1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU)
1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea, commonly known as MeCCNU, is a nitrosourea alkylating agent primarily used in the treatment of various cancers, including brain, lung, and digestive system cancers. Introduced in 1963, MeCCNU was designed to effectively cross the blood-brain barrier due to its lipophilic nature. However, it is recognized as a known human carcinogen, with significant evidence linking its use to an increased risk of leukemia and other hematological disorders. This drug works by interfering with the DNA in rapidly dividing cells, leading to cell death; yet, it does not discriminate between cancerous and normal cells, resulting in various toxic effects.
Patients taking MeCCNU may experience local side effects such as skin blistering and damage to the eyes and respiratory tract, as well as systemic issues like nausea, vomiting, and reductions in blood cell counts. Despite its potential risks, MeCCNU has been evaluated in clinical trials, particularly for its efficacy when combined with other agents in leukemia treatment regimens. Historical studies have consistently confirmed its carcinogenic properties, leading to a cautious approach regarding its use. As of now, MeCCNU has not received approval from the US Food and Drug Administration for any specific indication, emphasizing the need for further research and evaluation of its safety profile.
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Subject Terms
1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU)
ROC STATUS: Known human carcinogen since 1991
ALSO KNOWN AS: Semustine
RELATED CANCERS: Leukemia, preleukemia
DEFINITION: MeCCNU is used to treat various cancers, including some of the brain. A nitrosourea alkylating agent, MeCCNU contains alkyl groups that mainly react with the deoxyribonucleic acid (DNA) in the cell nuclei via a process called interstrand cross-linking. Local side effects of MeCCNU may include blistering of the skin as well as damage to the eyes and respiratory tract. Systemic toxic effects include nausea and vomiting, reduction in both leukocytes and erythrocytes, hemorrhagic tendencies, and nephrotoxicity. Busulfan and cyclophosphamide are among other alkylating agents used in cancer chemotherapy.
Exposure routes: Oral (ingestion of capsules)
Where found: 1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU) is an investigational drug. Patients may be exposed via oral adjuvant for various cancers, including those of the brain, lung, and digestive system.
At risk: The National Institute for Occupational Safety and Health (NIOSH) conducted a survey from 1981 to 1983 and determined that approximately 229 workers were potentially exposed to MeCCNU. According to the fifteenth edition of the US National Toxicology Program's Report on Carcinogens, in the twenty-first century, exposure is mostly limited to patients participating in clinical trials for treatment regimens involving this drug.
Etiology and symptoms of associated cancers: Though the exact mechanisms are unclear, it is believed that the most significant actions of alkylating agents are those that disturb cell growth, mitosis, and differentiation of rapidly dividing cells, providing the rationale for use in cancer therapy. However, because alkylating agents such as MeCCNU do not selectively kill cancer cells, they have a toxic effect on normal cells and are considered carcinogenic, mitogenic, and leukemogenic. Symptoms of leukemia may include weakness, fever, bleeding gums, petechiae (small red spots on the skin), lymphadenopathy (swollen glands), splenomegaly (enlarged spleen), and hepatomegaly (enlarged liver).
History: Introduced in 1963 because of their lipophilicity and, therefore, ability to cross the blood-brain barrier, nitrosourea alkylating agents such as MeCCNU were designed to treat brain and meningeal cancer. However, based on scientific data, MeCCNU has been shown to be carcinogenic in humans. In 1983, researcher J. D. Boice and colleagues found a twelvefold relative risk of leukemic disorders in 2,067 patients given adjuvant treatment with MeCCNU compared with those given other therapies. In 1987 the International Agency for Research on Cancer (IARC) demonstrated a significant dose-related response to MeCCNU with an adjusted relative risk of approximately fortyfold for patients who received the highest dose of MeCCNU. Also, in 1987, the IARC concluded that there was evidence that MeCCNU was carcinogenic in experimental animals. In 1977, researcher J. H. Weisburger found an increased incidence of tumors and leukemias in animals injected with MeCCNU. MeCCNU never received US Food and Drug Administration approval for any use, though research using the drug continued. Some efficacy was found by combining MeCCNU with etoposide, cytarabine, and melphalan in conditioning leukemia patients before stem cell transplantation.
Bibliography
Boice, John D., et al. "Leukemia and Preleukemia after Adjuvant Treatment of Gastrointestinal Cancer with Semustine (Methyl-CCNU)." New England Journal of Medicine, vol. 309, no. 18, 1983, pp. 1079–084. doi:10.1056/NEJM198311033091802.
"15th Report on Carcinogens." National Toxicology Program, Department of Health and Human Services, 2021, ntp.niehs.nih.gov/whatwestudy/assessments/cancer/roc. Accessed 20 June 2024.
Penning, Trevor. Chemical Carcinogenesis. Springer, 2011.
Schwab, Manfred. Encyclopedia of Cancer. 4th ed., Springer, 2020.
Tinwell, H., J. Ashby, and L. G. Littlefield. "Activity of the Human Carcinogen MeCCNU in the Mouse Bone Marrow Micronucleus Assay." Environmental and Molecular Mutagenesis, vol. 17, no. 3, 1991, pp. 152–54. doi.org/10.1002/em.2850170303.
Zhang, Lihong. "Efficacy and Toxicity of SEAM (Semustine, Etoposide, Cytarabine, and Melphalan) Conditioning Regimen Followed by Autologous Stem Cell Transplantation in Lymphoma." Hematology, vol. 27, no. 1, 2022, pp. 404-411. DOI: 10.1080/16078454.2022.2051864.