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. Author manuscript; available in PMC: 2011 Jun 2.
Published in final edited form as: Food Chem Toxicol. 2007 Aug 29;46(4):1371–1377. doi: 10.1016/j.fct.2007.08.028

Effects of antioxidants on cancer prevention and neuromotor performance in Atm deficient mice

Ramune Reliene 1, Sheila M Fleming 2, Marie-Françoise Chesselet 2,3, Robert H Schiestl 1,*
PMCID: PMC3107045  NIHMSID: NIHMS294265  PMID: 18037553

Abstract

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by immunodeficiency, neurodegeneration and cancer. The disease results from bi-allelic mutations in the AT mutated (ATM) gene involved in cell cycle checkpoint control and repair of DNA double-strand breaks. Evidence has been accumulating that oxidative stress is associated with AT and may be involved in the pathogenesis of the disease. This led to a hypothesis that antioxidants may alleviate the symptoms of AT. Consequently, several studies were conducted in Atm deficient mice to examine the role of antioxidants in cancer prevention and/or correction of neuromotor performance. N-acetyl-L-cysteine (NAC), EUK-189, tempol, and 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO) have been tested in Atm deficient mice. In contrast to other antioxidants, NAC has been used in the clinical practice for many decades and is available as a dietary supplement. In this article, we review chemoprevention studies in Atm deficient mice and, in more detail, our findings on the effect of NAC. Our short-tem study showed that NAC suppressed genome rearrangements linked to cancer. The long-term study demonstrated that NAC reduced the incidence and multiplicity of lymphoma and improved some aspects of motor performance.

Keywords: Atm, mouse, antioxidants, chemoprevention, lymphoma, neuromotor performance

Introduction

Ataxia Telangiectasia (AT) is an autosomal recessive human disorder caused by mutational inactivation of the AT mutated (ATM) gene. It is a severe pleiotropic disease characterized by progressive neurodegeneration, high incidence of cancer, immunodeficiency, oculocutaneous telangiectasias, growth retardation, endocrine abnormalities, infertility, and hypersensitivity to ionizing radiation (Boder, 1985; Boder et al., 1970; Gatti, 2001; Lavin et al., 1997; Meyn, 1999). The most prominent neuropathological manifestation of AT is atrophy of the cerebellar cortex associated with the loss of Purkinje and granule cells. An early sign of neurological degeneration is ataxia characterized by unstable gait and lack of coordination of head and eyes. About 40% of AT patients develop cancer, mostly in the lymphoid organs early in life and solid tumors at later age (Gatti et al., 1989; Taylor et al., 1996; Xu, 1999). AT patients display a variety of lymphoid tumors including non-Hodgkin's lymphoma, Hodgkin's lymphoma and several types of leukemia, most tumors being of T cell origin. AT patients suffer from increased mortality due to malignancy, infections of the respiratory system and various rare complications (Boder, 1975; Crawford et al., 2006). The median survival of AT patients is calculated to be 19 - 25 years (Crawford et al., 2006).

The gene defective in AT, ATM, encodes a phosphatidylinositol-3′ related kinase that is involved in cell cycle checkpoint and repair responses to DNA double-strand breaks (DSBs) via a series of phosphorylated intermediary proteins including p53, Chk2, Brca1 and Nbs1 (Lavin et al., 2005; Savitsky et al., 1995; Shiloh, 2003). A lack of ATM function results in genomic instability characterized by chromosome breaks, chromosome gaps, translocations and aneuploidy (Cohen et al., 1975; Gropp et al., 1967; Stumm et al., 2001). ATM deficiency is also associated with elevated oxidative stress. ATM deficient cells in culture are more sensitive to oxidative stress than normal cells, cells isolated from AT patients display elevated oxidative damage to lipids and DNA and AT patients have reduced plasma antioxidant concentrations (Reichenbach et al., 2002; Reichenbach et al., 1999; Yi et al., 1990). Further evidence that AT is linked to oxidative stress stems from studies with Atm deficient mice. Atm deficient mice exhibit elevated levels of reactive oxygen species (ROS), oxidative damage to proteins and DNA, lipid peroxidation and alterations in the levels and function of antioxidative enzymes (Barlow et al., 1999; Ito et al., 2007; Kamsler et al., 2001; Quick et al., 2001; Reliene et al., 2004b). Atm deficient mice largely recapitulate the human disease (Barlow et al., 1996; Borghesani et al., 2000; Elson et al., 1996; Xu et al., 1996). Similar to human AT phenotype, Atm deficient mice display growth retardation, infertility, immunodeficiency, radiosensitivity and malignant lymphomas (Barlow et al., 1996; Elson et al., 1996; Xu et al., 1996). Although Atm deficient mice do not show the gross cerebellar degeneration that characterizes the human disease, more subtle alterations in the cerebellum have been observed and are consistent with a mild decrease in their motor performance (Barlow et al., 1996; Borghesani et al., 2000; Kuljis et al., 1997).

