1,4-Butanediol dimethanesulfonate and cancer
1,4-Butanediol dimethanesulfonate, commonly known as busulfan, is a sulfonylurea alkylating agent used primarily in the treatment of chronic myeloid leukemia (CML). Classified as a known human carcinogen since 1985, busulfan has been associated with various cancers, including breast cancer, female genital cancers, and leukemias in patients undergoing treatment. The drug works by cross-linking DNA strands in rapidly dividing cells, affecting both cancerous and normal cells, which leads to significant side effects such as nausea, vomiting, and blood cell reduction.
Busulfan exposure typically occurs through intravenous administration or oral tablets, primarily in the context of chemotherapy and as a preparatory treatment for bone marrow transplants. While the drug has historically improved survival rates for CML, it has been largely replaced by more targeted therapies due to its non-selective nature and potential for severe cytotoxicity. The connection between busulfan and secondary malignancies has been established by the World Health Organization, which indicates its leukemogenic properties. Despite its risks, busulfan remains in use for certain malignancies and continues to be an important subject of study in cancer treatment and patient safety.
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1,4-Butanediol dimethanesulfonate and cancer
ROC STATUS: Known human carcinogen since 1985
ALSO KNOWN AS: Myleran, busulfan, busulfex
RELATED CANCERS: In patients receiving busulfan for chronic myeloid leukemia (CML), cytological anomalies and cancers were observed at a variety of sites, including breast cancer, female genital cancers, and leukemia. Cancer patients given busulfan for bronchial cancer developed leukemia that was not dose-related.
DEFINITION: Busulfan is a sulfonylurea alkylating agent that contains reactive alkyl groups that readily combine with other molecules via cross-linking of deoxyribonucleic acid (DNA) strands in the nuclei of rapidly dividing cells, thereby destroying them. A prescription drug employed in the chemotherapy of leukemias, especially CML, busulfan does not selectively harm cancer cells but kills normal cells as well, and it is considered to be mitogenic, carcinogenic, and leukemogenic. Locally, it may cause skin blistering and damage the eyes and respiratory tract. Systemic toxic effects include nausea and vomiting, reduction in both leukocytes and erythrocytes, and hemorrhage.
Exposure routes: Intravenous (IV), oral/ingestion of tablets
Where found: People may be exposed via chemotherapy (oral or IV) for treatment of various types of leukemia, especially CML, and before bone marrow transplants (used to treat CML), in combination with cyclophosphamide used as a conditioning regimen.
At risk: There is a potential for occupational exposure in employees who formulate and package busulfan tablets and for healthcare professionals who administer IV busulfan to patients.
Etiology and symptoms of associated cancers: Busulfan may cause cellular dysplasias and cytologic abnormalities. Busulfan, which is both leukemogenic and carcinogenic, has been shown to cause cancer of the breast and female reproductive organs as well as leukemias in humans, though the evidence is limited in animal studies. Related symptoms and signs vary by cancer. For leukemia, they include weakness, fever, bleeding gums, petechiae, swollen glands, and enlarged spleen or liver; for breast cancer, a new lump or mass in the breast; and for endometrial cancer, postmenopausal or irregular vaginal bleeding.
History: Introduced in 1950, busulfan raised the median survival time for CML to approximately 3.5 to 4.5 years. However, because busulfan proved more efficient at destroying normal stem cells than CML cells, it has been largely supplanted by more specific and less toxic agents. Malignant tumors and acute leukemias have been reported in patients who were treated with busulfan. The World Health Organization (WHO) found a cause-and-effect relationship between busulfan and secondary malignancies. The International Agency for Research on Cancer found four cases of acute leukemia among 243 patients treated with busulfan as adjuvant chemotherapy following surgical removal of bronchogenic carcinoma, suggesting that busulfan is leukemogenic. The FDA considers the drug an orphan drug. Still, it remains on the market in the twenty-first century for treating brain malignancies, CLM, and for use as a conditioning regimen before stem cell transplantation.
Bibliography
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