Ribonucleotide reductase, inhibition

Hydroxyurea inactivates the enzyme ribonucleotide reductase, inhibiting ceU synthesis in the S-phase of the DNA cycle. An antimetabolite that is primarily used to treat hematologic mahgnan-cies, it has been used for the treatment of psoriasis for more than 3 decades. It is selectively used, particularly in those with hver disease who would be at risk of adverse effects with other antipsoriatic agents. However, hydroxyurea is less effective than methotrexate. ... 

Inhibits ribonucleotide reductase inhibits DNA synthesis (does not interfere with RNA or protein synthesis)... 

Studies of the pathogenesis of ADA deficiency indicate that at least one mechanism for immunodeficiency in this disorder involves the inhibition of ribonucleotide reductase by toxic levels of deoxyATP (Cohen et al., 1978). Further, it has been shown in cell culture models of ADA deficiency that a limiting metabolite of ribonucleotide reductase inhibition is deoxyCTP and that deoxy-cytidine in certain cells can bypass the inhibition of ribonucleotide reductase by being directly metabolized to deoxyCTP (Ullman et al., 1978). 

For the majority of children with T cell immunodeficiency disease there is no effective therapy. In those who have a known biochemical defect, it may be possible to develop effective pharmacologic approaches to bypassing or correcting their deficiency. It is likely that at least one of the mechanisms responsible for the immunodeficiency seen in ADA deficiency is ribonucleotide reductase inhibition by deoxyATP and vitro cell studies suggest that deoxycytidine can bypass this inhibition (Ullman et al.,... 

When induced in macrophages, iNOS produces large amounts of NO which represents a major cytotoxic principle of those cells. Due to its affinity to protein-bound iron, NO can inhibit a number of key enzymes that contain iron in their catalytic centers. These include ribonucleotide reductase (rate-limiting in DNA replication), iron-sulfur cluster-dependent enzymes (complex I and II) involved in mitochondrial electron transport and cis-aconitase in the citric acid cycle. In addition, higher concentrations of NO,... 

Adenosine deaminase deficiency is associated with an immunodeficiency disease in which both thymus-derived lymphocytes (T cells) and bone marrow-derived lymphocytes (B cells) are sparse and dysfunctional. Purine nucleoside phosphorylase deficiency is associated with a severe deficiency of T cells but apparently normal B cell function. Immune dysfunctions appear to result from accumulation of dGTP and dATP, which inhibit ribonucleotide reductase and thereby deplete cells of DNA precursors. 

Hydroxyurea is an oral drug that inhibits ribonucleotide reductase, which converts ribonucleotides into the deoxyribuon-cleotides used in DNA synthesis and repair. The time to peak concentrations of hydroxyurea is 1 to 2 hours after oral administration. Approximately 50% is degraded by the liver to form urea and respiratory carbon dioxide. The remainder is excreted by the kidney. The half-life ranges from 3.5 to 4.5 hours. Hydroxyurea has shown clinical activity in the treatment of chronic myelocytic leukemia, polycythemia vera, and thrombocytosis. The major side effects are myelo-suppression, nausea and vomiting, diarrhea, and constipation. Rash, mucositis, and renal tubular dysfunction occur rarely. 

HU is an inhibitor of ribonucleotide reductase, a rate-limiting enzyme which catalyzes the conversion of ribonucleotides into deoxyribonucleotides. HU is thus a cytotoxic agent as it has the ability to inhibit DNA synthesis. Consequently, H U can affect only cells that are actively synthesizing DNA and, therefore, a drug of S-phase cell-cycle specific. Moreover, HU-mediated inhibition of ribonucleotide reductase is reversible, implying that the action of HU will exhibit a relatively straight forward concentration-time course dependence [2—4-]. 

Since HU needs to be taken lifelong in the treatment of non-neoplastic conditions such as SCA (since the inhibition of ribonucleotide reductase is reversible) a major concern is its long term secondary effects. Several studies have shown the potential leukomegenic effect of HU in myeloproliferative disorders [22], [23]. Such concern becomes quite legitimate in sickle cell patients with permanently expanded erythropoiesis in whom the use of HU is at the limit of marrow toxicity. Hence alternative therapies must be sought for. 