Since oxidative stress has been evidenced in AT and oxidative stress is linked to neurodegenerative diseases and cancer, it has been suggested that it may contribute to neuropathological and malignant phenotype of AT, while antioxidants might alleviate these symptoms (Barzilai et al., 2002). This hypothesis has been tested in Atm deficient mice in several studies that examined the effect of NAC, EUK-189, tempol and CTMIO (Browne et al., 2004; Gueven et al., 2006; Ito et al., 2007; Reliene et al., 2006; Schubert et al., 2004).

NAC

NAC is a low molecular weight thiol-containing molecule that is readily taken up by the cells (Kelly, 1998). It directly inhibits reactive electrophiles and ROS and can enhance the synthesis of glutathione (GSH) as a precursor of cysteine (De Flora et al., 2001). NAC has been used in the clinical practice more than 40 years and has found wide applications (Decramer et al., 2005; Kelly, 1998; Van Schooten et al., 2002). NAC has been used for the treatment of respiratory diseases as a mucolytic agent (Webb, 1962), for acetaminophen overdose, where it rescues from GSH depletion in the liver (Prescott et al., 1977), and is available as an over-the-counter dietary supplement. NAC is most frequently taken orally and thus, we examined the effect of NAC on Atm deficient mice by the oral route (Reliene et al., 2004b; Reliene et al., 2006). We gave NAC supplemented drinking water to Atm deficient mice from fertilization throughout their life. In this treatment scenario, Atm +/- mice were crossed with each other and dams were given NAC-containing drinking water throughout pregnancy and lactation. After weaning (at about 3 weeks of age) animals continued to receive NAC in their drinking water. The major reason to start antioxidant administration as early as from fertilization was to protect against genome rearrangements that can occur during mouse development and lead to carcinogenesis later in life.

Effect of NAC on cancer prevention

We found that NAC intake significantly increased the lifespan and reduced both the incidence and multiplicity of lymphoma in Atm deficient mice (Reliene et al., 2006). The mean survival of NAC treated mice was 68 weeks, while that of untreated mice was only 50 weeks (p = 0.03). We completed gross necropsy and histopathological examination to determine a possible cause of death. Consistent with previous studies, the most frequent tumor in Atm deficient mice was lymphoma (Barlow et al., 1996; Elson et al., 1996; Xu et al., 1996). Remarkably, the incidence of lymphoma in NAC treated mice decreased by two-fold (37.5 versus 76.5 %, p = 0.02). We examined the lymphoma tissue distribution and found tumors in various organs in both NAC treated and control mice (Fig 1.). However, in NAC treated Atm deficient mice, the multiplicity of tumors decreased from 4.6 to 2.8 tumors per mouse (p = 0.038). Lymphoma burden was similar in the thymus, spleen and liver, while in other organs, such as lymph nodes, lung, heart, kidney, pancreas, stomach, duodenum and adrenal glands there were fewer or no tumors in the NAC treatment group (Fig. 1).

Fig. 1. Lymphoma tissue distribution in untreated and NAC treated Atm deficient mice.

Fig. 1

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Only mice that had lymphoma are included in the calculation. Black bars depict untreated mice, gray bars show NAC treated mice. Lymph nodes affected were mesenteric and/or peripheral, thoratic and perirenal. Lymphoma in the heart was seen in epicardium and/or pericardium. Taken from (Reliene et al., 2007).

Subsequently the finding that NAC extends the reduced lifespan of Atm deficient mice was reproduced by another group of researchers (Ito et al., 2007). NAC was administered in drinking water and treatment was started from birth. In this study, the mean survival was approximately 20 weeks and 43 weeks in untreated Atm deficient mice and NAC treatment group, respectively.

In summary, NAC treatment prolonged the survival of Atm deficient mice by 36% in our study and by 2-fold in the subsequent study by Ito et al. (Ito et al., 2007). Although it is highly speculative to extrapolate such a prolongation of life in AT patients, NAC therapy from early age may result in the median survival of about 27 or 40 years, respectively, instead of 20 years (Crawford et al., 2006). This estimate, however, takes into consideration tumorigenesis as a major cause of death as it is in mice. It has been estimated that cancer and complications of lung diseases are two major causes of death in AT patients contributing to death to a similar extent (Crawford et al., 2006).

Possible mechanism of lymphoma prevention by NAC

Several studies examined the molecular action mechanism of NAC in cancer prevention in Atm deficient mice. NAC reduced abnormally high DNA synthesis and ROS levels in lymphocytes from Atm deficient mice (Ito et al., 2007; Yan et al., 2001). ROS causes oxidative DNA damage, while upregulated DNA synthesis results in a lack of time required for repair of damaged DNA template before it is used for replication. Oxidative DNA damage is often translated into irreversible genome rearrangements during replication (Kuzminov, 2001). We found that NAC suppressed both oxidative DNA damage and DNA deletions in Atm deficient mice supporting the interpretation that DNA deletions may be a consequence of abnormal DNA synthesis and oxidative damage (Fig. 2)(Reliene et al., 2004b). These studies showed that NAC may reduce cancer incidence by reducing oxidative stress and genomic instability.

Fig. 2. The correlation between oxidative DNA damage and the frequency of DNA deletions.

