What is Hydroxyurea?
Hydroxyurea, also known as hydroxycarbamide, is an oral medication classified as an antimetabolite [1.7.4]. It was originally developed as an anticancer drug and is used to treat various conditions, including certain types of cancer and blood disorders [1.2.1, 1.7.5]. Its primary function is to inhibit an enzyme called ribonucleotide reductase, which is essential for producing the building blocks of DNA [1.2.1, 1.2.5]. By interfering with DNA synthesis, hydroxyurea can slow or stop the growth of rapidly dividing cells, such as cancer cells [1.7.1]. This mechanism also leads to its beneficial effects in non-cancerous conditions like sickle cell disease [1.2.1].
How Hydroxyurea Works in the Body
The primary mechanism of action for hydroxyurea is the inhibition of the ribonucleotide reductase enzyme [1.2.1]. This enzyme is crucial for converting ribonucleosides into deoxyribonucleosides, which are necessary for DNA synthesis and repair [1.2.5]. By blocking this process, hydroxyurea effectively arrests cells in the S-phase of the cell cycle, where DNA replication occurs, leading to cell death in rapidly dividing populations [1.2.5, 1.7.5].
Beyond this primary action, hydroxyurea has several other effects:
- Increases Fetal Hemoglobin (HbF): In sickle cell disease, hydroxyurea induces "stress erythropoiesis," a process that leads to the production of red blood cells containing fetal hemoglobin (HbF) [1.2.4]. HbF inhibits the polymerization of sickle hemoglobin (HbS), preventing red blood cells from taking on the characteristic sickle shape [1.3.6]. This improves blood flow and oxygen delivery [1.3.2].
- Reduces Inflammatory Cells: The medication lowers the counts of neutrophils and platelets, which are involved in inflammation and vaso-occlusion (the blockage of blood vessels) [1.2.1, 1.3.6].
- Nitric Oxide (NO) Donor: The hydroxyurea molecule can release nitric oxide, which has beneficial effects on blood vessels, including vasodilation (widening of blood vessels) [1.2.1, 1.2.6]. This may contribute to the rapid clinical improvement some patients feel soon after starting treatment [1.2.1].
- Improves Red Blood Cell Health: Treatment often leads to an increase in the size of red blood cells (macrocytosis), better hydration, and less hemolysis (destruction of red blood cells) [1.2.1, 1.6.1].
Medical Uses of Hydroxyurea
Hydroxyurea is approved by the FDA for several conditions and is used for others off-label [1.7.4, 1.2.4].
Sickle Cell Anemia (SCA)
This is one of the most common uses for hydroxyurea. The FDA approved it for adults with SCA in 1998 and expanded the approval to children aged two and older in 2017 [1.2.4]. It is the only effective drug proven to reduce the frequency of painful vaso-occlusive crises, acute chest syndrome (ACS), and the need for blood transfusions [1.2.1, 1.3.1]. Clinical studies have shown it can reduce painful episodes by as much as 50% [1.2.1]. Early initiation of therapy in children can help prevent or reverse chronic organ damage [1.2.1].
Myeloproliferative Neoplasms (MPNs)
MPNs are a group of blood cancers where the bone marrow produces too many red blood cells, white blood cells, or platelets. Hydroxyurea is a first-line cytoreductive (cell-reducing) therapy for these conditions [1.7.2, 1.4.1].
- Polycythemia Vera (PV): Used to control high red blood cell counts and reduce the risk of blood clots (thrombosis) [1.7.2, 1.4.1].
- Essential Thrombocythemia (ET): Used to lower high platelet counts, especially in high-risk patients, to prevent thrombosis [1.4.2, 1.7.2].
Other Cancers
Hydroxyurea is used to treat specific types of cancer, often in combination with other treatments like radiation therapy [1.7.1, 1.7.3].
- Chronic Myeloid Leukemia (CML): It is used to treat a certain type of CML that is resistant to other treatments [1.5.6, 1.7.3].
