5-ブロモ-2'-デオキシウリジン

10 to 50 mg/mL at 72 °F (NTP, 1992)

Water 10 - 20 (mg/mL)

Dimethylacetamide ~ 200 (mg/mL)

1 N NaOH > 400 (mg/mL)

Dimethylsulfoxide ~ 160 (mg/mL)

Acetone ~ 4 (mg/mL)

365 to 369 °F (NTP, 1992)

187-189 °C

Solid BrdU is stable in the dark to heat and humidity for 3 months at temperatures below 60 °C. On exposure to sunlight there is discoloration to grayish-brown. Ultraviolet irritations of frozen aqueous solutions of BrdU results in liberation of bromide ion and formation of a debrominated dimer, while radiolysis of aqueous solutions in the presence of oxygen yields mainly bromide, isodialuric acid deoxyriboside, and smaller amounts of various oxygenated derivatives.

Bulk: The bulk drug should be stored in tightly closed containers at controlled room temperature. Solution: BUdR solutions (0.5 and 25 mg/mL) are stable for at least seven days at room temperature.

Danger

H340 (83.3%): May cause genetic defects [Danger Germ cell mutagenicity]

P203, P280, P318, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 54 reports by companies from 10 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

Fire, Explosion and Reactivity Hazard Data 1. BrdU does not require special fire-fighting procedures or equipment and does not present unusual fire and explosion hazards. 2. The presence of strong alkali, acid, and/or oxidant probably contributes to instability of BrdU. 3. No incompatibilities are known. 4. BrdU does not require non-spark equipment.

Store solid BrdU and its solutions in dark-colored, tightly closed containers, preferably under refrigeration. Avoid exposure to light and moisture. Store working quantities of BrdU and its solutions in an explosion-safe refrigerator in the work area.

Decontamination: Turn off equipment that could be affected by BrdU or the materials used for cleanup. ... Wipe off surfaces with water, then wash with copious quantities of water. Glassware should be rinsed in a hood with soap and water. Animal cages should be washed with water.

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Disposal: No waste streams containing BrdU /should/ be disposed of in sinks or general refuse. Surplus BrdU or chemical waste streams contaminated with BrdU /should/ be handled as hazardous chemical waste ... . Nonchemical waste (e.g., animal carcasses and bedding) containing BrdU /should/ be handled and packaged for incineration ... . Potentially infectious waste (e.g., tissue cultures) containing BrdU /should/ be disinfected by heat using a standard autoclave treatment and packaged for incineration, as above. Burnable waste (e.g., absorbent bench top liners) minimally contaminated with BrdU /should/ be handled as potentially infectious waste and packaged for incineration, as above. Absorbent materials (e.g., associated with spill cleanup) grossly contaminated /should/ be handled in accordance with the chemical waste disposal system.

The limited available research has not concluded how extensively BrDu is metabolized making it imperative that all potentially contaminated carcasses, bedding, and other nonsharps materials be disposed of as regulated medical waste through incineration. All contaminated sharps waste materials must be placed in proper sharps container and disposed of as regulated medical waste.

Principal investigators /should/ develop and implement standard operating procedures (SOPs) by which laboratory staff will prepare/administer BrDu with minimal potential for exposure. All tasks having potential for occupational BrDu exposure (mixing of doses, dose preparation, administering of injections, etc.) /should/ only be conducted by competent staff whom have received appropriate training (OSHA: "Worker Right to Know") regarding the specific BrDu-related health and safety risks, SOPs, and procedures to be followed in event of an exposure incident.

Avoid formation and breathing of aerosols. Laboratory operations should be conducted in a fume hood, glove box, or ventilated cabinet.

Avoid skin contact. If exposed, wash with soap and cold water. Avoid washing with solvents and exposure to UV light. Avoid rubbing of skin or increasing its temperature. For eye exposure, irrigate immediately with large amounts of water. ...