Fig. 2

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Oxidative DNA damage was determined as the number of oxidized guanine residues per 106 guanine residues (8-OHdG/106 dG) using HPLC. The frequency of DNA deletions was determined as the number of eye-spots in the retinal pigment epithelium (RPE) of the eye. The eye-spots are derived from 70 kb DNA deletions at the pink-eyed unstable (pun) locus of the pink-eyed dilution (p) gene, which result in black pigment accumulation in the affected cells (Reliene et al., 2004a). Data for untreated mice are shown by a black triangle; results for NAC treated mice are shown by a gray rectangle. Taken from (Reliene et al., 2007).

Other studies demonstrated that NAC reduces the number of aberrant V(D)J rearrangements between T cell receptor (TCR) β and γ genes, which can cause lymphoma (Ito et al., 2007; Lista et al., 1997). In fact, tumors in Atm deficient mice exhibit abnormal TCR rearrangements suggesting that development of lymphoma may be driven by aberrant V(D)J recombination (Liyanage et al., 2000). NAC reduced the number of defective rearrangements and restored the decreased T cell numbers, which probably accounted for reduced lymphomagenesis (Ito et al., 2007).

ROS have also been proposed to be involved in tumor metastasis, a process that includes epithelial-mesenchymal transition, migration, invasion of the tumor cells and angiogenesis (Nishikawa et al., 2006; Wu, 2006). ROS can oxidize the critical target molecules and thereby play a role in the transcription and expression of genes implicated in tumor progression. NAC can counteract some effects of ROS in tumor progression. NAC has been reported to limit invasion of human bladder cancer cells by inhibiting both the production and activity of matrix metalloproteinase -9 involved in cancer invasion and metastasis (Kawakami et al., 2001). NAC inhibits vascular endothelial growth factor (VEGF) production and growth of angiogenesis-driven Kaposi's sarcoma in nude mice (Albini et al., 2001), promotes anti-angiogenic factor angiostatin production and results in endothelial apoptosis and vascular collapse in an experimental breast cancer assay (Agarwal et al., 2004). We found that NAC reduced the multiplicity of lymphoma in Atm deficient mice, which may be explained by NAC's anti-invasive and anti- angiogenic properties (Reliene et al., 2006). The effect was most pronounced in nonlymphoid organs supporting the observation of other studies that NAC exhibits an anti-metastatic effect.

The studies reviewed in this article show that NAC significantly reduces lymphomagenesis in Atm deficient mice but these positive effects by no means suggest that NAC administration can replace the missing Atm protein. It has been recently reported that ATM prevents cancer progression through detection and response to oncogene-induced DNA replication stress and DNA damage (Bartkova et al., 2005). In this report, NAC had only a marginal effect suggesting that DNA damage caused by hyperproliferative oncogenic stimuli cannot be suppressed by antioxidants. Similarly in our studies the cancer frequency and multiplicity were significantly reduced but still much elevated above wildtype levels.

Effect of NAC on motor function

Unlike AT patients, Atm deficient mice do not develop cerebellar degeneration or show dramatic defects in their motor function (Barlow et al., 1996; Borghesani et al., 2000; Kuljis et al., 1997). We tested the effect of oral NAC administration on gait as well as several other motor tests, including, challenging beam traversal and spontaneous activity, which are sensitive to sensorimotor deficits in animal models of basal ganglia dysfunction (Fleming et al., 2004; Fleming et al., 2006; Hwang et al., 2005), to determine whether these could detect additional deficits in the Atm-/- mice. In our study, Atm deficient mice displayed mild motor impairments consistent with other reports (Table 1)(Barlow et al., 1996; Browne et al., 2004). The gait analysis showed that in Atm deficient mice, the stride length and width was shorter by about 10% (p < 0.05) compared with controls, confirming the original characterization of these animals (Barlow et al., 1996). The spontaneous activity test showed that grooming in Atm deficient mice was significantly reduced, perhaps as a result of a general increase in spontaneous activity as indicated by increased forelimb and hindlimb steps and a tendency to increased rearing. The challenging beam traversal test consisted of a tapered beam with a support platform and ledges and topped with an overlying grid. Atm deficient mice made significantly more steps while traversing the beam than control mice. NAC treatment had a positive effect on some aspects of motor function. Spontaneous activity overall returned to control levels with rears and hindlimb steps being significantly decreased compared to untreated Atm-/- mice. NAC treated Atm deficient mice made significantly fewer steps on the beam compared to untreated Atm deficient mice (p < 0.01) and the number of errors were reduced to control level. However, increases in gait length and width were not improved by NAC treatment. Overall, NAC showed a beneficial effect on some but not all motor deficits in the Atm-/- mice.

Table 1. The effect of oral NAC treatment on motor function in Atm deficient mice.