Hydroxyurea -antimetabolite inhibits ribonucleotide reductase cell cycle specific -bone marrow suppression -nausea and vomiting (uncommon at standard doses) -maculopapular rash -skin ulceration -megaloblastosis (elevated MCV)... 

Hydroxyurea, an anticancer drug, blocks DNA synthesis indirectly by inhibiting ribonucleotide reductase. 

Regulation of the balance of the concentrations of the four deoxyribonucleotides depends on the properties of only two enzymes, the ribonucleotide reductase complex and deoxy-CMP deaminase. The balance between pyrimidine deoxynucleotides is brought about by the properties of the deoxy-CMP deaminase, which is inhibited by deoxy-TTP and stimulated by deoxy-CTP. The ribonucleotide reductase also possesses allosteric sites which bind all four deoxynucleotide triphosphates, the effect of which is to maintain approximately similar concentrations of all the triphosphates. 

Hydroxyurea selectively inhibits ribonucleotide reductase (see p. 190). As a radical scavenger, it removes the tyrosine radicals that are indispensable for the functioning of the reductase. 

Uses Pancreatic CA, brain mets, NSCLC, gastric CA Action Antimetabolite -1-ribonucleotide reductase produces false nucleotide base-inhibiting DNA synth Dose 1000 mg/m over 30 min-1 h IV inf/wk x 3-4 wk or 6-8 wk modify dose based on hematologic Fxn (per protocol) Caution [D, /-] Contra PRG Disp Inj SE X BM, N/V/D, drug fever, skin rash Interactions t BM depression W/ radiation therapy, antineoplastic drugs -1- live virus vaccines EMS Monitor for S/Sxs of Infxn OD May cause N/V, p iphOTal tingling, fever and chills symptomatic and supportive... 

The answer is D. Impaired immune function in severe combined immunodeficiency (SCID) is the direct result of blocked DNA synthesis due to inadequate supplies of de-oxyribonucleotides in B and T cells. This effect arises by dATP-induced allosteric inhibition of ribonucleotide reductase, which catalyzes reduction of the 2 -hydroxyl groups on ADP and GDP to form dADP and dCDP. The ultimate cause of many cases of SCID is adenosine deaminase deficiency, which leads to accumulation of dATP and consequent inhibition of ribonucleotide reductase. Although the other enzymes mentioned are also involved in purine nucleotide metabolism, their deficiencies do not lead to SCID. 

Gemcitabine is intracellularly activated by nucleoside kinases to diphosphate and triphosphate nucleosides. Gemcitabine diphosphate inhibits DNA synthesis by inhibiting ribonucleotide reductase while gemcitabine triphosphate competes with deoxycytidine triphosphate for incorporation into DNA. Gemcitabine is used for the treatment of non-small cell lung carcinoma and of adenocarcinoma of the pancreas. It has to be administred intravenously and is eliminated by metabolism with an elimination half-life of approximately 50 minutes. Its spectrum of adverse effects is comparable to that of 5-FU. 

Hydroxyurea (Hydrea) inhibits the enzyme ribonucleotide reductase and thus depletes intracellular pools of deoxyribonucleotides, resulting in a specific impairment of DNA synthesis. The drug therefore is an S-phase specific agent whose action results in an accumulation of cells in the late Gj- and early S-phases of the cell cycle. 

Fig. lA. Anabolic and catabolic pathways of 5-FU. DPD dihydropyrimidine dehydrogenase, DP di-hydropyrimidinase, pUP beta-ureidopropionase, UP uridine phosphorylase, OPRT orotate phospho-ribosyl transferase, UK uridine kinase, TP thymidine phosphorylase, TK thymidine kinase, RNR ribonucleotide reductase. The three active metabolites (shown in rectangles) are FdUMP (5-fluoro-2 -deoxyuridine 5 -monophosphate) inhibiting TS (thymidylate synthase), and FUTP (5-fluorouridine 5 -triphosphate) and FdUTP (5-fluoro 2 -deoxyuridine 5 -triphosphate) interfering with RNA and DNA, respectively. 

Kwon, N. S., Stuehr, D. J., and Nathan, C. F. (1991). Inhibition of tumor cell ribonucleotide reductase by macrophage-derived nitric oxide. J. Exp. Med. 174, 761-767. 

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