Protection against hydroxyurea-induced cytotoxic effects in L5178Y cells by free radical scavengers

Przybyszewski, Waldemar M.; Malec, J

doi:10.1016/0304-3835(82)90036-2

Cited by 22 publications

(7 citation statements)

References 7 publications

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“…Subsequent studies by his group and other labs showed that radical scavengers substantially ameliorated the cytotoxic and teratogenic effects of HU [83,99,100]. These earlier studies suggest that accumulation of ROS might be involved in the cell-killing process of HU.…”

Section: Accumulation Of Reactive Oxygen Species (Ros)mentioning

confidence: 99%

“…However, earlier studies showed that at high concentrations or with prolonged exposure at lower doses, HU is cytotoxic to various mammalian cells such as Chinese hamster cells, mouse lymphoma cells, Ehrlich ascites tumor cells, and human lymphocytes [79,81,82,83,84], although HeLa and A549 lung carcinoma cells appear to be less sensitive [85,86]. Cytotoxicity after HU administration has also been found in rat and mouse proliferating tissues and embryos [87,88,89,90].…”

Section: S Phase Arrest Dna Damage and The Checkpoint Responsementioning

confidence: 99%

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The Cell Killing Mechanisms of Hydroxyurea

Singh

2016

Genes

188

157

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Hydroxyurea is a well-established inhibitor of ribonucleotide reductase that has a long history of scientific interest and clinical use for the treatment of neoplastic and non-neoplastic diseases. It is currently the staple drug for the management of sickle cell anemia and chronic myeloproliferative disorders. Due to its reversible inhibitory effect on DNA replication in various organisms, hydroxyurea is also commonly used in laboratories for cell cycle synchronization or generating replication stress. However, incubation with high concentrations or prolonged treatment with low doses of hydroxyurea can result in cell death and the DNA damage generated at arrested replication forks is generally believed to be the direct cause. Recent studies in multiple model organisms have shown that oxidative stress and several other mechanisms may contribute to the majority of the cytotoxic effect of hydroxyurea. This review aims to summarize the progress in our understanding of the cell-killing mechanisms of hydroxyurea, which may provide new insights towards the improvement of chemotherapies that employ this agent.

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Section: Accumulation Of Reactive Oxygen Species (Ros)mentioning

confidence: 99%

Section: S Phase Arrest Dna Damage and The Checkpoint Responsementioning

confidence: 99%

The Cell Killing Mechanisms of Hydroxyurea

Singh

2016

Genes

188

157

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“…Benzoic Acid and Sodium Benzoate are recognized as hydroxyl radical scavengers and researchers have reported that benzoates inhibited mechanisms that generated free radicals. In in vitro studies, benzoates reduced the cytotoxicity of drugs/chemicals such as hydroxyure a in L5178Y cells (Przybyszewski and Malec 1982), 6-hydroxydopamin e in mouse pancreatic islets (Grankvist, Sehlin, and Taeljedal 1986), doxorubicin in a Doxsensitive human ovarian cancer cell line (Cervantes et al 1988), and inhibited argemone oil-induced enzymatic and nonenzymatic hepatic lipid peroxidation in rat cells (Upreti, Das, and Khanna 1991). In other in vitro studies, benzoates inhibited some chemical-induced DNA lesions (Kaneko et al 1984;Sugioka et al 1984;Daniel, Mao, and Saf otti 1983;Mahmood et al 1993).…”

Section: Radical Scavenging Activity Benzoic Acid and Sodium Benzoatementioning

confidence: 99%

Final Report on the Safety Assessment of Benzyl Alcohol, Benzoic Acid, and Sodium Benzoate