Behavioral Test Control Untreated Atm -/- NAC treated Atm -/-
Gait Analysis Length (cm) 6.61 ± 0.12 6.13 ± 0.13* 5.93 ± 0.16**
Width (cm) 4.21 ± 0.09 3.81 ± 0.11* 3.78 ± 0.11**
Maximum Difference 2.98 ± 0.19 3.51 ± 0.41 2.94 ± 0.31
Spontaneous Activity Rears 21.88 ± 1.51 24.47 ± 2.50 16.87 ± 2.26Δ
Forelimb Steps 140.53 ± 4.68 168.12 ± 14.36* 152.47 ± 7.20
Hindlimb Steps 83.58 ± 5.09 111.00 ± 10.40** 82.47 ± 8.55Δ
Grooming (sec) 12.40 ± 1.06 8.88 ± 0.94* 10.00 ± 0.76
Challenging Beam Steps 20.56 ± 0.37 22.94 ± 0.47** 20.63 ± 0.28ΔΔ
Time (sec) 18.24 ± 1.06 22.88 ± 1.72* 23.15 ± 1.41*
Errors 0.11 ± 0.01 0.14 ± 0.02 0.11 ± 0.01
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Untreated Atm deficient (n=17) and wildtype mice (n=32) and NAC treated Atm deficient (n=15) and wildtype (n=8) mice at 2-6 months of age were tested on classical gait analysis, spontaneous activity measured in a clear cylinder, and a challenging beam traversal test that consisted of a tapered beam with a support platform and ledges and topped with an overlying grid {Fleming, 2004 #108}{Fleming, 2006 #109}{Hwang, 2005 #110}. Treatment group mice received 40 mM NAC in their drinking water from conception throughout life. Male and female mice did not differ (Fisher's LSD, p>0.05) in any of the behavioral tests and were pooled for statistical analysis. Similarly, untreated and NAC treated wildtype mice did not differ behaviorally (p>0.05) and were pooled (referred to as “control”). *, ** indicates significant differences from control mice (p<0.05, p<0.01, respectively). Δ, ΔΔ indicates significant differences from untreated Atm deficient mice (p<0.05, p<0.01, respectively).

EUK-189

EUK-189, a salen-manganese compound with catalase and superoxide dismutase activities, has been previously shown to be neuroprotective in animal models characterized by oxidative damage (Doctrow et al., 2002; Melov et al., 2001). Atm deficient mice were treated with EUK-189 from 40 days of age via an osmotic pump implanted subcutaneously. The EUK-189 treatment improved performance on a rotarod and showed a trend towards prolonged life span (p = 0.08) (Browne et al., 2004). When the study was terminated at 5 months, 31% vehicle-treated and 56% EUK-189-treated animals were still alive (Browne et al., 2004).

Tempol

Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) is a stable nitroxide free radical and superoxide dismutase mimetic (Damiani et al., 2000; Hahn et al., 1994; Mitchell et al., 1990). Tempol detoxifies oxygen metabolites, oxidizes redox-active trace metal ions, reduces quinone radicals and, in biological systems, is itself reduced by GSH and ascorbic acid (Branca et al., 1988; Krishna et al., 1992; Krishna et al., 1996; May et al., 2005). Tempol mixed in a mouse chow was chronically administered to Atm deficient mice either from fertilization or from weaning (Schubert et al., 2004). Tempol had no effect, when the treatment was started from fertilization. The intake of tempol food significantly increased the life span (mean survival 62 versus 30 weeks) in the second treatment scenario. Tempol reduced ROS levels, protein oxidation and restored mitochondrial membrane potential in thymocytes implying that chemoprevention by tempol is associated with its antioxidant activity. However, tempol treatment also reduced cell number in the thymus and decreased weight gain in Atm deficient mice. These effects were explained by tempol anti-proliferative activity and unknown effects, respectively. A possibility of caloric restriction was ruled out, mainly because no decrease in the intake of food containing tempol was observed.

CTMIO

Like tempol, CTMIO belongs to a class of stable nitroxide free radicals (Damiani et al., 2000; Hahn et al., 1994; Mitchell et al., 1990). The effect of CTMIO intake through drinking water was recently examined in Atm deficient mice (Gueven et al., 2006). The treatment was started immediately after weaning. CTMIO prolonged the survival of Atm deficient mice resulting in the median survival of 54 weeks versus 16 weeks. CTMIO chemoprevention mechanism does not appear to involve apoptosis, as tumors from CTMIO treated mice did not show higher levels of apoptosis compared to tumors from untreated Atm deficient mice. However, it was not shown whether CTMIO induced apoptosis in mice without tumors. This study also examined the effect of CTMIO on neuromotor performance by employing a multiparameter test based on performance on a narrow beam in which a cumulative score of performance using all individual parameters from 10 independent experiments was calculated (Gueven et al., 2006). Cumulative scores were subjected to several models of statistical analysis (univariate-linear, univariate-linear-mixed, and multi-linear-mixed). CTMIO treatment significantly improved overall motor performance and reduced oxidative damage to proteins in Purkinje cells (determined by 3-nitrotyrosination of protein) suggesting that CTMIO corrects neurobehavioral phenotype by its antioxidative activity.

