livers were removed for weight measurement, biochemical analysis (MDA, GSH, GSSG), and histopathological examination. [2]

Absorption, Distribution and Excretion
Bioavailability ranges from 5% to 28%. Approximately 60% to 70% of the total dose is excreted in the urine within 96 hours, and approximately 10% is excreted as respirable carbon dioxide. The mean steady-state volume of distribution after intravenous infusion of carmustine is 3.25 L/kg. Due to its high lipid solubility, carmustine and/or its metabolites readily cross the blood-brain barrier. Significant concentrations of carmustine are observed almost immediately in cerebrospinal fluid following intravenous administration; reportedly, cerebrospinal fluid radioactivity levels are 15% to 70% of concurrent plasma concentrations. Carmustine metabolites are distributed into breast milk, but at lower concentrations than in maternal plasma. The absorption of the copolymers contained in carmustine tablets in humans has not been evaluated. Plasma concentrations of carmustine after intracranial implantation of carmustine tablets in humans have not been determined; however, carmustine was not detected in plasma in rabbits that underwent implantation surgery with tablets containing 3.85% carmustine. When carmustine tablets are exposed to an aqueous environment in the resection cavity, the anhydride bonds in the copolymer hydrolyze, releasing carmustine and two monomers: carboxyphenoxypropane and sebacic acid. The carmustine contained in the tablet diffuses into the surrounding brain tissue. The metabolism and excretion of the copolymer contained in the carmustine tablet in humans have not been evaluated. Animal studies have shown that more than 70% of the copolymer degrades within 3 weeks after carmustine tablet implantation in brain tissue; after copolymer hydrolysis, carboxyphenoxypropane is excreted via the kidneys, while sebacic acid (an endogenous fatty acid) is metabolized in the liver and excreted as carbon dioxide. In humans, chip residues can be observed on brain imaging scans or during subsequent surgeries for up to 8 months after intracranial implantation. Analysis of chip residues removed from two patients approximately 2-3 months after implantation revealed that the main components were water and monomers, with only trace amounts of carmustine detected.
Differential pulse polarography was used to determine the disappearance of BCNU in plasma, liver, kidney, lung, brain, spleen, tumor tissue, and epididymal adipose tissue of tumor-bearing rats and healthy animals after intravenous injection. Polarographic analysis detected only BCNU, without its degradation products. The level of BCNU in the liver of tumor-bearing animals was significantly lower than that in healthy rats (approximately 10-fold lower). The kinetics of BCNU in plasma, kidney, lung, and brain were calculated using a bi-exponential fitting method, but no difference was found between healthy rats and Walker tumor-bearing rats. BCNU was cleared from the adipose tissue of tumor-bearing animals more rapidly than in normal animals.
Approximately 40 minutes after injection, BCNU lost its antitumor activity, and unmetabolized BCNU was undetectable in plasma within minutes of administration. Following intraperitoneal, subcutaneous, or oral administration, BCNU rapidly distributed to most tissues, including the brain and cerebrospinal fluid. Excretion is primarily via urine; mice excrete the fastest (80% of the dose is excreted within 24 hours), while monkeys and dogs excrete more slowly. Metabolism/Metabolites: Metabolism occurs mainly in the liver, rapidly, producing active metabolites. Metabolites may persist in plasma for several days. This study investigated the in vitro metabolism of the anticancer drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in the liver microsomes of male Fischer 344 rats. The previously identified product, 1,3-bis(2-chloroethyl)urea (BCU), was confirmed as the major metabolite. Stable isotope labeling and mass spectrometry analysis of the isolated metabolites showed that BCU is entirely generated from the metabolic denitrosation of BCNU. This study determined the chemocatabolism rate of BCNU in the liver microsomes of NADPH-deficient rats, as well as the metabolic disappearance rate of BCNU in the NADPH-added formulation, and compared it with the BCU metabolic generation rate measured under the same conditions. Within the experimental error range, the NADPH-dependent metabolic rate of BCNU and the production rate of BCU were equal. Studies have found that BCNU can inhibit the metabolism of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in 9000 g of rat liver supernatant. It is primarily metabolized by the liver; metabolism is rapid, producing active metabolites. These metabolites can persist in plasma for several days. Elimination pathway: Approximately 60% to 70% of the total dose is excreted in the urine within 96 hours, and approximately 10% is excreted as carbon dioxide (CO2) produced by respiration. Half-life: 15-30 minutes.

