Carmustine Lomustine and Semustine

The nitrosoureas are alkylating agents that are highly lipid soluble and share similar pharmacological and clinical properties. Carmustine (BCNU), lomustine (CCNU), and semustine (methyl-CCNu) are chemically unstable, forming highly reactive decomposition products. The chemical half-life of these drugs in plasma is only 5 to 15 minutes. Their marked lipid solubility facilitates distribution into the brain and cerebrospinal fluid (CSF).

The chloroethyl moiety of these nitrosoureas is capable of alkylating nucleic acids and proteins and producing single-strand breaks and interstrand cross-linkage of DNA. Both alkylation and carbamoylation contribute to the therapeutic and toxic effects of the nitrosoureas. These agents can kill cells in all phases of the cell cycle.

Oral absorption of lomustine and semustine is complete, but degradation and metabolism are so rapid that the parent drug cannot be detected after oral administration. Although the plasma half-lives of the parent drugs are only a few minutes, degradation products with antitumor activity may persist for longer periods.

Carmustine and lomustine can produce remissions that last from 3 to 6 months in 40 to 50% of patients with primary brain tumors. Both drugs also are used as secondary treatment of Hodgkin's disease and in experimental combination chemotherapy for various types of lung cancer. Other tumors in which remission rates of 10 to 30% have been obtained are non-Hodgkin's lymphomas, multiple myeloma, melanoma, renal cell carcinoma, and colorectal cancer.

The nitrosoureas produce severe nausea and vomiting in most patients 4 to 6 hours after administration. The major site of dose-limiting toxicity is the bone marrow; leukopenia and thrombocytopenia occur after 4 to 5 weeks. Less frequent side effects include alopecia, stomatitis, and mild abnormalities of liver function. Pulmonary toxicity, manifested by cough, dyspnea, and interstitial fibrosis, is becoming increasingly recognized as a complication of long-term nitrosourea treatment. As alkylating agents, these drugs are potentially muta-genic, teratogenic, and carcinogenic.

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