Carmustine

Absorption

5 to 28% bioavailability

Toxicity

The oral LD50s in rat and mouse are 20 mg/kg and 45 mg/kg, respectively. Side effects include leukopenia, thrombocytopenia, nausea. Toxic effects include pulmonary fibrosis (20-0%) and bone marrow toxicity.

Description

Carmustine is a nitrogen mustard β-chloro-nitrosourea compound that is used as an alkylating agent. It forms interstrand crosslinks in DNA, which prevents DNA replication and transcription leading to apoptosis. Carmustine is also reported to inhibit glutathione reductase, thioredoxin reductase, and lipoamide dehydrogenase. Carmustine has been tested in clinical trials as a cytostatic agent for Hodgkin’s and non-Hodgkin’s lymphoma, myeloma, malignant melanoma, glioblastoma, and other brain tumors.

Description

Bischloroethyl nitrosourea (BCNU) is a mustard-gas-derived alkylating agent that underwent clinical trials for use as an antineoplastic agent in the mid-1960s. Intravenous BCNU received US Food and Drug Administration (FDA) approval for brain tumor treatments in 1977. Further development and trials led to the FDA approval of a BCNU-impregnated polymer wafer for use as an intracavity surgical adjunct for recurrent glioblastoma moltiforme in 1996. These wafers were again reapproved in 2003 for use in high-grade malignant glioma as an adjunct to surgery and radiation.

Chemical properties

Light Yellow Powder

Chemical properties

Carmustine is an orange-yellow crystalline solid or powder.

Originator

BCNU,Gencorp Aerojet,US

The Uses of Carmustine

Carmustine is a nitrogen mustard β-chloro-nitrosourea compound that is used as an alkylating agent. It forms interstrand crosslinks in DNA, which prevents DNA replication and transcription leading to apoptosis. Carmustine is also reported to inhibit glutathione reductase, thioredoxin reductase, and lipoamide dehydrogenase. Carmustine has been tested in clinical trials as a cytostatic agent for Hodgkin’s and non-Hodgkin’s lymphoma, myeloma, malignant melanoma, glioblastoma, and other brain tumors.

The Uses of Carmustine

An alkylating and carbamoylating nitrosourea compound. It interacts with DNA, RNA and proteins causing DNA interstrand cross linking which is cytotoxic and leads to apoptotic cell death

The Uses of Carmustine

antidepressant

The Uses of Carmustine

BCNU has been used since 1971 as an anticancer drug and in 1977 was approved by the U.S. Food and Drug Administration, as carmustine, to be marketed for the treatment of Hodgkin’s disease, nonHodgkin’s lymphoma, multiple myeloma, and primary or metastatic brain tumors (IARC 1981, FDA 2009a, MedlinePlus 2009). It has also been used to treat malignant melanoma, breast cancer, gastrointestinal cancer, Ewing’s sarcoma, and Burkitt’s lymphoma and to be applied to the skin to treat mycosis fungoides (MedlinePlus 2009). BCNU may be used alone or in combination with other antineoplastic agents (ClinicalTrials 2009).

What are the applications of Application

Carmustine is a DNA alkylating and cross-linking agent used in the treatment of brain tumors and various other malignant neoplasms

Indications

For the treatment of brain tumors, multiple myeloma, Hodgkin's disease and Non-Hodgkin's lymphomas.

Background

A cell-cycle phase nonspecific alkylating antineoplastic agent. It is used in the treatment of brain tumors and various other malignant neoplasms. (From Martindale, The Extra Pharmacopoeia, 30th ed, p462) This substance may reasonably be anticipated to be a carcinogen according to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985). (From Merck Index, 11th ed)

Definition

ChEBI: A member of the class of N-nitrosoureas that is 1,3-bis(2-chloroethyl)urea in which one of the nitrogens is substituted by a nitroso group.

Manufacturing Process

A solution of sodium nitrite (6.9 g, 0.10 mole) in water (60 ml) was added dropwise to a cold (0-5°C), stirred solution of 1,3-bis(2-chloroethyl)urea (8.0 g, 0.044 mole) in formic acid (50 ml). The reaction mixture was stirred further at 0°C until the pale yellow oil that had formed solidified. The nitrosourea was collected and washed quickly with cold water (2 x 10 ml), and dried in vacuum; yield 6.7 g. (71%).

brand name

Bicnu (Bristol-Myers Squibb); Gliadel (Millot Laboratories, France).

Therapeutic Function

Antitumor

General Description

Orange-yellow solid.

General Description

Carmustine is available in a 100-mg vial for IV administrationin the treatment of several types of brain tumors,Hodgkin’s and non-Hodgkin’s disease, and multiplemyeloma. The agent is also available as an implantablewafer containing 7.7 mg of drug for intracavity implantationin the treatment of glioblastoma multiforme. Cytotoxicity isassociated with cross-linking of DNA and RNA and carbamoylationof glutathione reductase. Cross-resistance isnot seen with other alkylating agents. The agent is very lipidsoluble and easily crosses the blood-brain barrier, achievingconcentrations greater than 50% of those seen in plasma.Metabolism involves both the nonenzymatic formation ofreactive intermediates that may react with glutathione andother thiol-containing proteins, as well as enzymatic reductivedenitrosation and dechlorination. The half-life of theagent in plasma is short (15–20 minutes) because of rapiddecomposition. Myelosuppression is dose limiting and maypresent as thrombocytopenia, leucopenia, or more rarely asanemia. This is generally seen 24 to 48 days after treatment.Pulmonary toxicity occurs rarely at low doses but at highdoses such as those seen during bone marrow transplantmay present as dyspnea, cough, pulmonary infiltrates, andprogress to respiratory failure. This may be seen years afterthe completion of therapy. Other toxicities include nausea,vomiting, pain at the injection site, impotence, sterility,amenorrhea, and infertility. Hepatotoxicity may initiallypresent as elevations in serum transaminase levels. There isalso an increased risk of secondary cancers as is often seenwith the alkylating agents.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

Carmustin decomposes rapidly in acid and in solutions above pH 7; most stable in petroleum ether or aqueous solution at pH 4.

