Difluoromethylornithine (DFMO), also known as eflornithine, is a medication that stops a specific enzyme involved in cell growth. Originally investigated as an anti-cancer drug, its development led to applications for other conditions where rapid cell growth is a factor. The drug has a unique history, with uses ranging from treating parasitic infections to being a focal point in modern cancer research.
How DFMO Interrupts Cell Growth
Difluoromethylornithine’s action is to halt the function of an enzyme called ornithine decarboxylase (ODC). This enzyme is a key step in producing compounds known as polyamines. Polyamines are molecules necessary for cell division and differentiation, and they are especially important for cells that multiply rapidly.
DFMO works as an irreversible inhibitor of ODC. It is structurally similar to ornithine, the molecule ODC normally acts upon. Due to this similarity, DFMO binds to the enzyme and permanently deactivates it in a “suicide inhibition” mechanism, which blocks the production of polyamines.
By depleting the cell’s supply of polyamines, DFMO slows or stops cell proliferation. This effect is cytostatic, meaning it inhibits cell growth rather than being cytotoxic, which would directly kill the cells. This mechanism is what allows DFMO to be used against diseases characterized by rapid cell growth.
Treating African Sleeping Sickness with DFMO
One established use for DFMO is treating human African trypanosomiasis, or African sleeping sickness. This disease is caused by the parasite Trypanosoma brucei gambiense and transmitted by the tsetse fly. The medication is effective against the T. b. gambiense subspecies found in West and Central Africa, but not the East African subspecies, T. b. rhodesiense.
DFMO is particularly useful for the late stage of the disease, when the parasite has crossed the blood-brain barrier and entered the central nervous system. The drug penetrates the central nervous system to act on the parasites where they are causing the most damage. Since the parasites depend on polyamines for growth and replication, they are vulnerable to ODC inhibition.
The effectiveness of DFMO lies in a key difference between the parasite’s ODC enzyme and the human version. While the drug inhibits both, the human ODC enzyme has a very rapid turnover rate, with a half-life of less than an hour. In contrast, the parasite’s ODC enzyme has a much longer half-life of over six hours, making the parasite’s polyamine production much more susceptible to long-term disruption by DFMO. This selective vulnerability allows the drug to target the infection with a manageable impact on the host.
Investigating DFMO for Cancer Treatment
Initially developed as an anti-cancer agent, DFMO is now a focus of research for certain cancers, especially neuroblastoma. Neuroblastoma is an aggressive childhood cancer that originates from immature nerve cells. Because cancer cells are defined by rapid, uncontrolled proliferation that relies on polyamines, they are a logical target for the drug.
Research shows a strong connection between neuroblastoma and the ODC enzyme. Many aggressive neuroblastomas have high levels of an oncoprotein called N-Myc, which drives tumor growth. The gene for N-Myc, MYCN, is often amplified in these tumors. Studies show the gene for ODC, ODC1, is also frequently amplified alongside MYCN, and high levels of ODC1 expression are linked to poorer patient outcomes.
Clinical trials are exploring DFMO’s role in treating neuroblastoma. It is being tested as a maintenance therapy to prevent relapse in high-risk patients who have completed standard treatments like chemotherapy and immunotherapy. Other trials are investigating its use in combination with chemotherapy for relapsed or hard-to-treat disease. These studies are examining a wide range of dosages to find the most effective strategies. Pre-clinical studies in mice have shown that DFMO can delay tumor formation and improve survival, supporting its use in the clinic.
DFMO: Dosage, Side Effects, and Drug Development
One of the most noted side effects, particularly at high doses, is ototoxicity, or hearing loss. This occurs because DFMO can interfere with polyamine synthesis in the inner ear, affecting both inner and outer hair cells. However, some studies have shown this hearing loss can be reversible, and lower doses used for cancer prevention are associated with fewer significant side effects.
The medication is administered as a racemic mixture, meaning it contains equal amounts of two mirror-image molecules called enantiomers: D-DFMO and L-DFMO. Research has shown that the L-enantiomer is more potent at inhibiting the ODC enzyme. Conversely, animal studies have suggested that the D-enantiomer is less toxic, particularly concerning ototoxicity. This has led to research into whether using a specific form of the drug could optimize its therapeutic effects while minimizing adverse reactions.
DFMO’s pharmacokinetic profile, which describes how the drug is absorbed and processed by the body, presents some challenges. Achieving effective concentrations in the body can require large doses. This has prompted researchers to explore ways to improve the drug’s formulation and delivery. Current strategies include developing structural analogs of DFMO and using it in combination with other drugs to enhance its overall effectiveness.