How does hydroxyurea work in sickle cell disease?

Mechanism of Action of Hydroxyurea in Sickle Cell Disease

Hydroxyurea works primarily by inhibiting ribonucleotide reductase, which blocks DNA synthesis and causes an immediate increase in fetal hemoglobin (HbF) production—this elevated HbF inhibits the sickling of red blood cells and reduces vaso-occlusive complications. 1, 2

Primary Mechanism

• Ribonucleotide reductase inhibition is the central mechanism by which hydroxyurea exerts its antineoplastic and therapeutic effects in sickle cell disease 1
• This enzyme inhibition blocks DNA synthesis without interfering with RNA or protein synthesis 1
• The result is a substantial increase in fetal hemoglobin (HbF) levels—typically increasing total and fetal hemoglobin concentrations by 4-20% relative to baseline 3, 4

How Elevated HbF Prevents Sickling

• Fetal hemoglobin directly inhibits the polymerization of sickle hemoglobin (HbS), preventing red blood cells from assuming the characteristic sickle shape 2
• Higher HbF levels are strongly associated with reduced morbidity and mortality in sickle cell disease 5
• The therapeutic benefit appears when HbF levels reach ≥0.5 g/dL, with cumulative 9-year mortality of 15% compared to 28% when HbF remains below this threshold 5

Secondary Beneficial Effects

Beyond HbF induction, hydroxyurea produces additional therapeutic effects:

• Reduces hemolysis by improving red blood cell membrane stability 3
• Decreases white blood cell and reticulocyte counts, reducing the inflammatory cascade that contributes to vaso-occlusion 3
• May improve nitric oxide bioavailability, though this mechanism is less well-established 6

Clinical Impact of the Mechanism

The mechanism translates into measurable clinical benefits:

• 50% reduction in painful vaso-occlusive crises compared to placebo 3, 2
• Decreased acute chest syndrome episodes by approximately 50% 3
• Reduced hospitalizations by 18-32% and decreased transfusion requirements 3, 4
• 40% reduction in mortality observed in long-term follow-up studies extending to 9-17 years 3, 5

Cell Cycle Effects

Hydroxyurea also affects the cell cycle in ways that may contribute to its efficacy:

• Arrests cells in the G1 phase (pre-DNA synthesis stage) of the cell cycle 1
• This arrest may allow damaged cells to undergo repair rather than propagating with DNA damage 1
• The drug is particularly lethal to S-phase cells, which are normally more resistant to certain stresses 1

Important Caveats

• The fetal hemoglobin response is variable between patients, and our ability to predict individual responses remains limited despite advances in genomic understanding 6
• While HbF elevation is the primary mechanism, elevated HbF alone does not guarantee complete protection from vaso-occlusive complications—some patients experience major events despite HbF levels exceeding 20% 7
• The drug requires prolonged therapy (at least 5 years) to achieve maximal mortality benefit, suggesting that sustained HbF elevation is necessary 3
• Myelosuppression is the dose-limiting toxicity, occurring through the same mechanism that produces therapeutic benefit—inhibition of DNA synthesis in rapidly dividing bone marrow cells 1, 8