In case of laboratory spill, wear protective clothing during cleanup. Avoid skin contact or breathing of aerosols. Use water to dissolve compound. Use absorbent paper to mop up spill. Wash down area with soap and water.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

Staff involved with any tasks where potential for BrDu exposure exists must don the following PPE: (a) examination gloves, (b) safety glasses or safety goggles (ANSI Z-87 approved, (c) lab coat, (d) appropriate laboratory attire, (e) if aerosol exposure threat exists suitable respiratory protection must be provided. Whenever feasible, procedures with the potential for producing BrDu aerosols should be conducted with a certified biosafety cabinet.

EYES: irrigate opened eyes for several minutes under running water. INGESTION: do not induce vomiting. Rinse mouth with water (never give anything by mouth to an unconscious person). Seek immediate medical advice. SKIN: should be treated immediately by rinsing the affected parts in cold running water for at least 15 minutes, followed by thorough washing with soap and water. If necessary, the person should shower and change contaminated clothing and shoes, and then must seek medical attention. INHALATION: supply fresh air. If required provide artificial respiration.

5-Bromo-2'-deoxyuridine (BrdUrd) was found to increase the cytotoxicity induced by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and cisplatin in human glioma cells. At a fixed concentration of BrdUrd and BCNU, the greatest cell loss was observed in exponentially growing cells. As cells approached plateau growth, cytotoxicity was reduced as indicated by greater cell viability. Under varying growth conditions the percentage of thymine replacement by bromouracil in DNA, as determined by gas chromatography/mass spectrometry analysis, declined as cultures approached maximum density. These data indicate BrdUrd must be incorporated into DNA for the enhanced effect to be observed. In exponentially growing cells, sensitization was dependent upon both the concentration of BrdUrd and alkylating agent. Using regression analysis (at 95% CL), a relationship between the level of bromouracil in DNA and the extent of enhanced cytotoxicity was observed at two concentrations of BCNU (r2 = 0.99, 0.96). Although it is known that bifunctional alkylating agents exert cytotoxicity by forming cross-links between cDNA strands, increased cross-link formation was not observed in BrdUrd substituted DNA as determined by alkaline elution. The data suggest that DNA damage induced by halogenated pyrimidines may not involve interstrand cross-links and that these agents may be useful in the treatment of glioma in combination with alkylating agents.

5-bromodeoxyuridine is a mutagen (causes mutations), a cytotoxin, a teratogen and a weak carcinogen. The primary harmful effects are genetic mutation, anemia, reproductive disorders (fetal death or abnormality), cataracts, and skin irritation. It can cause respiratory tract irritation if inhaled, skin irritation if it contacts the skin and eye irritation if it contacts the eyes. As a reproductive toxin BrDU would be considered a “particularly hazardous substance” under the OSHA lab standard.

5-bromodeoxyuridine acts on DNA. It induces a random DNA point mutation via base substitution. The base pair will change from an A-T to a G-C or from a G-C to an A-T after a number of replication cycles. As a thymine analog, 5-bromodeoxyuridine normally pairs with adenine.

/HUMAN EXPOSURE STUDIES/ /The authors/ report here the results of a Phase I study conducted to determine the toxicity and serum levels that could be tolerated by patients receiving i.v. bromodeoxyuridine concomitantly with radiation therapy. Because of severe thrombocytopenia and leukopenia that was produced in three patients treated by a 96 hour infusion of bromodeoxyuridine at a dose of 1.5 g/sq m/24 hours, the dose was reduced to 0.8 g/sq m/24 hours in these patients and the remaining 9 patients in the study group. Even at this dosage, myelotoxicity was observed.

/SIGNS AND SYMPTOMS/ Twelve patients were treated with continuous intravenous (24-hour) infusions of bromodeoxyuridine (BUdR) at 650 or 1,000 mg/sq m/d for up to two weeks. Myelosuppression, especially thrombocytopenia, was the major systemic toxicity and limited the infusion period to nine to 14 days. However, bone marrow recovery occurred within seven to ten days, allowing for a second infusion in most patients.

