Detection of Oxidative Clustered DNA Lesions in X-Irradiated Mouse Skin Tissues and Human MCF-7 Breast Cancer Cells

Gollapalle, Esha; Wang, Rong; Adetolu, Ronke; Tsao, Doug; Francisco, Dave; Sigounas, George; Georgakilas, Alexandros G.

doi:10.1667/rr0659.1

Cited by 70 publications

(41 citation statements)

References 50 publications

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“…OCDLs were measured after digestion with enzymes that cleave the DNA at modified DNA residues, human APE1, which cleaves primarily at abasic sites, Escherichia coli EndoIII at oxypyrimidine sites, and human OGG1 at oxypurine sites (21). The number of sites was quantified by analysis of constant-field gel electrophoresis (22).…”

Section: Resultsmentioning

confidence: 99%

Tumors induce complex DNA damage in distant proliferative tissues in vivo

Redon

Dickey

Nakamura

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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133

113

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That tumors cause changes in surrounding tissues is well documented, but whether they also affect distant tissues is uncertain. Such knowledge may be important in understanding the relationship between cancer and overall patient health. To address this question, we examined tissues distant to sites of implanted tumors for genomic damage using cohorts of C57BL/6 and BALB/c mice with early-stage subcutaneous syngeneic grafts, specifically, B16 melanoma, MO5076 sarcoma, and COLON26 carcinoma. Here we report that levels of two serious types of DNA damage, double-strand breaks (DSBs) measured by γ-H2AX focus formation and oxidatively induced non-DSB clustered DNA lesions (OCDLs), were elevated in tissues distant from the tumor site in tumor-bearing mice compared with their age-and sex-matched controls. Most affected were crypts in the gastrointestinal tract organs and skin, both highly proliferative tissues. Further investigation revealed that, compared with controls, tumor-bearing mice contained elevated amounts of activated macrophages in the distant gastrointestinal tissues, as well as elevated serum levels of several cytokines. One of these cytokines, CCL2/ MCP-1, has been linked to several inflammation-related conditions and macrophage recruitment, and strikingly, CCL2-deficient mice lacked increased levels of DSBs and OCDLs in tissues distant from implanted tumors. Thus, this study is unique in being a direct demonstration that the presence of a tumor may induce a chronic inflammatory response in vivo, leading to increased systemic levels of DNA damage. Importantly, these findings suggest that tumors may have more profound effects on their hosts than heretofore expected.tumor-induced bystander effect | oxidative DNA damage | cytokines

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Section: Resultsmentioning

confidence: 99%

Tumors induce complex DNA damage in distant proliferative tissues in vivo

Redon

Dickey

Nakamura

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

133

113

View full text Add to dashboard Cite

show abstract

“…These lesions include DNA DSBs and non-DSB oxidative clustered DNA lesions (OCDL) [57,58]. For non-DSB oxidative clustered DNA lesions, both Monte Carlo simulation and experimental measurements using DNA base excision repair enzymes, such as DNA glycosylases and AP endonucleases isolated from E. Coli.…”

Section: Induction Of Dna Damage By High Let Radiationmentioning

confidence: 99%

Alpha Particle Emitter Radiolabeled Antibody for Metastatic Cancer: What Can We Learn from Heavy Ion Beam Radiobiology?

Song¹,

Senthamizhchelvan²,

Hobbs³

et al. 2012

Antibodies

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Alpha-particle emitter labeled monoclonal antibodies are being actively developed for treatment of metastatic cancer due to the high linear energy transfer (LET) and the resulting greater biological efficacy of alpha-emitters. Our knowledge of high LET particle radiobiology derives primarily from accelerated heavy ion beam studies. In heavy ion beam therapy of loco-regional tumors, the modulation of steep transition to very high LET peak as the particle approaches the end of its track (known as the Bragg peak) enables greater delivery of biologically potent radiation to the deep seated tumors while sparing normal tissues surrounding the tumor with the relatively low LET track segment part of the heavy ion beam. Moreover, fractionation of the heavy ion beam can further enhance the peak-to-plateau relative biological effectiveness (RBE) ratio. In contrast, internally delivered alpha particle radiopharmaceutical therapy lack the control of Bragg peak energy deposition and the dose rate is determined by the administered activity, alpha-emitter half-life and biological kinetics of the radiopharmaceutical. The therapeutic ratio of tumor to normal tissue is mainly achieved by tumor specific targeting of the carrier antibody. In this brief overview, we review the radiobiology of high LET radiations learned from ion beam studies and identify the features that are also applicable for the development of alpha-emitter labeled antibodies. The molecular mechanisms underlying DNA double strand break repair response to high LET radiation are also discussed.

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“…Georgakilas and his team through collaborations with various elite research groups (ECU, NCI) have taken advantage of the properties of human repair enzymes OGG1 (oxidized purines), EndoIII (oxidized pyrimidines) and APE1 (abasic sites) in order to detect a variety of bistranded OCDLs in human and mouse tissues, using adaptations of DNA gel electrophoresis [4][5][6][7][8] . The concepts in DNA cluster quantification are simple, but their execution is technically and analytically demanding.…”

Section: Detection Of Ocdls In Vivo: Potential Clinical Applicationsmentioning

confidence: 99%

“…Dr. Georgakilas' group, using novel adaptations of DNA gel electrophoresis, has been able to provide to the scientific community relatively easy and reliable methodologies for the detection of OCDLs in a variety of cell and tissues [3,[9][10][11] . In early 2007, Gollapalle et al [4] showed for the first time in vivo that X-rays can induce a radiation-delayed effect in mice several weeks after the initial irradiation. In addition, they showed evidence of bystander or so-called distal effects [12] .…”

Section: Detection Of Ocdls In Vivo: Potential Clinical Applicationsmentioning

confidence: 99%

Detection of clustered DNA lesions: Biological and clinical applications

Georgakilas

2011

WJBC

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Humans are daily exposed to background radiation and various sources of oxidative stress. My research has focused in the last 12 years on the effects of ionizing radiation on DNA, which is considered as the key target of radiation in the cell. Ionizing radiation and endogenous cellular oxidative stress can also induce closely spaced oxidatively induced DNA lesions called "clusters" of DNA damage or locally multiply damage sites, as first introduced by John Ward. I am now interested in the repair mechanisms of clustered DNA damage, which is considered as the most difficult for the cell to repair. A main part of my research is devoted to evaluating the role of clustered DNA damage in the promotion of carcinogenesis in vitro and in vivo . Currently in my laboratory, there are two main ongoing projects. (1) Study of the role of BRCA1 and DNA-dependent protein kinase catalytic subunit repair proteins in the processing of clustered DNA damage in human cancer cells. For this project, we use several tumor cell lines, such as breast cancer cell lines MCF-7 and HCC1937 (BRCA1 deficient) and human glioblastoma cells MO59J/K; and (2) Possible use of DNA damage clusters as novel cancer biomarkers for prognostic and therapeutic applications related to modulation of oxidative stress. In this project human tumor and mice tissues are being used.

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Detection of Oxidative Clustered DNA Lesions in X-Irradiated Mouse Skin Tissues and Human MCF-7 Breast Cancer Cells

Cited by 70 publications

References 50 publications

Tumors induce complex DNA damage in distant proliferative tissues in vivo

Tumors induce complex DNA damage in distant proliferative tissues in vivo

Alpha Particle Emitter Radiolabeled Antibody for Metastatic Cancer: What Can We Learn from Heavy Ion Beam Radiobiology?

Detection of clustered DNA lesions: Biological and clinical applications

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