VOL.: 76 (2000) (p. 347)
CAS No.:
Chem. Abstr. Name: Hydroxyurea
Hydroxyurea is a chemically simple antimetabolite that inhibits the enzyme ribonucleotide reductase. It has been in clinical use since the 1960s and is widely used for the treatment of severe sickle-cell disease, chronic myeloid leukaemia, myeloproliferative disorders such as polycythaemia vera and essential thrombocythaemia and, increasingly, in combination with didanosine in HIV infection. Hydroxyurea is sometimes used for the treatment of psoriasis and various solid tumours.
5.2 Human carcinogenicity data
The risk for leukaemia associated with administration of hydroxyurea in the treatment of chronic myeloproliferative disorders has been evaluated in a number of small cohort studies. Overall, 5–6% of patients developed either acute leukaemia or myelodysplastic syndrome subsequent to the start of hydroxyurea treatment. Large variation in the length of active follow-up was not taken into account in the analyses. The risk for leukaemia in patients with chronic myeloproliferative disorders who were not treated with hydroxyurea or other agents (e.g. polycythaemia vera patients treated with phlebotomy alone) was also increased in comparison with that of the general population. The available data do not allow a conclusion about whether the occurrence of acute leukaemia and myelodysplastic syndrome in the hydroxyurea-treated patients represents progression of the myeloproliferative process or an effect of the treatment.
5.3 Animal carcinogenicity data
Hydroxyurea was tested in one experiment in mice by intraperitoneal administration beginning at two days of age. No increase in the incidence of tumours was reported. Hydroxyurea has also been tested in combination with other chemical carcinogens to assess the effect of inhibition of DNA synthesis on carcinogenesis. The experiments are inadequate to assess the carcinogenicity of hydroxyurea.
5.4 Other relevant data
Hydroxyurea is readily absorbed after oral administration. In one study, 35% of an administered dose was excreted unchanged in the urine of humans. Hydroxyurea is widely distributed in tissues. Its main toxic effect is neutropenia.
Hydroxyurea is teratogenic and causes postnatal behavioural deficits after prenatal exposure in all species of animals in which it has been tested. It has commonly been used as positive control substance in studies of developmental toxicity.
In one study of patients treated with hydroxyurea for essential thrombocythaemia who developed leukaemia, a statistically non-significant association was found with a 17p chromosomal deletion in leukaemic cells.
Hydroxyurea neither bonds chemically nor otherwise binds to DNA. Instead, it inhibits ribonucleotide reductase, which converts ribonucleoside diphosphates to deoxyribonucleotide diphosphate precursers for de-novo DNA synthesis. Hydroxyurea does not induce gene mutation in bacteria and does not cause mutation at the Hprt locus in mammalian cells. It causes chromosomal mutations and mutagenic effects at the Tk locus in mouse lymphoma cells. It is an effective recombinogen in yeast and induces sister chromatid exchange in mammalian cells. It also causes gene amplification in mammalian cells and may lead to transformation of some but not all cell lines. Although it has been reported to be ineffective in causing germ-cell mutation, it has not been extensively tested for that end-point.
5.5 Evaluation
There is inadequate evidence in humans for the carcinogenicity of hydroxyurea.
There is inadequate evidence in experimental animals for the carcinogenicity of hydroxyurea.
Overall evaluation
Hydroxyurea is not classifiable as to its carcinogenicity to humans (Group 3).
For definition of the italicized terms, see Preamble Evaluation.
Synonyms
See Also:
Toxicological Abbreviations