Nitrosoureas Toxicity

Excerpt

Nitrosoureas are cytotoxic chemotherapeutic drugs that cause cell death by DNA damage. They are used to treat malignancies, including malignant glioblastomas, Hodgkin's and non-Hodgkin lymphomas, and pancreatic islet cell tumors. Three of the most commonly used nitrosourea compounds are carmustine (BCNU), lomustine (CCNU), and fotemustine. Nitrosoureas are lipophilic chemicals with antitumor and cytotoxic effects via alkylating and carbamoylating compounds; they are active in multiple cell cycle phases.

Lomustine readily crosses the blood-brain barrier and is commonly used for recurrent glioblastoma multiforme; in some European countries, fotemustine is used instead of lomustine. Carmustine was the first nitrosourea developed for public use (United States Food and Drug Administration approval in 1977). The drug has been widely discontinued due to toxicity, intravenous (IV) administration, and low availability..

Nitrosoureas are used alongside other chemotherapeutic agents (such as procarbazine, lomustine, and vincristine, a first-line regimen for oligodendroglioma) or as stand-alone chemotherapy agents. Streptozocin has methylnitrosourea activity against pancreatic islet cell tumors. Nitrosoureas are associated with significant and severe adverse effects, including leukoencephalopathy, pulmonary toxicity, nephrotoxicity, hepatotoxicity, neurotoxicity, myelosuppression, secondary leukemias, nausea, vomiting, stomatitis, alopecia, anemia, anorexia, and phlebitis and burning at the injection site. Due to their severe side effect profiles, nitrosoureas are mostly used for tumor recurrence or refractory cases. Nitrosourea metabolites are primarily excreted through the kidneys.