Chemical formula: C₅H₉Cl₂N₃O₂ Molecular mass: 214.05 g/mol PubChem compound: 2578
Carmustine is a cell-cycle phase nonspecific antineoplastic agent of the nitrosourea type, which exerts tumor cytotoxicity via multiple mechanisms. As an alkylating agent, it can alkylate reactive sites on nucleoproteins, thus interfering with DNA and RNA synthesis and DNA repair. It is able to form interstrand crosslinks in DNA, which prevents DNA replication and transcription. In addition, carmustine is known to carbamoylate lysine residues on proteins causing irreversible inactivation of enzymes including glutathione reductase. The carbamoylating activity of carmustine is generally considered less significant than the alkylating activity in its action on tumors, but carbamoylation may serve to inhibit DNA repair.
The antineoplastic and toxic activities of carmustine may be due to its metabolites. Carmustine and related nitrosoureas are unstable in aqueous solutions and degrade spontaneously to reactive intermediates that are capable of alkylation and carbamoylation. The alkylating intermediates are believed to be responsible for the antitumor effect of carmustine. However, opinion is divided over the role of the carbamoylating intermediates as mediators of the biological effects of the nitrosoureas. On one hand, their carbamoylating activity was reported to contribute to the cytotoxic properties of their parent drugs by inhibiting DNA repair enzymes. On the other hand, it has been speculated that the carbamoylating species may mediate some of toxic effects of carmustine.
Carmustine crosses the blood-brain barrier readily because of its lipophilic nature.
Carmustine should not be used in children and adolescents due to high risk of pulmonary toxicity.
Carmustine implant delivers carmustine directly into the surgical cavity created after tumoural resection. On exposure to the aqueous environment of the cavity the anhydride bonds in the copolymer are hydrolysed, releasing carmustine, carboxyphenoxypropane and sebacic acid. The carmustine released from implant diffuses into the surrounding brain tissue and produces an antineoplastic effect by alkylating DNA and RNA.
Carmustine is spontaneously both degraded and metabolised. The alkylating moiety thus produced and presumed to be chloroethyl carbonium ion, leads to the formation of irreversible DNA cross-links.
The tumourcidal activity of carmustine implant is dependent on release of carmustine into the tumour cavity in concentrations sufficient for effective cytotoxicity.
More than 70% of the copolymer degrades by three weeks. The metabolic disposition and excretion of the monomers differ. Carboxyphenoxypropane is predominantly eliminated by the kidney and sebacic acid, an endogenous fatty acid, is metabolised by the liver and expired as CO2 in animals.
Intravenously administered carmustine is rapidly degraded, with no substance intact detectable after 15 minutes. Because of the good lipid solubility and the lack of ionisation at the physiological pH, carmustine is very well transferred through the blood-brain barrier. Levels of radioactivity in the cerebrospinal fluid are at least 50% higher than those measured concurrently in plasma. The kinetic of carmustine in humans is characterised by a two-chamber model. After the intravenous infusion over 1 hour, the carmustine-plasma level drops in a biphasic manner. The half-life α is 1-4 minutes and the half-life β is 18-69 minutes.
Carmustine concentrations delivered by carmustine implant in human brain tissue have not been determined. Plasma levels of carmustine after implantation cannot be assayed. In rabbits that had implants containing 3.85% carmustine placed, carmustine is not detected in the blood or cerebrospinal fluid.
It is presumed that the metabolites of carmustine cause its antineoplastic and toxic activity.
Carmustine implants are biodegradable in human brain when placed into the cavity after tumour resection. The rate of biodegradation is variable from patient to patient.
Approximately 60-70% of a total dose is excreted in the urine in 96 hours and about 10% as respiratory CO2. The fate of the remainder is undetermined.
During the biodegradation process an implant remnant may be observed on brain imaging scans or at re-operation even though extensive degradation of all components has occurred.
Carmustine was embryotoxic and teratogenic in rats and embryotoxic in rabbits at dose levels equivalent to the human dose. Carmustine affected the fertility of male rats at doses higher than the human dose. Carmustine, at clinically relevant dose levels, was carcinogenic in rats and mice.
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