Summary

The effect of NAC, EUK-189, tempol and CTMIO was studied in Atm deficient mice to understand whether antioxidant therapy has a potential in the management of AT. All the described compounds had some beneficial effects, particularly, in extending the life span and reducing lymphomagenesis. Of the tested antioxidants, only NAC has a long history of safety and efficacy in the clinical settings. Therefore, NAC has a strong potential to emerge as a dietary supplement against high risk of cancer in AT and possibly other oxidative stress linked disorders. At present there is an ongoing clinical trial in pediatric AT patients, where a cocktail of antioxidants including NAC, is employed (personal communication with Dr. G. Berry, Thomas Jefferson University Medical College, also see http://www.treat-at.org). The trial is being conduced in Philadelphia, PA, and is a result of the combined efforts of the national organization to Treat-AT, Dr. Gerald Berry and his colleagues at DuPont Children's and Children's Hospital of Philadelphia, and SHS International Ltd (Liverpool, UK). The aim of this study is to determine whether lymphocytes from AT patients show abnormal levels of ROS and increased apoptosis and whether chronic broad antioxidant therapy retards development of lymphocyte and cerebellar dysfunction or arrest destruction of these tissues.

Acknowledgments

This work is supported by grants from the National Institute of Environmental Health Sciences (NIH RO1 grant No. ES09519) and the American Institute for Cancer Research both to RHS, a post-doctoral research fellowship of the Lymphoma Research Foundation Elizabeth Banks Jacobs & Byron Wade Strunk Memorial Fellowship to RR, PHS grants P50NS38367 and U54ES12078 to MFC and T32 NS07449-05 to SMF. SMF is a Chen Family Fellow.