- Head and Neck Cancers: It is used with radiation therapy for locally advanced squamous cell carcinomas of the head and neck (excluding the lip) [1.7.3, 1.5.6]. It can make cancer cells more susceptible to being killed by radiation [1.7.1].
| Feature | Hydroxyurea for Sickle Cell Anemia | Hydroxyurea for MPNs & Cancer |
|---|---|---|
| Primary Goal | Reduce sickling, prevent crises, and increase fetal hemoglobin (HbF) [1.3.1, 1.2.4]. | Control high blood cell counts, reduce thrombosis risk, and slow/stop cancer cell growth [1.7.2, 1.7.1]. |
| Mechanism Focus | Induces HbF, reduces inflammation, improves red blood cell properties [1.2.1]. | Inhibits DNA synthesis in rapidly dividing cancer cells (cytotoxic effect) [1.7.2, 1.7.5]. |
| Typical Dosage | Lower dose, typically 15-20 mg/kg/day, adjusted to Maximum Tolerated Dose (MTD) [1.2.4]. | Higher dose, which varies based on the specific cancer and may be intermittent [1.7.3, 1.3.3]. |
| Common Outcome | Fewer pain crises, fewer hospitalizations, reduced need for transfusions [1.3.1, 1.2.1]. | Normalized blood counts, reduced spleen size, decreased risk of blood clots [1.7.2]. |
Side Effects and Monitoring
While effective, hydroxyurea is a powerful medication with significant potential side effects. Patients require regular monitoring, including blood tests, to manage their response and watch for toxicity [1.6.2].
Common Side Effects
Many side effects are mild and may resolve as the body adjusts [1.3.2].
- Gastrointestinal issues: Nausea, vomiting, diarrhea, constipation, loss of appetite [1.5.1].
- Skin and nail changes: Skin darkening (hyperpigmentation), rash, dry skin, and darkening of the nails [1.5.1, 1.6.4].
- Other common effects: Headache, dizziness, hair loss, and fever [1.5.1, 1.5.3].
Serious Side Effects
- Myelosuppression (Bone Marrow Suppression): This is the most common serious side effect [1.6.5]. Hydroxyurea can severely lower the counts of white blood cells (increasing infection risk), red blood cells (causing anemia), and platelets (increasing bleeding risk) [1.7.4]. Regular blood count monitoring is essential [1.6.2].
- Secondary Cancers: Long-term use of hydroxyurea is associated with an increased risk of developing other cancers, particularly leukemia and skin cancer [1.5.1, 1.6.1]. Patients are advised to use sun protection and undergo regular skin exams [1.6.2].
- Skin Ulcers: Painful ulcers, especially on the legs, can occur, particularly with long-term therapy [1.6.1, 1.6.5].
- Fertility Issues: Hydroxyurea can decrease sperm count and motility in men, potentially causing infertility [1.6.1, 1.5.6]. The effects may be reversible [1.6.4].
- Pregnancy and Breastfeeding: The medication can cause harm to a fetus and should not be taken during pregnancy [1.6.2]. Effective contraception is required for both men and women during and for a period after treatment [1.8.4]. It is also not recommended while breastfeeding [1.8.2].
Conclusion
Hydroxyurea has a profound and multifaceted effect on the body. Its ability to inhibit DNA synthesis makes it a potent agent against certain cancers and myeloproliferative neoplasms by controlling the overproduction of blood cells [1.7.5, 1.7.2]. In sickle cell disease, its effects are even more complex, leading to an increase in protective fetal hemoglobin, a reduction in inflammatory cells, and improved red blood cell health, all of which combine to significantly reduce the disease's debilitating complications [1.2.1]. Despite its benefits, the drug carries significant risks, including bone marrow suppression and a potential for secondary malignancies, necessitating careful and continuous medical supervision [1.6.2, 1.6.6].
For more information, a good resource is the National Cancer Institute: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/hydroxyurea [1.7.1].