/ALTERNATIVE and IN VITRO TESTS/ /The authors/ identified genes that immediately respond to 5-bromodeoxyuridine (BrdU) in SUSM-1, an immortal fibroblastic line, with DNA microarray and Northern blot analysis. At least 29 genes were found to alter gene expression greater than twice more or less than controls within 36 h after addition of BrdU. They took several different expression patterns upon addition of BrdU, and the majority showed a significant alteration within 12 hr. When compared among SUSM-1, HeLa, and TIG-7 normal human fibroblasts, 19 genes behaved similarly upon addition of BrdU. In addition, 14 genes, 9 of which are novel as regards senescence, behaved similarly in senescent TIG-7 cells. The genes do not seem to have a role in proliferation or cell cycle progression. These results suggest that the early BrdU-responsive genes represent early signs of cellular senescence and can be its new biomarkers.

/GENOTOXICITY/ The existence of a high frequency of spontaneous sister-chromatid exchanges (SCEs) in Bloom syndrome (BS) has thus far been supported by data on a small number of BS cell lines. To examine the cause of baseline SCEs more broadly, the frequencies of SCEs, as well as chromosomal aberrations (CAs) in 4 additional BS fibroblast strains were compared, under different assay and cell culture conditions, with those of normal cells in the range of approximately 0.9-90% 5-bromodeoxyuridine (BrdUrd) substitution into template DNA. SCEs at low levels of BrdUrd substitution were detected by an extremely sensitive immunofluorescent technique. From approximately 0.9% to 4.5% BrdUrd substitution, the SCE frequency in BS cells remained constant, at a level (40/cell) 8 times higher than that of normal cells. As BrdUrd substitution increased further, the SCE frequency in BS cells increased almost linearly, reaching 70-100 per cell at approximately 90% substitution, while the SCE increment in control fibroblasts was less than 5 per cell. Analysis of SCEs in 3 successive replication cycles similarly revealed that the SCE increment in BS cells depended on BrdUrd only at a high BrdUrd substitution level. In contrast to data on SCEs, CA induction by incorporated BrdUrd in BS cells was only slightly higher than that in normal cells. Thus, BS cells are extremely sensitive to BrdUrd for SCE induction, but much less so for CA induction.

For more Human Toxicity Excerpts (Complete) data for BROMODEOXYURIDINE (9 total), please visit the HSDB record page.

/LABORATORY ANIMALS: Acute Exposure/ The acute toxicity of BrdU appears to be quite low in rodents; various authors list acute LD50a by various parenteral routes in mice and rats to be in the range of 1.5-4 g/kg, and by the oral route 8.4 g/kg.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ No clinical or hematological signs of acute toxicity were noticed in rats receiving up to 500 mg/kg/day for 28 days in their drinking water.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Subacute effects in rodents include inflammatory skin lesions, decreased weight and hair growth, and hematological effects (anemia, leukocytopenia, thrombocytopenia).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ This study was designed to examine the pathogenesis of bromodeoxyuridine-induced (BrdU) clefts of the secondary palate in mice. Intraperitoneal injections of BrdU (500 mg/kg body weight) were given on days 11 and 12 to some pregnant mice and on days 12 and 13, and days 11, 12 and 13 to others. Evaluation of craniofacial relations and palate development in BrdU-treated mice revealed inhibition of vertical development of the palatal shelves, mandibular hypoplasia which led to failure of downward displacement of the tongue and the creation of an obstacle to reorientation of the palatal shelves. The results of this study demonstrate a strong correlation between induction of cleft palate and the presence of structural alterations in the mandible, and the mechanism of BrdU-induced cleft palate resembles the defect in the Pierre Robin anomaly.

For more Non-Human Toxicity Excerpts (Complete) data for BROMODEOXYURIDINE (15 total), please visit the HSDB record page.

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

Rat(po): LD50: 8400 mg/kg

Rat(ip): LD50: 1500 mg/kg

Rat(sc): LD50: 3900 mg/kg

Rat(iv): LD50: 2320 mg/kg

Mouse(po): LD50: 9100 mg/kg

Mouse(ip): LD50: 3050 mg/kg

LD50 Mouse iv 2500 mg/kg

LD50 Mouse sc 3500 mg/kg

LD50 Mouse ip 3050 mg/kg

LD50 Mouse oral 9100 mg/kg

For more Non-Human Toxicity Values (Complete) data for BROMODEOXYURIDINE (8 total), please visit the HSDB record page.