Abbreviations

AT

ataxia telangiectasia

Atm

ataxia telangiectasia mutated

CTMIO

5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl

DSBs

double-strand breaks

HPLC

high performance liquid chromatography

GSH

glutathione

NAC

N-acetyl-L-cysteine

p

pink-eyed dilution gene

pun

pink-eyed unstable locus

ROS

reactive oxygen species

TCR

T cell receptor

Footnotes

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Literature Cited

  1. Agarwal A, Munoz-Najar U, Klueh U, Shih SC, Claffey KP. N-acetyl-cysteine promotes angiostatin production and vascular collapse in an orthotopic model of breast cancer. Am J Pathol. 2004;164:1683–1696. doi: 10.1016/S0002-9440(10)63727-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Albini A, Morini M, D'Agostini F, Ferrari N, Campelli F, Arena G, Noonan DM, Pesce C, De Flora S. Inhibition of angiogenesis-driven Kaposi's sarcoma tumor growth in nude mice by oral N-acetylcysteine. Cancer Res. 2001;61:8171–8178. [PubMed] [Google Scholar]
  3. Barlow C, Dennery PA, Shigenaga MK, Smith MA, Morrow JD, Roberts LJ, 2nd, Wynshaw-Boris A, Levine RL. Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs. Proc Natl Acad Sci U S A. 1999;96:9915–9919. doi: 10.1073/pnas.96.17.9915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, Shiloh Y, Crawley JN, Ried T, Tagle D, Wynshaw-Boris A. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell. 1996;86:159–171. doi: 10.1016/s0092-8674(00)80086-0. [DOI] [PubMed] [Google Scholar]
  5. Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K, Guldberg P, Sehested M, Nesland JM, Lukas C, Orntoft T, Lukas J, Bartek J. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature. 2005;434:864–870. doi: 10.1038/nature03482. [DOI] [PubMed] [Google Scholar]
  6. Barzilai A, Rotman G, Shiloh Y. ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage. DNA Repair (Amst) 2002;1:3–25. doi: 10.1016/s1568-7864(01)00007-6. [DOI] [PubMed] [Google Scholar]
  7. Boder E. Ataxia-telangiectasia: some historic, clinical and pathologic observations. Birth Defects Orig Artic Ser. 1975;11:255–270. [PubMed] [Google Scholar]
  8. Boder E. Ataxia-telangiectasia: an overview. Kroc Found Ser. 1985;19:1–63. [PubMed] [Google Scholar]
  9. Boder E, Sedgwick RP. Ataxia-telangiectasia. (Clinical and immunological aspects) Psychiatr Neurol Med Psychol Beih. 1970;13–14:8–16. [PubMed] [Google Scholar]
  10. Borghesani PR, Alt FW, Bottaro A, Davidson L, Aksoy S, Rathbun GA, Roberts TM, Swat W, Segal RA, Gu Y. Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice. Proc Natl Acad Sci U S A. 2000;97:3336–3341. doi: 10.1073/pnas.050584897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Branca M, Denurra T, Turrini F. Reduction of nitroxide free radical by normal and G6PD deficient red blood cells. Free Radic Biol Med. 1988;5:7–11. doi: 10.1016/0891-5849(88)90057-3. [DOI] [PubMed] [Google Scholar]
  12. Browne SE, Roberts LJ, 2nd, Dennery PA, Doctrow SR, Beal MF, Barlow C, Levine RL. Treatment with a catalytic antioxidant corrects the neurobehavioral defect in ataxia-telangiectasia mice. Free Radic Biol Med. 2004;36:938–942. doi: 10.1016/j.freeradbiomed.2004.01.003. [DOI] [PubMed] [Google Scholar]
  13. Cohen MM, Shaham M, Dagan J, Shmueli E, Kohn G. Cytogenetic investigations in families with ataxia-telangiectasia. Cytogenet Cell Genet. 1975;15:338–356. doi: 10.1159/000130530. [DOI] [PubMed] [Google Scholar]
  14. Crawford TO, Skolasky RL, Fernandez R, Rosquist KJ, Lederman HM. Survival probability in ataxia telangiectasia. Arch Dis Child. 2006;91:610–611. doi: 10.1136/adc.2006.094268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Damiani E, Kalinska B, Canapa A, Canestrari S, Wozniak M, Olmo E, Greci L. The effects of nitroxide radicals on oxidative DNA damage. Free Radic Biol Med. 2000;28:1257–1265. doi: 10.1016/s0891-5849(00)00242-2. [DOI] [PubMed] [Google Scholar]
  16. De Flora S, Izzotti A, D'Agostini F, Balansky RM. Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking-related end-points. Carcinogenesis. 2001;22:999–1013. doi: 10.1093/carcin/22.7.999. [DOI] [PubMed] [Google Scholar]
  17. Decramer M, Rutten-van Molken M, Dekhuijzen PN, Troosters T, van Herwaarden C, Pellegrino R, van Schayck CP, Olivieri D, Del Donno M, De Backer W, Lankhorst I, Ardia A. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet. 2005;365:1552–1560. doi: 10.1016/S0140-6736(05)66456-2. [DOI] [PubMed] [Google Scholar]
  18. Doctrow SR, Huffman K, Marcus CB, Tocco G, Malfroy E, Adinolfi CA, Kruk H, Baker K, Lazarowych N, Mascarenhas J, Malfroy B. Salen-manganese complexes as catalytic scavengers of hydrogen peroxide and cytoprotective agents: structure-activity relationship studies. J Med Chem. 2002;45:4549–4558. doi: 10.1021/jm020207y. [DOI] [PubMed] [Google Scholar]
