Mechanism of Action of Hydroxyurea
Hydroxyurea inhibits ribonucleotide reductase, blocking DNA synthesis by preventing the conversion of ribonucleotides to deoxyribonucleotides, which is the primary mechanism underlying its therapeutic effects in both chronic myeloid leukemia and sickle cell disease. 1
Primary Molecular Mechanism
Hydroxyurea is converted to a free radical nitroxide in vivo that quenches the tyrosyl free radical at the active site of the M2 protein subunit of ribonucleotide reductase, thereby inactivating this enzyme. 2
This inhibition selectively blocks de novo DNA synthesis without interfering with RNA or protein synthesis, causing cell death specifically in S-phase of the cell cycle. 1, 2
The entire replitase complex becomes inactivated, producing synchronization of surviving cells and rendering them more susceptible to other therapeutic interventions. 2
Mechanism in Sickle Cell Disease
In sickle cell disease, hydroxyurea increases fetal hemoglobin (HbF) production, which inhibits sickling of red blood cells and reduces painful vaso-occlusive episodes. 3
This HbF induction represents a distinct therapeutic mechanism separate from its cytotoxic effects, reducing the incidence of vasoocclusive crises by approximately 50%. 3, 2
The drug decreases the frequency of acute chest syndrome episodes, hospitalizations, and need for blood transfusions. 3
Mechanism in Chronic Myeloid Leukemia
In CML, hydroxyurea serves only as a temporary cytoreductive agent before initiating tyrosine kinase inhibitor (TKI) therapy—it does NOT address the underlying BCR-ABL1 molecular pathophysiology. 4
Hydroxyurea should be used only for a short time (days, not weeks) before initiating a TKI, until the diagnosis of CML has been confirmed. 4
The drug provides rapid cytoreduction in symptomatic hyperleukocytosis (WBC >100 × 10⁹/L) or leukostasis, preventing complications like respiratory failure and neurological symptoms. 4
Once BCR-ABL1 positivity is confirmed, TKI therapy must commence immediately with hydroxyurea tapered before discontinuation—every day without TKI therapy represents lost opportunity for achieving optimal molecular responses. 4
Additional Mechanistic Properties
Hydroxyurea inhibits repair of DNA damaged by chemicals or irradiation, offering potential synergy with radiation therapy or alkylating agents. 2
The drug renders cells sensitive to bleomycin because the quenched tyrosyl free radical no longer stabilizes the adjacent iron center, making it more susceptible to bleomycin's chelating properties. 2
Recent evidence suggests catalase may be a direct target of hydroxyurea, with the drug acting as a competitive inhibitor of catalase-mediated hydrogen peroxide decomposition, potentially functioning as a catalase-activated pro-drug. 5
Clinical Pharmacology Considerations
Hydroxyurea reaches peak plasma concentrations in 1 to 4 hours after oral administration and distributes throughout the body with a volume approximating total body water. 1
Up to 60% undergoes conversion through saturable hepatic metabolism, with about 40% of the administered dose recovered unchanged in urine. 1
In patients with creatinine clearance <60 mL/min or ESRD, exposure to hydroxyurea increases by 64%, requiring dose reduction. 1
Critical Pitfall to Avoid
The most critical error in CML management is continuing hydroxyurea beyond the brief period needed for diagnosis confirmation and initial cytoreduction—this drug cannot achieve the deep molecular responses that TKIs provide and that predict long-term survival. 4