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3.2. Radical scavengers as inhibitors of RNR

The best-known inhibitor of RNR is hydroxyurea, a cell cycle phase-specific (S-phase) inhibitor that is also known to behave as a radiosensitizer. After oral administration, this compound is well absorbed and transported into cells, where it quenches the tyrosyl radical at the active site of RNR, inactivating the enzyme (Fig. 2.8).4 Hydroxyurea is primarily used in the management of myeloprolifera-tive disorders, such as chronic granulocytic leukemia, polycythemia vera, and essential thrombocytosis, and is sometimes combined with other antitumor drugs such as the tyrosine kinase inhibitor imatinib.5 Hydroxyurea is also useful in the treatment of sickle cell anemia because it eases the pain of the patients, which has been attributed to its ability to generate nitric oxide, a potent vasodilator.6 Nitric oxide may also contribute to the antitumor effect of hydroxyurea, since it is known to inhibit RNR probably because it contains an unpaired electron and therefore it is able to quench the tyrosine radical.7

Thiosemicarbazones, represented by triapine, are another important class of inhibitors of RNR that are being the subject of Phase I studies.8 Besides quenching the tyrosyl radical similarly to hydroxyurea, triapine is an iron chelator, which

Tyr-122

Tyr-122

Tyr-122

Tyr-122

Tyr-122

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