Toxicity Summary
Carmustine can cause DNA and RNA cross-linking, thereby inhibiting DNA synthesis, RNA production, and RNA translation (protein synthesis). Carmustine also binds to and modifies (carbamylated) glutathione reductase, ultimately leading to cell death. Hepatotoxicity
Up to 25% of patients receiving carmustine treatment experience a mild and transient increase in serum transaminase levels. Because carmustine is often used in combination with other drugs, its role in causing these serum enzyme elevations is not always clear. These abnormalities are usually transient, asymptomatic, and do not require dose adjustment. Clinically significant carmustine-induced liver injury is limited to a small number of cases of cholestatic hepatitis and the more common case of hepatic sinusoidal obstruction syndrome, which is mainly seen when used at high doses or as a pretreatment drug for hematopoietic stem cell transplantation. Hepatic sinusoidal obstruction syndrome usually develops within two to three weeks after bone marrow ablation and is characterized by sudden onset of abdominal pain, weight gain, ascites, and a significant increase in serum transaminase (and lactate dehydrogenase) levels, followed by jaundice and liver dysfunction. The severity of hepatic sinusoidal obstruction syndrome varies, ranging from transient, self-limiting injury to acute liver failure. Diagnosis is typically based on clinical features such as liver tenderness and enlargement, weight gain, ascites, and jaundice appearing within three weeks of chemotherapy. Liver biopsy is diagnostically valuable, but it is generally not recommended due to the potential for severe thrombocytopenia following hematopoietic stem cell transplantation.
Probability score: E (Unproven but suspected cause of clinically significant liver injury, especially when used for bone marrow ablation).

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Effects during pregnancy and lactation
◉ Overview of medication use during lactation
There is currently no information regarding the use of carmustine during lactation. Most sources consider breastfeeding contraindicated during maternal treatment with anti-tumor drugs, especially alkylating agents such as carmustine. The manufacturer recommends discontinuing breastfeeding during carmustine treatment and for one month after the last dose.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
Some evidence suggests that carmustine may increase serum prolactin levels. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed.

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Protein Binding
80%Toxicity Data
The oral LD50 for rats and mice is 20 mg/kg and 45 mg/kg, respectively.

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Drug Interactions
In patients treated with both carmustine and phenytoin sodium, serum concentrations of phenytoin sodium may be decreased. Patients treated with carmustine should have their serum phenytoin concentrations closely monitored and the dose adjusted as needed.
Changes in the quality and quantity of the tear film, leading to corneal and conjunctival epithelial damage, have been reported in patients receiving high doses of carmustine and mitomycin. Cimetidine may enhance the myelosuppressive effects (e.g., neutropenia, agranulocytosis) of myelosuppressive drugs (e.g., alkylating agents, antimetabolites) or therapies (e.g., radiotherapy). Concomitant cimetidine treatment has been reported to enhance neutropenia and thrombocytopenia induced by carmustine alone or in combination with radiotherapy.

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Non-human toxicity values
Oral LD50 in rats: 20 mg/kg
Intraperitoneal LD50 in rats: 17,420 ug/kg
Subcutaneous LD50 in rats: 83,200 ug/kg
Intravenous LD50 in rats: 13,800 ug/kg
For more complete non-human toxicity data for carmustine (9 out of 9), please visit the HSDB record page.

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Compared to baseline, rats showed a significant decrease in body weight within 48 hours following intraperitoneal injection of 25 mg/kg carmustine (BCNU) (P<0.005). It induces intrahepatic cholestasis, characterized by decreased bile flow, increased conjugated bilirubin, oxidative stress (increased malondialdehyde and decreased glutathione), and mild liver histological damage (cellular edema and mononuclear cell infiltration). [2]

[1]. Hung CF. Effects of carmustine and lomustine on arylamine N-acetyltransferase activity and 2-aminofluorene-DNA adducts in rat glial tumor cells. Neurochem Res. 2000 Jun;25(6):845-51.

[2]. The effect of trimetazidine on intrahepatic cholestasis caused by carmustine in rats. Hepatol Res. 2001 May 1;20(1):133-143.

