Nitrosoureas are a specific class of synthetic compounds used in chemotherapy to treat various cancers. Chemically, they are distinguished by a nitroso group and a urea structure. As cytotoxic drugs, their primary function is to interfere with the fundamental processes of cell division and replication, targeting rapidly multiplying cells found in tumors.
How Nitrosoureas Work
Nitrosoureas are classified as alkylating agents, a group of compounds that exert their anti-cancer effect by chemically modifying the cell’s genetic material. The mechanism involves the drug’s spontaneous decomposition within the body, producing highly reactive metabolites. These metabolites, which include alkylating and carbamoylating species, attach to DNA bases.
This process, known as alkylation, adds an alkyl group to the DNA strand, primarily targeting the O6 position of guanine. This modification disrupts the DNA molecule’s normal structure and function. A key action is the formation of interstrand cross-links, where the drug bonds the two opposing strands of the DNA double helix.
When a cancer cell attempts to divide, these cross-links prevent the DNA strands from separating correctly. This irreparable damage triggers programmed cell death (apoptosis), eliminating the cancerous cell. This drug class is highly lipophilic, meaning they are fat-soluble.
Clinical Applications in Cancer Treatment
The high fat solubility of nitrosoureas allows them to readily penetrate biological membranes throughout the body. This property enables them to bypass the blood-brain barrier (BBB), a protective network that prevents many substances from entering the central nervous system (CNS). By crossing the BBB, nitrosoureas achieve therapeutic concentrations in the brain and cerebrospinal fluid. This makes them particularly effective for treating CNS malignancies, which are often difficult to reach with standard systemic chemotherapy. Nitrosoureas are frequently used to manage primary brain tumors such as glioblastoma and medulloblastoma.
Systemic Cancers
Beyond the CNS, nitrosoureas are used to manage other systemic cancers. They treat certain blood cancers, including Hodgkin’s and non-Hodgkin’s lymphoma. These agents are also incorporated into regimens for malignant melanoma.
Key Examples and Delivery Methods
The nitrosourea class includes several agents distinguished by their chemical structure and method of administration.
Carmustine (BCNU)
Carmustine (BCNU) is typically administered through intravenous (IV) infusion. It also has a unique local delivery method involving the Gliadel wafer, a biodegradable polymer. This wafer, containing the drug, can be surgically implanted directly into the tumor resection cavity in the brain. Local placement allows for high drug concentrations at the tumor site while minimizing systemic exposure.
Lomustine (CCNU) and Streptozocin
Lomustine (CCNU) is administered orally in capsule form. Its lipophilicity ensures it is well-absorbed and efficiently crosses the blood-brain barrier, making it a convenient option for brain tumors and other indications. Streptozocin is notable for its specific application in treating pancreatic neuroendocrine tumors.
Understanding Toxicity and Monitoring
The cell-killing nature of nitrosoureas extends to healthy cells, leading to severe side effects requiring careful management.
Hematological Toxicity
The most common and dose-limiting adverse effect is hematological toxicity, manifesting as myelosuppression. This condition involves the suppression of bone marrow activity, resulting in low counts of white blood cells, red blood cells, and platelets. Myelosuppression is often delayed and cumulative; the lowest blood cell counts (nadir) may not occur until four to six weeks after a dose. This delayed onset requires treatment cycles to be spaced out, often at six-week intervals, allowing for bone marrow recovery. Frequent blood tests are mandatory to monitor counts and adjust dosing to prevent life-threatening infections or bleeding.
Pulmonary and Renal Toxicity
Non-hematological toxicities are also a significant concern, particularly pulmonary fibrosis, an irreversible scarring of the lungs. This lung damage is most associated with Carmustine and can develop years after treatment has concluded, sometimes progressing even after the drug is stopped. Patients receiving high cumulative doses (over 1400 mg per square meter of body surface area) are at increased risk for this serious complication.
Renal toxicity (nephrotoxicity) is another progressive complication that can occur with long-term nitrosourea use. Since the drugs and their metabolites are excreted by the kidneys, prolonged exposure can lead to damage to the renal tubules and glomeruli. Monitoring kidney function, including blood urea nitrogen and creatinine levels, is required throughout treatment and follow-up to detect and manage this organ damage.