Medical Pharmacology Chapter 33-34: Anticancer Drugs
Alkylating Agents (Continued):
"Nitrosourea" represents a class of compounds (and the name of the molecule) that includes both a nitroso group (R-NO) and a urea group.
Nitrosoureas have significant use clinically in management of brain tumors (e.g. glioblastoma multiforme) and may also be used in treating lymphomas.
Some nitrosoureas have a role also at high doses in the context of bone marrow transplants.1
Carmustine (BiCNU, Gliadel wafer) and Lomustine
Carmustine is classified as a cell-cycle nonspecific alkylating anticancer drug and is a member of the anti-neoplastic class of drugs described as nitrosoureas.6
Carmustine cross-links DNA and alkylates during all cell cycle phases.
The consequence of these actions interferes with DNA function resulting in cell cycle arrest and programmed cell death (apoptosis).
Enhancement of the cytotoxic activity is associated with protein carbamoylation which interferes with DNA repair enzyme activity.
The highly lipophilic character of carmustine and lomustine allows these drugs to cross the blood brain barrier.6
The ability of these drugs to cross the blood brain barrier, because of their highly lipophilic nature, is important given the prominence of these agents in brain tumor treatment.1
The principal mechanism of action of carmustine is DNA alkylation at the the O6-guanine position.
The adduct formed at the site is a substrate for the repair enzyme O6-methylguanine-DNA methyltransferase (MGMT).
However, methylation of the MGMT promoter inhibits expression of the DNA repair enzyme in about a third of primary gliomas.
This inhibition of the repair enzyme promotes sensitivity to nitrosourea anticancer agents.
Absorption, Distribution, Metabolism, Excretion:
Nitrosoureas are unstable in aqueous environments.2
Following IV administration, the half-life in plasma varies from 15 min. to an excess of 90 min.1
From 30%-80% of drug appears in the urine as degradation products within a day and about 60%-70% found in the urine within four days. About 10% is associated with respiratory CO2.1,6
Alkylating metabolites gain entry into the CSF and CSF concentrations approximate 15%-30% of the associated plasma values.1
Some Clinical Uses:
Carmustine and lomustine have been promoted for use in brain tumors and Hodgkin's disease.6
Carmustine appears useful also in treating non-Hodgkin's lymphoma and multiple myeloma.
The agent may be administered intravenously or incorporated into a wafer implanted directly into the CNS (brain) following tumor resection (Gliadel Wafer).
The implantable carmustine wafer may be employed as an adjunct to surgery in cases of recurrent glioblastoma multiforme.1
Carmustine high lipophilicity precludes a totally aqueous IV formulation; therefore, the agent is administered in 10% ethanol.
Carmustine degrades rapidly following IV administration; however, lomustine is more stable allowing oral use and is available in capsule form.6
Generally, the nitrosourea group including carmustine and lomustine induce significant and delayed myelosuppression.1
Myelosuppression can manifest as both thrombocytopenia and leukopenia and may result in significant infection in hemorrhage.2
Recovery, following a single dose may require an excess of a month.
Long-term administration of nitrosoureas, particularly semustine, a methylated carmustine derivative, may result in renal failure.
Nitrosoureas generally are both mutagenic and highly carcinogenic.1
Both acute and delayed pulmonary toxicity also presents risk.
Pulmonary toxicity appears dose-related and administration of these agents in childhood (or early adolescence) appears associated with higher risk for delayed adverse pulmonary effects.2