Nair¹

2001

Int J Toxicol

215

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Benzyl Alcohol is an aromatic alcohol used in a wide variety of cosmetic formulations as a fragrance component, preservative, solvent, and viscosity-decreasing agent. Benzoic Acid is an aromatic acid used in a wide variety of cosmetics as a pH adjuster and preservative. Sodium Benzoate is the sodium salt of Benzoic Acid used as a preservative, also in a wide range of cosmetic product types. Benzyl Alcohol is metabolized to Benzoic Acid, which reacts with glycine and excreted as hippuric acid in the human body. Acceptable daily intakes were established by the World Health Organization at 5 mg/kg for Benzyl Alcohol, Benzoic Acid, and Sodium Benzoate. Benzoic Acid and Sodium Benzoate are generally recognized as safe in foods according to the U.S. Food and Drug Administration. No adverse effects of Benzyl Alcohol were seen in chronic exposure animal studies using rats and mice. Effects of Benzoic Acid and Sodium Benzoate in chronic exposure animal studies were limited to reduced feed intake and reduced growth. Some differences between control and Benzyl Alcohol-treated populations were noted in one reproductive toxicity study using mice, but these were limited to lower maternal body weights and decreased mean litter weights. Another study also noted that fetal weight was decreased compared to controls, but a third study showed no differences between control and Benzyl Alcohol-treated groups. Benzoic Acid was associated with an increased number of resorptions and malformations in hamsters, but there were no reproductive or developmental toxicty findings in studies using mice and rats exposed to Sodium Benzoate, and, likewise, Benzoic Acid was negative in two rat studies. Genotoxicity tests for these ingredients were mostly negative, but there were some assays that were positive. Carcinogenicity studies, however, were negative. Clinical data indicated that these ingredients can produce nonimmunologic contact urticaria and nonimmunologic immediate contact reactions, characterized by the appearance of wheals, erythema, and pruritis. In one study, 5% Benzyl Alcohol elicited a reaction, and in another study, 2% Benzoic Acid did likewise. Benzyl Alcohol, however, was not a sensitizer at 10%, nor was Benzoic Acid a sensitizer at 2%. Recognizing that the nonimmunologic reactions are strictly cutaneous, likely involving a cholinergic mechanism, it was concluded that these ingredients could be used safely at concentrations up to 5%, but that manufacturers should consider the nonimmunologic phenomena when using these ingredients in cosmetic formulations designed for infants and children. Additionally, Benzyl Alcohol was considered safe up to 10% for use in hair dyes. The limited body exposure, the duration of use, and the frequency of use were considered in concluding that the nonimmunologic reactions would not be a concern. Because of the wide variety of product types in which these ingredients may be used, it is likely that inhalation may be a route of exposure. The available safety tests are not considered sufficient to support the safety of these ingredients in formulations where inhalation is a route of exposure. Inhalation toxicity data are needed to complete the safety assessment of these ingredients where inhalation can occur.

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“…It has been recommended that the use of HU therapy in children with SCD should be followed with caution because its long-term cytotoxic effects are yet to be determined (8)(9)(10)(11). It has also been suggested that the teratogenic and toxic effects of HU may be mediated through free radical reactions (12,13). In an in vitro study, Malec et al have shown that HU has the ability to induce damage to normal erythrocyte membranes, as indicated by increased red blood cell (RBC) lysis and lipid peroxidation (14).…”

mentioning

confidence: 99%

Hydroxyurea-induced oxidative damage of normal and sickle cell hemoglobins in vitro: Amelioration by radical scavengers

Iyamu

Fasold

Roa

et al. 2001

J. Clin. Lab. Anal.

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Hydroxyurea (HU) induces fetal hemoglobin (Hb F) production in patients with sickle cell anemia. The therapeutic dosage of HU used for Hb F induction often elicits myelosuppression, which becomes its major associated complication. We examined the effect of HU on hemoglobin modulation and the role of radical scavengers on these induced changes. In vitro exposure of human blood to various concentrations of HU at predetermined time intervals induced a progressive dose‐dependent oxidation (MetHb formation) of both adult (Hb AA) and sickle (Hb SS) hemoglobins. The oxidative effect of HU on Hb SS was 3 times greater than its effect on Hb AA. Similar but less profound changes were observed in H2O2‐treated samples. Hb F was, however, observed to be relatively resistant to HU‐induced oxidative damage. A substantial protective effect of Hb by α‐tocopherol, ascorbic acid, and D‐mannitol was observed during pretreatment of Hb AA and Hb SS blood samples. Analyses of the hemoglobins and their globin chain components by high‐performance liquid chromatography revealed a considerable protective effect by these free radical scavengers. These results indicate that the HU‐induced damage of hemoglobin and their component globin chains can be reduced by radical scavengers. J. Clin. Lab. Anal. 15:1–7, 2001. © 2001 Wiley‐Liss, Inc.

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Protection against hydroxyurea-induced cytotoxic effects in L5178Y cells by free radical scavengers

Cited by 22 publications

References 7 publications

The Cell Killing Mechanisms of Hydroxyurea

The Cell Killing Mechanisms of Hydroxyurea

Final Report on the Safety Assessment of Benzyl Alcohol, Benzoic Acid, and Sodium Benzoate

Hydroxyurea-induced oxidative damage of normal and sickle cell hemoglobins in vitro: Amelioration by radical scavengers

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