The principal effects of BrdU in the animal body result from its incorporation into tissue DNA in place of thymidine (the 5-methyl analog of BrdU). Since chromosomal proteins have a greater affinity for BrdU-substituted DNA than for unsubstituted DNA, this results in a variety of chromosomal aberrations including chromosome lengthening, chromatid breakage, and effects on sister chromatid exchange frequency. Effects on meiosis as well as on mitosis have been reported.

5-Bromodeoxyuridine induces a senescence-like phenomenon in mammalian cells. This effect was dramatically potentiated by AT-binding ligands such as distamycin A, netropsin, and Hoechst 33258. The genes most remarkably affected by these ligands include the widely used senescence-associated genes and were located on or nearby Giemsa-dark bands of human chromosomes. /The authors/ hypothesize that AT-rich scaffold/nuclear matrix attachment region sequences are involved in this phenomenon. In fact, upon substitution of thymine with 5-bromouracil, a rat S/MAR sequence reduced its degree of bending and became insensitive to cancellation of the bending by distamycin A. The S/MAR sequence containing 5-bromouracil also bound more tightly to nuclear scaffold proteins in vitro and this binding was not inhibited by distamycin A. Under the same conditions, the S/MAR sequence containing thymine easily dissociated from the nuclear scaffold proteins. Taken together, the synergistic induction of the genes may be explained not only by opening of condensed chromatin by distamycin A but also by increase in the binding of 5-bromouracil-containing S/MAR sequences to the nuclear scaffolds.

An ectopic gene integrated in the host genome is occasionally silenced due to a position effect of its adjacent chromatin structure. /The authors/ found that 5-bromodeoxyuridine clearly activated such a transgene in HeLa cells. The transgene was also activated to various degrees by inhibitors of histone deacetylase, DNA topoisomerases, or DNA methyltransferase. The peptide antibiotic distamycin A potentiated markedly the effect of 5-bromodeoxyuridine. Transient expression of an artificial AT-hook protein termed MATH20 also potentiated its effect although significantly activated the transgene alone. Since distamycin A and MATH20 are able to displace histone H1 and other DNA-binding proteins bound to specific AT-rich sequences by a dominant, mutually exclusive fashion, these results suggest that 5-bromodeoxyuridine targets such an AT-rich sequence located adjacent to the silenced transgene, resulting in chromatin accessibility.

5-Bromodeoxyuridine (BrdU) universally induces a senescence-like phenomenon in mammalian cells. To assess this phenomenon at the level of gene expression, /the authors/ constructed a PCR-based subtractive cDNA library enriched for mRNA species that immediately increase by administration of BrdU to HeLa cells. Candidate cDNA clones were isolated by differential colony hybridization, and then positive clones were identified by Northern blot analysis. Sequencing analysis revealed that the identified cDNA species were classified into three groups: widely used senescence-markers, known species whose relevance to senescence is yet to be reported, and known or novel ESTs. As expected, the majority of them showed an increase in expression in senescent human diploid fibroblasts. These results suggest that similar mechanisms operate in the regulation of BrdU-induced genes and senescence-associated genes.

For more Mechanism of Action (Complete) data for BROMODEOXYURIDINE (7 total), please visit the HSDB record page.

BrdU is degraded at a fairly rapid rate in mice and rats upon injection, in at least two metabolic pathways; one is hydrolysis at the glycosyl bond to yield bromouracil and 2-deoxyribose which is presumably then further metabolized. The other is debromination which is evidenced by liberation of bromide ion. The further fate of the remainder of the molecule has not been investigated

5-bromodeoxyuridine is phosphorylated by thymidine kinase to produce 5-bromodeoxyuridine-phosphate. (L626)

Drugs that are chemically similar to naturally occurring metabolites, but differ enough to interfere with normal metabolic pathways. (From AMA Drug Evaluations Annual, 1994, p2033)

Antimetabolites that are useful in cancer chemotherapy.

Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly.

Drugs used to potentiate the effectiveness of radiation therapy in destroying unwanted cells.

