What is the mechanism of action of Hydroxeura?

Mechanism of Action of Hydroxyurea

Hydroxyurea works primarily by inhibiting ribonucleotide reductase (RNR), which blocks DNA synthesis and causes cell cycle arrest, while in sickle cell disease it specifically increases fetal hemoglobin (HbF) production to prevent red blood cell sickling. 1

Primary Mechanism: Ribonucleotide Reductase Inhibition

• Hydroxyurea suppresses ribonucleotide reductase, the enzyme responsible for converting ribonucleotides to deoxyribonucleotides needed for DNA synthesis 2
• This inhibition slows DNA polymerase movement at replication forks and induces S-phase cell cycle arrest in rapidly proliferating cells 2
• The cytotoxic effect results from collapsed replication forks and aberrant mitosis in cells attempting to divide without adequate DNA precursors 2

Disease-Specific Mechanisms

In Sickle Cell Disease

• Hydroxyurea increases fetal hemoglobin (HbF) production, which is the key therapeutic mechanism in sickle cell disease 1
• Higher HbF levels inhibit sickling of red blood cells by preventing deoxygenated sickle hemoglobin polymerization 3
• This mechanism reduces painful vaso-occlusive episodes by approximately 50% and decreases acute chest syndrome, hospitalizations, and transfusion requirements 1
• The HbF induction is a complex inherited trait with variable response between patients, though baseline HbF remains the best predictor of drug-induced levels 3

In Myeloproliferative Disorders

• Hydroxyurea controls excessive proliferation of myeloid cells through its cytoreductive effects on rapidly dividing bone marrow cells 1
• It is the first-choice cytoreductive agent in polycythemia vera and essential thrombocythemia to reduce platelet counts, white blood cell counts, and splenomegaly 4
• The drug reduces organomegaly in myeloproliferative neoplasms by controlling the proliferation of myelomonocytic cells 1

In Acute Leukemia

• Hydroxyurea rapidly lowers blast cell counts by approximately 50% after a single dose in patients with peripheral blast counts >100,000/mm³ 5
• This prevents leukostasis syndrome by quickly reducing the burden of circulating blast cells before definitive chemotherapy takes effect 5

Secondary and Alternative Mechanisms

• Emerging evidence suggests hydroxyurea may have secondary unknown targets beyond RNR, as demonstrated by its ability to induce cytokinesis arrest in certain mutant cells at low doses 2
• In cells with defects in the ergosterol biosynthesis pathway, hydroxyurea causes stable cytokinesis arrest rather than S-phase arrest, suggesting additional cellular targets 2

Clinical Implications of Mechanism

• The S-phase arrest in normal cells is reversible, which explains why temporary discontinuation allows blood count recovery 1
• Myelosuppression is the most common dose-limiting toxicity because hydroxyurea preferentially affects rapidly dividing cells including bone marrow precursors 1, 6
• The variable HbF response in sickle cell disease (accounting for only a portion of therapeutic variability) necessitates individualized dose titration based on clinical response and blood count monitoring 3