Therapeutic Uses
BiCNU is indicated for palliative treatment of the following conditions, as a monotherapy or in combination with other approved chemotherapy agents: Brain tumors—glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumors. Multiple myeloma—in combination with prednisone. Hodgkin lymphoma—as second-line treatment, in combination with other approved agents for patients who have relapsed during first-line therapy or who have failed first-line therapy. Non-Hodgkin lymphoma—as second-line treatment, in combination with other approved agents for patients who have relapsed during first-line therapy or who have failed first-line therapy. Bis(chloroethyl)nitrosourea has been used as an antineoplastic agent since 1971 for the treatment of Hodgkin lymphoma, multiple myeloma, and primary or metastatic brain tumors. It has been reported to have antiviral, antibacterial, and antifungal activities, but there is currently no evidence to support its use in these areas. Previous Uses.
Drug (Veterinary): A chemotherapy regimen using carmustine in combination with vincristine and prednisone was tested in dogs with multicentric malignant lymphosarcoma. Of the 7 dogs treated, 6 (85.7%) achieved complete remission. 1 dog achieved partial remission. The median survival was 224 days (mean 386 days), and the median duration of remission was 183 days (mean 323 days). Significant neutropenia was observed after carmustine administration. No significant changes were observed in platelet and red blood cell counts during treatment, and no chemotherapy-related abnormalities were found in serum biochemistry. These results suggest that carmustine is an effective alternative therapy for canine lymphosarcoma.
Drug Warning /Black Box Warning/ Warning: BiCNU (carmustine for injection) should be used under the supervision of a qualified veterinarian experienced in the use of cancer chemotherapy drugs. Bone marrow suppression, particularly thrombocytopenia and leukopenia, can lead to bleeding and serious infections, especially in immunocompromised patients. This is the most common and serious toxicity of BiCNU. Because the primary toxicity is delayed bone marrow suppression, blood cell counts should be monitored weekly for at least 6 weeks after administration. At the recommended dose, the dosing interval of BiCNU should not be less than 6 weeks. BiCNU bone marrow toxicity is cumulative; therefore, dose adjustments must be considered based on the lowest blood cell count following the previous dose. Pulmonary toxicity of BiCNU appears to be dose-related. Patients with a cumulative dose exceeding 1400 mg/m² are at significantly higher risk than those with lower doses. Delayed pulmonary toxicity can occur years after treatment and can be fatal, especially in patients treated in childhood. Carmustine, administered via parenteral, intravenous, and other possible routes, can cause systemic reactions, including nausea or vomiting, decreased white blood cell and platelet counts, bone marrow damage, and potentially fatal respiratory damage such as pulmonary fibrosis, dyspnea, and cyanosis. In a study of 17 children aged 1 to 16 years who received carmustine at a cumulative dose ranging from 770 to 1800 mg/m² and concurrently received cranial radiotherapy for intracranial tumors, 8 children (47%) died from delayed pulmonary fibrosis, including all 5 children under 5 years of age who received initial treatment. Pulmonary fibrosis was observed up to 17 years after carmustine treatment. Clinical manifestations included chest X-ray showing pulmonary hypoplasia with upper lung field atrophy, and chest CT scan showing an abnormal pattern of upper lung field fibrosis; gallium scans were normal. Delayed decline in lung function was observed in all long-term survivors in the study. Carmustine-induced pulmonary fibrosis can progress slowly and lead to death. Patients receiving systemic carmustine treatment have experienced pulmonary toxicity, including acute or delayed pulmonary fibrosis leading to death. Pulmonary toxicity characterized by lung infiltration and/or fibrosis has been reported in patients receiving carmustine or related nitrosoureas within 9 days to 43 months after treatment. Most reported cases of pulmonary toxicity occurred in patients receiving long-term carmustine treatment with a total dose exceeding 1400 mg/m²; however, pulmonary fibrosis can occur even with lower total doses. Other risk factors include a history of lung disease and the duration of carmustine treatment. Pulmonary toxicity can sometimes progress rapidly and/or be fatal. For more complete data on drug warnings for carmustine (41 total), please visit the HSDB records page. Pharmacodynamics: Carmustine is a nitrosourea that is used as monotherapy or in combination with other approved chemotherapy agents for the palliative treatment of brain tumors, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma. Although carmustine is generally believed to alkylate DNA and RNA, it does not exhibit cross-resistance with other alkylating agents. Like other nitrosoureas, carmustine may also inhibit a variety of key enzymatic processes by carbamylation of amino acids in proteins. Carmustine is a nitrosourea antitumor chemotherapeutic drug primarily used to treat central nervous system diseases. [1] This study is the first to demonstrate that carmustine inhibits the activity of arylamine N-acetyltransferase (NAT) in rat glioma cells (C6 glioma) in vitro and reduces the formation of DNA-arylamine adducts. [1] The inhibitory effect of carmustine on NAT activity is dose-dependent and affects its kinetic constants (Km and Vmax), suggesting that it may be a non-competitive inhibitor. The hypothesized mechanism involves carmustine carbamylation of lysine residues in the NAT protein. [1]
Carmustine can interfere with the initiation steps of aromatic amine-induced chemical carcinogenesis by reducing the formation of DNA adducts. [1]

C5H9CL2N3O2

214.0499

213.007

C, 28.06; H, 4.24; Cl, 33.12; N, 19.63; O, 14.95

154-93-8

Carmustine-d8

2578

Light yellow solid (low temperature); soild if <30°C; liquid if >30°C

1.5±0.1 g/cm3

404ºC

30 °C(lit.)

1.549

1.3

1

3

4

12

156

0

ClC([H])([H])C([H])([H])N(C(N([H])C([H])([H])C([H])([H])Cl)=O)N=O

DLGOEMSEDOSKAD-UHFFFAOYSA-N

InChI=1S/C5H9Cl2N3O2/c6-1-3-8-5(11)10(9-12)4-2-7/h1-4H2,(H,8,11)

1,3-bis(2-chloroethyl)-1-nitrosourea

NSC409962; NCI-C04773; NCIC04773; NCI C04773; Nitrumon; NSC 409962; NSC-409962; SK 27702; SRI 1720; DTI 015;; FDA 0345; BCNU Becenum; Bi CNU; BiCNU; 154-93-8; 1,3-Bis(2-chloroethyl)-1-nitrosourea; BCNU; Carmustin; Carmubris; Gliadel; Carmustine

29241900

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ≥ 35 mg/mL (~163.5 mM)
H2O: ~100 mg/mL (~467.2 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (9.72 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 2: ≥ 2.08 mg/mL (9.72 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.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (9.72 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 of corn oil and mix evenly.

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Solubility in Formulation 4: 5%DMSO+ 40%PEG300+ 5%Tween 80+ 50%ddH2O: 2.0mg/ml (9.34mM)

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Solubility in Formulation 5: 100 mg/mL (467.18 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)