Twelve patients were treated with continuous intravenous (24-hour) infusions of bromodeoxyuridine (BUdR) at 650 or 1,000 mg/sq m/d for up to two weeks. ... Pharmacology studies revealed a steady-state arterial plasma level of 6 X 10-7 mol/L and 1 X 10-6 mol/L during infusion of 650 and 1,000 mg/sq m/d, respectively. In vivo BUdR uptake into normal bone marrow was evaluated in two patients by comparison of preinfusion and postinfusion in vitro radiation survival curves of marrow CFUc with enhancement ratios (D0-pre/D0-post) of 1.8 (with 650 mg/sq m/d) and 2.5 (with 1,000 mg/sq m/d). In vivo BUdR incorporation into normal skin and tumor cells using an anti-BUdR monoclonal antibody and immunohistochemistry was demonstrated in biopsies from three patients revealing substantially less cellular incorporation into normal skin (less than 10%) compared with tumor (up to 50% to 70%).

BrdU is absorbed from the gastrointestinal tract following parenteral injection and is presumably absorbed transplacentally (because of its teratogenic effects).

Distribution and pharmacokinetics: Intra-arterial injection of BrdU into rodents results in extensive degradation... . Most of the portion which is not so degraded is incorporated into DNA of various tissues, particularly the colon, stomach, bone marrow, and spleen. The label of intraperitoneally injected deuterated BrdU in pregnant mice is also found in the liver of both mothers and embryos.

BrdU tablets were implanted subcutaneously in rats, and BrdU concentrations were determined in the serum. Within 5 hr peak concentrations of 10 ug BrdU/mL blood were reached. ... With the use of agar-coated tablets, BrdU concentrations in the blood were reduced by half, and no peak concentration was found. ...

A drug that makes cancer cells more sensitive to radiation and is also used as a diagnostic agent to determine how fast cancer cells grow.

A nucleoside that substitutes for thymidine in DNA and thus acts as an antimetabolite. It causes breaks in chromosomes and has been proposed as an antiviral and antineoplastic agent. It has been given orphan drug status for use in the treatment of primary brain tumors.

A thymidine analog that incorporates /into/ DNA of dividing cells during the S-phase of the cell cycle. ... However, BrdU is not a marker of the S-phase of the cell cycle. As a thymidine analog, it is a marker of DNA synthesis. BrdU immunohistochemistry has been instrumental for the study of the development of the nervous system, and to confirm that neurogenesis occurs in the adult mammalian brain, including in human. ... BrdU labeling is currently the most used technique for studying adult neurogenesis in situ.

The standard method for assessment of cell proliferation in paraffin-embedded tissue sections is 5-bromodeoxyuridine (BrdU) immunohistochemistry (IHC). BrdU can be administered to laboratory animals via IP injections, is readily incorporated into nuclei during the DNA synthetic phase of the cell cycle, and is detected with an anti-BrdU antibody. ...

Laboratory chemical used as a mutagen in mutagenesis experiments. It is more commonly used in the detection of proliferating cells in living tissues.

Nucleosides are manufactured by base exchange reaction of inosine and/or deoxyinosine with pyrimidine bases by thermostable purine nucleoside phosphorylase and thermostable pyrimidine nucleoside phosphorylase in aqueous solutions containing /phosphoric acid/ or phosphate salts and conversion of the resulting hypoxanthine into uric acid by thermostable xanthine dehydrogenase in the presence of electron receptors. Alternatively, nucleosides are manufactured by base exchange reaction of inosine and/or deoxyinosine with purine bases by thermostable purine nucleoside phosphorylase in aqueous solutions containing /phosphoric acid/ or phosphate salts and conversion of the resulting hypoxanthine into uric acid by thermostable xanthine dehydrogenase in the presence of electron receptors.

Treatment of an aqueous solution of /deoxyuridine/ with saturated bromine water at 0 °C followed by removal of excess /bromine/ by suction, concentration at 30 °C, refluxing with /ethanol/, concentration at <35 °C, and crystallization from absolute /ethanol/ gave 60% /5-bromodeoxyuridine/ (purity 99%).