Hazard

Extremely toxic, central nervous system depression, pulmonary fibrosis, renal and hepatic damage, cytotoxic, immunosuppressive, carcino- gen.

Fire Hazard

Flash point data for Carmustin are not available. Carmustin is probably combustible.

Biochem/physiol Actions

Carmustine is a DNA alkylating agent causing DNA interstrand crosslinks. Effective against glioma and other solid tumors.

Pharmacokinetics

Carmustine is one of the nitrosoureas indicated as palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in treatment of brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Although it is generally agreed that carmustine alkylates DNA and RNA, it is not cross resistant with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins.

Clinical Use

Alkylating agent:

Myeloma, lymphoma and brain tumours

Safety Profile

Confirmed carcinogen withexperimental carcinogenic and tumorigenic data. A humanpoison by parenteral route. An experimental poison byingestion, intravenous, intraperitoneal, parenteral, andsubcutaneous routes. Human systemic effects byparenteral, int

Synthesis

Carmustin, 1,3-bis-(2-chloroethyl)-1-nitrosourea (30.2.4.4), is made by nitrating 1,3-bis(2-chloroethyl)urea with nitrogen trioxide.

Potential Exposure

BCNU has been used since 1971 as an antineoplastic agent in the treatment of Hodgkin’slymphoma; multiple meyloma; and primary or metastatic brain tumors. It also has been reported to have antiviral, antibacterial, and antifungal activity, but no evidence was found that it is used in these ways. BCNU is not known to be naturally occurring. Health professionals who handle this drug (for example, pharmacists, nurses, and physicians) may possibly be exposed to BCNU during drug preparation, administration, or cleanup; however, the risks can be avoided through use of containment equipment and proper work practices

Drug interactions

Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine (increased risk of agranulocytosis).

First aid

Skin Contact: Flood all areas of body that havecontacted the substance with water. Do not wait to removecontaminated clothing; do it under the water stream. Usesoap to help assure removal. Isolate contaminated clothingwhen removed to prevent contact by others. Eye Contact:Remove any contact lenses at once. Immediately flush eyeswell with copious quantities of water or normal saline for atleast 20-30 min. Seek medical attention. Inhalation: Leavecontaminated area immediately; breathe fresh air. Properrespiratory protection must be supplied to any rescuers. Ifcoughing, difficult breathing, or any other symptomsdevelop, seek medical attention at once, even if symptomsdevelop many hours after exposure. Ingestion: Contact aphysician, hospital, or poison center at once. If the victim isunconscious or convulsing, do not induce vomiting or giveanything by mouth. Assure that the patient’s airway is openand lay him on his side with his head lower than his bodyand transport immediately to a medical facility. If consciousand not convulsing, give a glass of water to dilute the substance. Vomiting should not be induced without a physician’s advice.

Carcinogenicity

Bis(chloroethyl) nitrosourea (BCNU) is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.

Environmental Fate

It is generally assumed that BCNU exerts its cytotoxicity through the liberation of alkylating and carbamoylating moieties. An alkylating entity, particularly chloroethyl carbonium ion, is strongly electrophilic and can alkylate a variety of biomolecules, including the purine and pyrimidine bases of DNA. BCNU causes DNA interstrand cross-linking, which is associated with cytotoxicity. The carbamoylation of lysine residues of protein can inactivate certain enzymes, thus interfering with DNA and RNA synthesis and repair processes. The inhibition of glutathione reductase by this carbamoylation further contributes to cytotoxicity.

Metabolism

Hepatic and rapid with active metabolites. Metabolites may persist in the plasma for several days.

Metabolism

Intravenous carmustine is rapidly metabolised, and no intact drug is detectable after 15 minutes. It is partially metabolised to active metabolites by liver microsomal enzymes, which have a long half-life. It is thought that the antineoplastic activity may be due to metabolites. Approximately 30% of a dose is excreted in the urine after 24 hours, and 60-70% of the total dose after 96 hours. About 10% is excreted as respiratory CO2 . Terminal halflife of the metabolites is about 1 hour.

storage

Color Code—Blue: Health Hazard/Poison: Storein a secure poison location. Prior to working with thischemical you should be trained on its proper handling andstorage. Store in tightly closed containers in a cool, wellventilated area away from acids. A regulated, markedarea should be established where this chemical is handled,used, or stored in compliance with OSHA Standard1910.1045.

Shipping

UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials. UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1- Poisonous materials, Technical Name Required.

Toxicity evaluation

There is no information available on the environmental fate of BCNU. However, it is predicted that BCNU spontaneously decomposes due to its high reactivity. Estimates indicate that the half-life of BCNU particulates and vapor in air is 4.4 days. Though expected to be highly mobile when adsorbed to soil and suspended solids, it is likely that this adsorption may be precluded by hydrolysis. Volatilization from soil or water is not expected, and the potential for bioaccumulation is low. BCNU degrades into 2-chloroethylamine, which is not considered hazardous to the environment.

Incompatibilities

Acids and acid solutions above pH 7 cause rapid decomposition. Most stable at pH 4 in aqueous solution or petroleum ether.

Waste Disposal

It is inappropriate and possibly dangerous to the environment to dispose of expired or waste pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.