Nitrosoureas

NITROSOUREAS

These drugs appear to be non-cross-resistant with other alkylating agents; all require biotransformation, which occurs by nonenzy-matic decomposition, to metabolites with both alkylating and carbamoylating activities. The nitrosoureas are highly lipid-soluble and are able to cross the blood-brain barrier, making them effective in the treatment of brain tumors. 

Although the majority of alkyla-tions by the nitrosoureas are on the N7 position of guanine in DNA, the critical alkylation responsible for cytotoxicity appears to be on the O6 position of guanine, which leads to G-C crosslinks in DNA. After oral administration of lomustine, peak plasma levels of metabolites appear within 1–4 hours; central nervous system concentrations reach 30–40% of the activity present in the plasma. Urinary excretion appears to be the major route of elimination from the body. One naturally occurring sugar-containing nitrosou-rea, streptozocin, is interesting because it has minimal bone mar-row toxicity. This agent has activity in the treatment of insulin-secreting islet cell carcinoma of the pancreas.