  19. Elson A, Wang Y, Daugherty CJ, Morton CC, Zhou F, Campos-Torres J, Leder P. Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. Proc Natl Acad Sci U S A. 1996;93:13084–13089. doi: 10.1073/pnas.93.23.13084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Fleming SM, Salcedo J, Fernagut PO, Rockenstein E, Masliah E, Levine MS, Chesselet MF. Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein. J Neurosci. 2004;24:9434–9440. doi: 10.1523/JNEUROSCI.3080-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Fleming SM, Salcedo J, Hutson CB, Rockenstein E, Masliah E, Levine MS, Chesselet MF. Behavioral effects of dopaminergic agonists in transgenic mice overexpressing human wildtype alpha-synuclein. Neuroscience. 2006;142:1245–1253. doi: 10.1016/j.neuroscience.2006.07.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Gatti RA. The inherited basis of human radiosensitivity. Acta Oncol. 2001;40:702–711. doi: 10.1080/02841860152619115. [DOI] [PubMed] [Google Scholar]
  23. Gatti RA, Nieberg R, Boder E. Uterine tumors in ataxia-telangiectasia. Gynecol Oncol. 1989;32:257–260. doi: 10.1016/s0090-8258(89)80045-9. [DOI] [PubMed] [Google Scholar]
  24. Gropp A, Flatz G. Chromosome breakage and blastic transformation of lymphocytes in ataxia-telangiectasia. Humangenetik. 1967;5:77–79. doi: 10.1007/BF00286217. [DOI] [PubMed] [Google Scholar]
  25. Gueven N, Luff J, Peng C, Hosokawa K, Bottle SE, Lavin MF. Dramatic extension of tumor latency and correction of neurobehavioral phenotype in Atm-mutant mice with a nitroxide antioxidant. Free Radic Biol Med. 2006;41:992–1000. doi: 10.1016/j.freeradbiomed.2006.06.018. [DOI] [PubMed] [Google Scholar]
  26. Hahn SM, Krishna CM, Samuni A, DeGraff W, Cuscela DO, Johnstone P, Mitchell JB. Potential use of nitroxides in radiation oncology. Cancer Res. 1994;54:2006s–2010s. [PubMed] [Google Scholar]
  27. Hwang DY, Fleming SM, Ardayfio P, Moran-Gates T, Kim H, Tarazi FI, Chesselet MF, Kim KS. 3,4-dihydroxyphenylalanine reverses the motor deficits in Pitx3-deficient aphakia mice: behavioral characterization of a novel genetic model of Parkinson's disease. J Neurosci. 2005;25:2132–2137. doi: 10.1523/JNEUROSCI.3718-04.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ito K, Takubo K, Arai F, Satoh H, Matsuoka S, Ohmura M, Naka K, Azuma M, Miyamoto K, Hosokawa K, Ikeda Y, Mak TW, Suda T, Hirao A. Regulation of reactive oxygen species by Atm is essential for proper response to DNA double-strand breaks in lymphocytes. J Immunol. 2007;178:103–110. doi: 10.4049/jimmunol.178.1.103. [DOI] [PubMed] [Google Scholar]
  29. Kamsler A, Daily D, Hochman A, Stern N, Shiloh Y, Rotman G, Barzilai A. Increased oxidative stress in ataxia telangiectasia evidenced by alterations in redox state of brains from Atm-deficient mice. Cancer Res. 2001;61:1849–1854. [PubMed] [Google Scholar]
  30. Kawakami S, Kageyama Y, Fujii Y, Kihara K, Oshima H. Inhibitory effect of N-acetylcysteine on invasion and MMP-9 production of T24 human bladder cancer cells. Anticancer Res. 2001;21:213–219. [PubMed] [Google Scholar]
  31. Kelly GS. Clinical applications of N-acetylcysteine. Altern Med Rev. 1998;3:114–127. [PubMed] [Google Scholar]
  32. Krishna MC, Grahame DA, Samuni A, Mitchell JB, Russo A. Oxoammonium cation intermediate in the nitroxide-catalyzed dismutation of superoxide. Proc Natl Acad Sci U S A. 1992;89:5537–5541. doi: 10.1073/pnas.89.12.5537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Krishna MC, Russo A, Mitchell JB, Goldstein S, Dafni H, Samuni A. Do nitroxide antioxidants act as scavengers of O2-. or as SOD mimics? J Biol Chem. 1996;271:26026–26031. doi: 10.1074/jbc.271.42.26026. [DOI] [PubMed] [Google Scholar]
  34. Kuljis RO, Xu Y, Aguila MC, Baltimore D. Degeneration of neurons, synapses, and neuropil and glial activation in a murine Atm knockout model of ataxia-telangiectasia. Proc Natl Acad Sci U S A. 1997;94:12688–12693. doi: 10.1073/pnas.94.23.12688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Kuzminov A. DNA replication meets genetic exchange: chromosomal damage and its repair by homologous recombination. Proc Natl Acad Sci U S A. 2001;98:8461–8468. doi: 10.1073/pnas.151260698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Lavin MF, Birrell G, Chen P, Kozlov S, Scott S, Gueven N. ATM signaling and genomic stability in response to DNA damage. Mutat Res. 2005;569:123–132. doi: 10.1016/j.mrfmmm.2004.04.020. [DOI] [PubMed] [Google Scholar]
  37. Lavin MF, Shiloh Y. The genetic defect in ataxia-telangiectasia. Annu Rev Immunol. 1997;15:177–202. doi: 10.1146/annurev.immunol.15.1.177. [DOI] [PubMed] [Google Scholar]
  38. Lista F, Bertness V, Guidos CJ, Danska JS, Kirsch IR. The absolute number of trans-rearrangements between the TCRG and TCRB loci is predictive of lymphoma risk: a severe combined immune deficiency (SCID) murine model. Cancer Res. 1997;57:4408–4413. [PubMed] [Google Scholar]
  39. Liyanage M, Weaver Z, Barlow C, Coleman A, Pankratz DG, Anderson S, Wynshaw-Boris A, Ried T. Abnormal rearrangement within the alpha/delta T-cell receptor locus in lymphomas from Atm-deficient mice. Blood. 2000;96:1940–1946. [PubMed] [Google Scholar]
  40. May JM, Qu ZC, Juliao S, Cobb CE. Ascorbic acid decreases oxidant stress in endothelial cells caused by the nitroxide tempol. Free Radic Res. 2005;39:195–202. doi: 10.1080/10715760400019661. [DOI] [PubMed] [Google Scholar]
