Hydroxyurea was synthesised in Germany in 1860 and was found inhibit granulocyte production. It was only a hundred years after this that its potential as an anticancer drug was realized.
Mechanism of Action of Hydroxyurea
Hydroxyurea enters the cell by passive diffusion. It inhibits of ribonucleotide reductase (RR). RR converts ribonucleotide diphosphates to deoxyribonucleotide diphosphates. Deoxyribonucleotide diphosphates are converted to deoxyribonucleotide triphosphates and incorporated into DNA. Depletion of deoxyribonucleotide triphosphates results in impaired DNA synthesis. RR has two subunits M-1 and M2. The M-2 subunit is the catalytic subunit and contains iron. Hydroxyurea inhibits RR by chelating iron. Hydroxyurea is an S phase specific drug. The cells exposed to hydroxyurea progress normally through the cell cycle, have a normal G1-S transition but accumulate in the S phase because of an inability to synthesise DNA. They then undergo apoptosis by p53 dependent and independent mechanisms. Hydroxyurea may be transformed to nitric oxide. Nitric oxide is also an inhibitor of RR and may be responsible for drugs ability to induce foetal haemoglobin. This is important for treatment of sickle cell anaemia. Resistance to HU develops by elevated cellular activity of RR.
Pharmacokinetics of Hydroxyurea
Oral bioavailability of hydroxyurea is 80-100%. Parenteral formulation has no advantage over oral formulation. The drug is well distributed. It enters breast milk, cerebrospinal fluid and third space collections. The ratio of plasma to CSF levels is 4-9:1 and plasma to ascites levels is 2-7.5:1. The elimination half-life is 3.5-4.5 hours. Renal elimination is the main pathway of elimination. Sixty to eighty per cent of the dose eliminated by kidney unchanged. Patients with creatinine clearance of 10-50ml/hr should receive 50% and those with creatinine clearance of less than 10ml/hr should receive 20% of the planned dose. Hydroxyurea is metabolized but the metabolic pathways are not known.
- Myeloproliferative diseases
- Chronic myeloid leukaemia
- Essential thrombocytosis
- Polycythaemia Vera
- Acute leukaemia to control counts
- Sickle cell anaemia
Myelosuppression is the dose limiting effect of hydroxyurea. The dose of hydroxyurea needs to be titrated to the leucocyte and platelet counts. The acceptable lower limits of these counts will depend on the indication but generally speaking a leukocyte count less than 2.5X109/L or a platelet count less than 100X109/L is an indication for discontinuing therapy. With the abovementioned provisions in mind the dose of hydroxyurea for different indications are as follows:
- Myeloproliferative diseases: The usual dose is 20-30mg/kg/day.
- Acute leukaemia: 50-100mg/kg per day
- Sickle cell anaemia: 15-20mg/kg/day
- HU inhibits formation of deoxynucleotides and enhanced the effect of agents damaging the DNA, as no nucleotides are available for repair. The effects of purine and pyrimidine analogues. When hydroxyurea is combined with any of these agents it should be done as a part of a protocol whose toxicity has been evaluated. This will prevent unacceptable toxicity.
- It has been shown to be synergistic with agents damaging the DNA like cisplatin, alkylating agents and topoisomerase II inhibitors.
- It has been used as a radiosensitizing agent in the treatment of head and neck and cervical cancer. It depletes the deoxynucleotide pool needed for DNA repair after radiation-induced damage.
- Enhanced anti HIV activity of azidothymidine, dideocytidine and dideoxyinosine
- Myelosuppression: The dose limiting toxicity of hydroxyurea is myelosuppression. Hydroxyurea causes rapid fall in leucocyte counts. When used in non-haematological malignancies the fall in leucocyte counts is evident by days 2-5. When used in patients with leukaemia the fall is evident faster, sometimes within a day. This property of hydroxyurea is useful in myeloid leukaemia with very high leucocyte count. Hydroxyurea is the treatment of choice for patients with chronic myeloid leukaemia presenting with very high counts. Though used in acute myeloid leukaemia with hyperleucocytosis, benefit from its use has not been proven in clinical trials.
- Gastrointestinal: Oral ulceration and gastrointestinal tract effects may be seen in some patients. They are particularly common in patients who receive chemoradiation with hydroxyurea.
- Skin: Dermatological changes may be seen with prolonged use. These include
- Skin Pigmentation and rash: Hyperpigmentation, erythema of the face and hands, diffuse maculopapular rash and dry skin. Severe reactions may resemble lichen planus.
- Nail Changes: The nails may show atrophy and formation of multiple pigmented bands.
- Leg Ulcers: Leg ulcerations may be seen in patients with prolonged therapy with hydroxyurea.
- Alopecia: Alopecia may occasionally be seen with the use of hydroxyurea
- Radiation Recall: Erythema or pigmentation of previously radiated skin may be seen in some patients.
- Mutagenicity and Teratogenicity: Hydroxyurea is a proven teratogen and contraindicated in women are pregnant or are planning a pregnancy. Women in the reproductive age group must be advised about contraception. The carcinogenic potential of hydroxyurea is uncertain. In view of the mechanism of action it is prudent not to use hydroxyurea for non-malignant disease.