Alkylating Agents: Nitrosoureas

Nitrosoureas

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 chemi-cally 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 fa-cilitates distribution into the brain and cerebrospinal fluid (CSF).

The chloroethyl moiety of these nitrosoureas is capa-ble of alkylating nucleic acids and proteins and produc-ing 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 com-plete, but degradation and metabolism are so rapid that the parent drug cannot be detected after oral adminis-tration. 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 exper-imental 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 lym-phomas, multiple myeloma, melanoma, renal cell carci-noma, and colorectal cancer.

The nitrosoureas produce severe nausea and vomit-ing in most patients 4 to 6 hours after administration. The major site of dose-limiting toxicity is the bone mar-row; 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.

Streptozocin

Streptozocin (Zanosar), a water-soluble nitrosourea produced by the fungus Streptomyces achromogenes, acts through methylation of nucleic acids and proteins. In addition, it produces rapid and severe depletion of the pyridine nucleotides nicotinamide adenine dinu-cleotide (NAD) and its reduced form (NADH) in liver and pancreatic islets.

Streptozocin is not well absorbed from the gastroin-testinal tract and must be administered intravenously or intraarterially. In preclinical studies, the plasma half-life was 5 to 10 minutes.

Streptozocin produces remission in 50 to 60% of pa-tients with islet cell carcinomas of the pancreas. It is also useful in malignant carcinoid tumors.

Almost all patients have nausea and vomiting. The major toxicity is renal tubular damage, which may be se-vere in 5 to 10% of patients taking streptozocin. Treatment of metastatic insulinomas may result in the release of insulin from the tumor and subsequent hypo-glycemic coma. Less severe toxicities include diarrhea, anemia, and mild alterations in glucose tolerance or liver function tests.