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Hydroxyurea


ACCESSION NB: DB01005 (APRD00023)


TYPE: small molecule


GROUP: approved


DESCRIPTION:
An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase. [PubChem]

VOLUME OF DISTRIBUTION: Not Available

CATEGORIES:
Antineoplastic Agents Enzyme Inhibitors Nucleic Acid Synthesis Inhibitors Antisickling Agents

ABSORPTION: Well absorbed from the gastrointestinal tract.

INDICATION:
For management of melanoma, resistant chronic myelocytic leukemia, and recurrent, metastatic, or inoperable carcinoma of the ovary and Sickle-cell anemia.

PHARMACODYNAMICS:
Hydroxyurea has dose-dependent synergistic activity with cisplatin in vitro. In vivo Hydroxyurea showed activity in combination with cisplatin against the LX-1 and CALU-6 human lung xenografts, but minimal activity was seen with the NCI-H460 or NCI-H520 xenografts. Hydroxyurea was synergistic with cisplatin in the Lewis lung murine xenograft. Sequential exposure to Hydroxyurea 4 hours before cisplatin produced the greatest interaction.

MECHANISM OF ACTION:
Hydroxyurea is converted to a free radical nitroxide (NO) in vivo, and transported by diffusion into cells where it quenches the tyrosyl free radical at the active site of the M2 protein subunit of ribonucleotide reductase, inactivating the enzyme. The entire replicase complex, including ribonucleotide reductase, is inactivated and DNA synthesis is selectively inhibited, producing cell death in S phase and synchronization of the fraction of cells that survive. Repair of DNA damaged by chemicals or irradiation is also inhibited by hydroxyurea, offering potential synergy between hydroxyurea and radiation or alkylating agents. Hydroxyurea also increases the level of fetal hemoglobin, leading to a reduction in the incidence of vasoocclusive crises in sickle cell anemia. Levels of fetal hemoglobin increase in response to activation of soluble guanylyl cyclase (sGC) by hydroxyurea-derived NO.

PROTEIN BINDING:
Not Available

METABOLISM:
Hepatic.

TOXICITY:
Oral, mouse: LD50 = 7330 mg/kg; Oral, rat: LD50 = 5760 mg/kg Teratogenicity: Teratogenic effects have occurred in experimental animals.Hydroxyurea use during a small number of human pregnancies has been reported. Adverse effects have not been observed in any of the exposed newborns. Reproductive Effects: Adverse reproductive effects have occurred in experimental animals. Mutagenicity: Mutagenic effects have occurred in experimental animals.Mutagenic effects have occurred in humans.

AFECTED ORGANISMS:
Humans and other mammals