Lomustine (CCNU) | Nitrosourea | CAS 13010-47-4

Product Name: Lomustine (CCNU)
CAS No.: 13010-47-4
Chemical Name: N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea
Molecular Formula: C₉H₁₆ClN₃O₂
Appearance: Yellowish powder
Solubility: Practically insoluble in water; freely soluble in ethanol, chloroform, and other organic solvents
Stability: Unstable in aqueous solutions; sensitive to light and moisture

1. Introduction

Lomustine (CCNU) is an antineoplastic agent from the nitrosourea group with alkylating and carbamoylating actions. It is highly lipophilic and penetrates the blood-brain barrier well. It is used for the treatment of brain tumors and lymphomas.

Nitrosourea drugs, including lomustine, are characterized by their ability to alkylate DNA and RNA, as well as carbamoylate proteins. A key feature of lomustine is its high lipophilicity, providing good penetration into the central nervous system, making it a valuable drug for the treatment of primary and metastatic brain tumors.

2. Chemical Structure & Synthesis

Lomustine is synthesized in several stages. A typical route involves the reaction of cyclohexylamine with phosgene to form cyclohexyl isocyanate. The cyclohexyl isocyanate then reacts with 2-chloroethylamine to form N-(2-chloroethyl)-N'-cyclohexylurea, which is then nitrosated (e.g., with sodium nitrite in acidic medium) to obtain lomustine.

3. Mechanism of Action

Lomustine is a prodrug that undergoes non-enzymatic breakdown in the body to form active metabolites.

• Alkylating action: 2-Chloroethyldiazohydroxide is formed, which further decomposes to generate the 2-chloroethylcarbonium ion. This ion alkylates DNA (primarily at the O6 position of guanine), leading to DNA crosslinking, disruption of DNA replication and transcription, and cell death.

• Carbamoylating action: Cyclohexyl isocyanate is formed, which can carbamoylate amino groups of proteins, including DNA repair enzymes (e.g., O6-alkylguanine-DNA alkyltransferase), enhancing the cytotoxic effect of alkylation. It can also inhibit RNA synthesis and processing.

• Blood-brain barrier penetration: Due to its high lipophilicity, lomustine readily penetrates the blood-brain barrier, achieving therapeutic concentrations in the cerebrospinal fluid and brain tissue.

4. Pharmacokinetics

Taken orally. Rapidly and almost completely absorbed. Actively metabolized in the liver. Excreted primarily by the kidneys as metabolites.

5. Applications

• Primary and metastatic brain tumors: Glioblastoma, astrocytoma, oligodendroglioma, ependymoma, medulloblastoma

• Hodgkin's lymphoma – as part of combination therapy for relapses or resistance to standard regimens

• Non-Hodgkin lymphomas – less commonly

• Melanoma – in some combination therapy regimens

• Renal cancer, lung cancer, gastrointestinal cancer – less commonly, in clinical trials or when resistant to other drugs

6. Conclusion

Lomustine is an important antineoplastic agent, particularly valuable in the treatment of central nervous system tumors due to its ability to penetrate the blood-brain barrier. Its dual mechanism of action (alkylation and carbamoylation) contributes to its efficacy against various tumor types. However, the use of lomustine is associated with significant toxicity, primarily delayed and cumulative myelosuppression (thrombocytopenia and leukopenia), as well as pulmonary and renal toxicity with long-term use.