Much of the pharmacological research to treat sickle cell focused on drugs that would induce the production of fetal haemoglobin because of its protective role. The first drug to be tested in patients that showed an increase in fetal haemoglobin production was 5-azacytidine, but this drug was never tested in large-scale clinical trials because of suspected carcinogenic (cancer causing) effects. In experiments where rats were treated with 5-azacytidine, there were increased incidents of tumors.
The next obvious choice was to find a drug with similar effects on HbF levels as 5-azacytidine and HU was one of these. The very first experiments with hydroxyurea were performed in anemic monkeys, followed by a successful study on just two patients that showed in increased in HbF levels after being treated with hydroxyurea. But to gain FDA approval, drugs need to prove success through multiple phases of clinical trials, so the preliminary studies were followed by many small scale clinical studies with both adults and children. Once hydroxyurea was proven effective in these small scale studies it was then tested in a large multicenter clinical trial that involved 150 patients with sickle cell who were monitored for over a two-year period. The multicenter trial produced a positive outcomes leading to the approaval of hydroxyurea by the FDA as the first disease-modifying drug.
A timeline of the growth in hydroxyurea research since the 1980s can be found here.
The mechanism by hydroxyurea increases HbF levels is currently not very well understood. Inhibition of ribonucleotide reductase, an enzyme that is needed to produce nucleotides that makes up DNA, by hydroxyurea is thought to be the most important. By inhibiting the production of ribonucleotides, hydroxyurea essentially stops DNA synthesis and eventually cells will die because long-term exposure to hydroxyurea is toxic. Hydroxyurea also decreases the frequency of painful episodes, acute chest syndrome, need for transfusions and the number of hospital admissions for patients with sickle cell. Hydroxyurea is also favoured over other drugs because it can be taken orally and it has low toxic effects.