  41. Melov S, Doctrow SR, Schneider JA, Haberson J, Patel M, Coskun PE, Huffman K, Wallace DC, Malfroy B. Lifespan extension and rescue of spongiform encephalopathy in superoxide dismutase 2 nullizygous mice treated with superoxide dismutase-catalase mimetics. J Neurosci. 2001;21:8348–8353. doi: 10.1523/JNEUROSCI.21-21-08348.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Meyn MS. Ataxia-telangiectasia, cancer and the pathobiology of the ATM gene. Clin Genet. 1999;55:289–304. doi: 10.1034/j.1399-0004.1999.550501.x. [DOI] [PubMed] [Google Scholar]
  43. Mitchell JB, Samuni A, Krishna MC, DeGraff WG, Ahn MS, Samuni U, Russo A. Biologically active metal-independent superoxide dismutase mimics. Biochemistry. 1990;29:2802–2807. doi: 10.1021/bi00463a024. [DOI] [PubMed] [Google Scholar]
  44. Nishikawa M, Hashida M. Inhibition of tumour metastasis by targeted delivery of antioxidant enzymes. Expert Opin Drug Deliv. 2006;3:355–369. doi: 10.1517/17425247.3.3.355. [DOI] [PubMed] [Google Scholar]
  45. Prescott LF, Park J, Ballantyne A, Adriaenssens P, Proudfoot AT. Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. Lancet. 1977;2:432–434. doi: 10.1016/s0140-6736(77)90612-2. [DOI] [PubMed] [Google Scholar]
  46. Quick KL, Dugan LL. Superoxide stress identifies neurons at risk in a model of ataxia-telangiectasia. Ann Neurol. 2001;49:627–635. [PubMed] [Google Scholar]
  47. Reichenbach J, Schubert R, Schindler D, Muller K, Bohles H, Zielen S. Elevated oxidative stress in patients with ataxia telangiectasia. Antioxid Redox Signal. 2002;4:465–469. doi: 10.1089/15230860260196254. [DOI] [PubMed] [Google Scholar]
  48. Reichenbach J, Schubert R, Schwan C, Muller K, Bohles HJ, Zielen S. Anti-oxidative capacity in patients with ataxia telangiectasia. Clin Exp Immunol. 1999;117:535–539. doi: 10.1046/j.1365-2249.1999.01000.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Reliene R, Bishop AJ, Aubrecht J, Schiestl RH. In vivo DNA deletion assay to detect environmental and genetic predisposition to cancer. Methods Mol Biol. 2004a;262:125–139. doi: 10.1385/1-59259-761-0:125. [DOI] [PubMed] [Google Scholar]
  50. Reliene R, Fischer E, Schiestl RH. Effect of N-acetyl cysteine on oxidative DNA damage and the frequency of DNA deletions in atm-deficient mice. Cancer Res. 2004b;64:5148–5153. doi: 10.1158/0008-5472.CAN-04-0442. [DOI] [PubMed] [Google Scholar]
  51. Reliene R, Schiestl RH. Antioxidant N-acetyl cysteine reduces incidence and multiplicity of lymphoma in Atm deficient mice. DNA Repair (Amst) 2006;5:852–859. doi: 10.1016/j.dnarep.2006.05.003. [DOI] [PubMed] [Google Scholar]
  52. Reliene R, Schiestl RH. Antioxidants suppress lymphoma and increase longevity in Atm-deficient mice. J Nutr. 2007;137:229S–232S. doi: 10.1093/jn/137.1.229S. [DOI] [PubMed] [Google Scholar]
  53. Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science. 1995;268:1749–1753. doi: 10.1126/science.7792600. [DOI] [PubMed] [Google Scholar]
  54. Schubert R, Erker L, Barlow C, Yakushiji H, Larson D, Russo A, Mitchell JB, Wynshaw-Boris A. Cancer chemoprevention by the antioxidant tempol in Atm-deficient mice. Hum Mol Genet. 2004;13:1793–1802. doi: 10.1093/hmg/ddh189. [DOI] [PubMed] [Google Scholar]
  55. Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer. 2003;3:155–168. doi: 10.1038/nrc1011. [DOI] [PubMed] [Google Scholar]
  56. Stumm M, Neubauer S, Keindorff S, Wegner RD, Wieacker P, Sauer R. High frequency of spontaneous translocations revealed by FISH in cells from patients with the cancer-prone syndromes ataxia telangiectasia and Nijmegen breakage syndrome. Cytogenet Cell Genet. 2001;92:186–191. doi: 10.1159/000056900. [DOI] [PubMed] [Google Scholar]
  57. Taylor AM, Metcalfe JA, Thick J, Mak YF. Leukemia and lymphoma in ataxia telangiectasia. Blood. 1996;87:423–438. [PubMed] [Google Scholar]
  58. Van Schooten FJ, Besaratinia A, De Flora S, D'Agostini F, Izzotti A, Camoirano A, Balm AJ, Dallinga JW, Bast A, Haenen GR, Van't Veer L, Baas P, Sakai H, Van Zandwijk N. Effects of oral administration of N-acetyl-L-cysteine: a multi-biomarker study in smokers. Cancer Epidemiol Biomarkers Prev. 2002;11:167–175. [PubMed] [Google Scholar]
  59. Webb WR. Clinical evaluaton of a new mucolytic agent, acetyl-cysteine. J Thorac Cardiovasc Surg. 1962;44:330–343. [PubMed] [Google Scholar]
  60. Wu WS. The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev. 2006;25:695–705. doi: 10.1007/s10555-006-9037-8. [DOI] [PubMed] [Google Scholar]
  61. Xu Y. ATM in lymphoid development and tumorigenesis. Adv Immunol. 1999;72:179–189. doi: 10.1016/s0065-2776(08)60020-6. [DOI] [PubMed] [Google Scholar]
  62. Xu Y, Ashley T, Brainerd EE, Bronson RT, Meyn MS, Baltimore D. Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev. 1996;10:2411–2422. doi: 10.1101/gad.10.19.2411. [DOI] [PubMed] [Google Scholar]
  63. Yan M, Qiang W, Liu N, Shen J, Lynn WS, Wong PK. The ataxia-telangiectasia gene product may modulate DNA turnover and control cell fate by regulating cellular redox in lymphocytes. Faseb J. 2001;15:1132–1138. doi: 10.1096/fj.00-0601com. [DOI] [PubMed] [Google Scholar]
  64. Yi M, Rosin MP, Anderson CK. Response of fibroblast cultures from ataxia-telangiectasia patients to oxidative stress. Cancer Lett. 1990;54:43–50. doi: 10.1016/0304-3835(90)90089-g. [DOI] [PubMed] [Google Scholar]

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