TITLE

Deprenyl Enhances the Teratogenicity of Hydroxyurea in Organogenesis Stage Mouse Embryos

AUTHOR(S)
Schlisser, Ava E.; Hales, Barbara F.
PUB. DATE
August 2013
SOURCE
Toxicological Sciences;Aug2013, Vol. 134 Issue 2, p391
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Hydroxyurea, an antineoplastic drug, is a model teratogen. The administration of hydroxyurea to CD1 mice on gestation day 9 induces oxidative stress, increasing the formation of 4-hydroxy-2-nonenal adducts to redox-sensitive proteins such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the caudal region of the embryo. GAPDH catalytic activity is reduced, and its translocation into the nucleus is increased. Because the nuclear translocation of GAPDH is associated with oxidative stress–induced cell death, we hypothesized that this translocation plays a role in mediating the teratogenicity of hydroxyurea. Deprenyl (also known as selegiline), a drug used as a neuroprotectant in Parkinson’s disease, inhibits the nuclear translocation of GAPDH. Hence, timed pregnant CD1 mice were treated with deprenyl (10mg/kg) on gestation day 9 followed by the administration of hydroxyurea (400 or 600mg/kg). Deprenyl treatment significantly decreased the hydroxyurea-induced nuclear translocation of GAPDH in the caudal lumbosacral somites. Deprenyl enhanced hydroxyurea-mediated caudal malformations, inducing specifically limb reduction, digit anomalies, tail defects, and lumbosacral vertebral abnormalities. Deprenyl did not augment the hydroxyurea-induced inhibition of glycolysis or alter the ratio of oxidized to reduced glutathione. However, it did dramatically increase cleaved caspase-3 in embryos. These data suggest that nuclear GAPDH plays an important, region-specific, role in teratogen-exposed embryos. Deprenyl exacerbated the developmental outcome of hydroxyurea exposure by a mechanism that is independent of oxidative stress. Although the administration of deprenyl alone did not affect pregnancy outcome, this drug may have adverse consequences when combined with exposures that increase the risk of malformations.
ACCESSION #
89102690

 

Related Articles

  • Hydroxyurea Exposure Triggers Tissue-Specific Activation of p38 Mitogen-Activated Protein Kinase Signaling and the DNA Damage Response in Organogenesis-Stage Mouse Embryos. Banh, Serena; Hales, Barbara F. // Toxicological Sciences;Jun2013, Vol. 133 Issue 2, p298 

    Editor’s Highlight: Hydroxyurea, a commonly used antineoplastic agent, induces teratogenesis accompanied by oxidative stress in rodent models. Banh and Hales report on the early and transient activation of p38 MAPK downstream of MEK3/6 following in utero exposure of murine embryos to...

  • Successful outcome of pregnancy in a case of essential thrombocytosis treated with hydroxyurea. Oskuie, A. Eishi; Valizadeh, N. // Indian Journal of Cancer;Apr-Jun2011, Vol. 48 Issue 2, p268 

    The article presents a case study of a 42-year-old pregnant woman with essential thrombocytosis in 2005 when she presented with spontaneous splenic rupture and thrombocytosis. The patient underwent a series of examinations, including splenomegaly, thrombocytosis, and bone marrow aspiration,...

  • Teratogenicity of asbestos in mice. Tomoko Fujitani; Motoki Hojo; Akiko Inomata; Akio Ogata; Akihiko Hirose; Tetsuji Nishimura; Dai Nakae // Journal of Toxicological Sciences;May2014, Vol. 39 Issue 2, p363 

    Possible teratogenicity of 3 different asbestos (crocidolite, chrysotile and amosite) was assessed in CD1(ICR) mice. Dams on day 9 of gestation were given a single intraperitoneal administration at dose of 40 mg/kg body weight of asbestos suspended in 2% sodium carboxymethyl cellulose solution...

  • Hydroxycarbamide.  // Reactions Weekly;Sep2015, Vol. 1567 Issue 1, p111 

    The article presents case report of a patient who developed severe anaemia during treatment with hydroxycarbamide.

  • The Effect of Cell Cycle Synchronization on Tumor Sensitivity to Reovirus Oncolysis. Heinemann, Lucy; Simpson, Guy R.; Annels, Nicola E.; Vile, Richard; Melcher, Alan; Prestwich, Robin; Harrington, Kevin J.; Pandha, Hardev S. // Molecular Therapy;Dec2010, Vol. 18 Issue 12, p2085 

    The potential for increased sensitivity of tumor cells to oncolytic reovirus by altering the normal cell cycle using clinically available pharmacological agents was investigated. B16.F10 mouse melanoma cells were partially synchronized with hydroxyurea, thymidine, or by mitotic shake-off. Cell...

  • Ribonucleotide Reductase as One Important Target of [Tris(1,10-phenanthroline)lanthanum(III)] Trithiocyanate (KP772). Heffeter, P.; Popovic-Bijelic, A.; Saiko, P.; Dornetshuber, R.; Jungwirth, U.; Voevodskaya, N.; Biglino, D.; Jakupec, M. A.; Elbling, L.; Micksche, M.; Szekeres, T.; Keppler, B. K.; Gräslund, A.; Berger, W. // Current Cancer Drug Targets;Aug2009, Vol. 9 Issue 5, p595 

    KP772 is a new lanthanum complex containing three 1,10-phenathroline molecules. Recently, we have demonstrated that the promising in vitro and in vivo anticancer properties of KP772 are based on p53-independent G0/G1 arrest and apoptosis induction. A National Cancer Institute (NCI) screen...

  • Antitumor Mechanisms of Amino Acid Hydroxyurea Derivatives in the Metastatic Colon Cancer Model. Šaban, Nina; Stepanić, Višnja; Vučinić, Srđan; Horvatić, Anita; Cindrić, Mario; Perković, Ivana; Zorc, Branka; Oršolić, Nada; Mintas, Mladen; Pavelić, Krešimir; Pavelić, Sandra Kraljević // International Journal of Molecular Sciences;Dec2013, Vol. 14 Issue 12, p23654 

    The paper presents a detailed study of the biological effects of two amino acid hydroxyurea derivatives that showed selective antiproliferative effects in vitro on the growth of human tumor cell line SW620. Tested compounds induced cell cycle perturbations and apoptosis. Proteins were identified...

  • Molecular cytogenetic study of derivative chromosome 9 deletion in chronic myeloid leukemia patients. Bennour, Ayda; Ouahchi, Ines; Ben Youssef, Yosra; Zaier, Monia; Laatiri, Mohamed; Harrabi, Imed; Meddeb, Balkis; Elloumi, Moez; Khelif, Abderrahim; Saad, Ali; Sennana, Halima // Medical Oncology;Jun2012, Vol. 29 Issue 2, p1151 

    The aims of this study are to investigate the frequency of derivative chromosome 9 (der (9)) deletion in Tunisian patients with chronic myeloid leukemia (CML) and to assess the correlation between this deletion and the cytogenetic response for patients treated with hydroxyurea (HU) or imatinib...

  • SOUND OFF! You can't be too careful with cytotoxic drugs. Krahe, Elayne M. // RN;Feb85, Vol. 48 Issue 2, p71 

    Deals with nursing considerations in the administration of cytotoxic drugs. Clinical manifestations of allergy from cytotoxic drug use; Tips on safe drug preparation; Aseptic techniques in drug administration.

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics