Disease relevance of Radiation Tolerance

• Whereas ataxia telangiectasia-mutated (ATM) kinase normally represses ceramide synthase, its derepression in Atm(-/-) mice increased crypt stem cell radiosensitivity 3.7-fold without sensitizing the microvascular response [1].
• Targeted disruption of the catalytic subunit of the DNA-PK gene in mice confers severe combined immunodeficiency and radiosensitivity [2].
• Male sterility and enhanced radiation sensitivity in TLS(-/-) mice [3].
• ATM is the protein product of the gene mutated in the human genetic disorder ataxia-telangiectasia (A-T), which is characterized by neuronal degeneration, immunodeficiency, sterility, genomic instability, cancer predisposition, and radiation sensitivity [4].
• Furthermore, skin fibroblasts from individuals with genetic diseases predisposing to a high risk of cancer, including ataxia-telangiectasia, Bloom syndrome, Fanconi anemia, and xeroderma pigmentosum exhibited enhanced G2-phase chromosomal radiosensitivity [5].

Psychiatry related information on Radiation Tolerance

• This autosomal recessive disease is characterized by microcephaly, growth and mental retardation, chromosomal instability, radiosensitivity, and high cancer incidence [6].
• There are several variants of ataxia-telangiectasia (A-T): classical A-T with marked radiation sensitivity; classical A-T with intermediate levels of radiation sensitivity; mild A-T with intermediate levels of radiation sensitivity; A-T without telangiectasia; A-T without oculomotor apraxia; and A-T with microcephaly [7].

High impact information on Radiation Tolerance

• DNA nonhomologous end-joining (NHEJ) is a predominant pathway of DNA double-strand break repair in mammalian cells, and defects in it cause radiosensitivity at the cellular and whole-organism levels [8].
• Human T-B-severe combined immunodeficiency associated with increased cellular radiosensitivity (RS-SCID) is characterized by a defect in the V(D)J recombination leading to an early arrest of both B and T cell maturation [9].
• Phosphorylation of this site appears to be functionally important because mutated nibrin (S343A) does not completely complement radiosensitivity in NBS cells [10].
• The Rad50 hook is functional, because mutations in this motif confer radiation sensitivity in yeast and disrupt binding at the distant Mre11 nuclease interface [11].
• This reciprocal relationship of radiosensitivity to anomalies and to embryonic or fetal lethality supports the notion that embryonic or fetal tissues have a p53-dependent "guardian" of the tissue that aborts cells bearing radiation-induced teratogenic DNA damage [12].

Chemical compound and disease context of Radiation Tolerance

• Flavopiridol, a cyclin-dependent kinase inhibitor, enhances radiosensitivity of ovarian carcinoma cells [13].
• Our data suggest that the relative levels of sphingolipid metabolites may play a role in determining the radiosensitivity of prostate cancer cells, and that the enhancement of ceramide and sphingosine generation could be of therapeutic value [14].
• The results of this study also demonstrate that MTH increases radiosensitivity with and without carbogen breathing up to 24 h after the mild hyperthermia treatment [15].
• Role of gamma-glutamyltranspeptidase-mediated glutathione transport on the radiosensitivity of B16 melanoma variant cell lines [16].
• Effect of hyperthermia and misonidazole on the radiosensitivity of a transplantable murine tumor: influence of factors modifying the fraction of hypoxic cells [17].

Biological context of Radiation Tolerance

• Nijmegen breakage syndrome (NBS) is characterized by extreme radiation sensitivity, chromosomal instability and cancer [18].
• Here we investigated the putative roles of PARP in cell proliferation, cell death, radiosensitivity, and DNA recombination, as well as chromosomal stability [19].
• In summary, this EGF-induced radiosensitivity enhancement was not correlated with the effects of EGF on PE, cell growth, PLDR, or SLDR [20].
• By using epistasis analysis of the UV radiation sensitivity and by analyzing the kinetics of Rhp51 (Rad51 homologue), Rqh1, and Top3 focus formation in response to UV in synchronized cells, we identify the first evidence of a function for Rqh1 and Top3 in the repair of UV-induced DNA damage in G(2) [21].
• In keeping with this prediction, inhibition of H-ras processing using FTI-277 resulted in higher levels of apoptosis after irradiation and increased radiosensitivity in H-ras-transformed rat embryo cells but did not affect control cells [22].

Anatomical context of Radiation Tolerance

• A complementary DNA that corrects the radiation sensitivity and DNA synthesis defects in fibroblasts from an AT group D patient was isolated by expression cloning and shown to encode a truncated form of I kappa B-alpha, an inhibitor of the nuclear factor kappa B (NF-kappa B) transcriptional activator [23].
• Analysis of GF and conventionally raised Rag1-/- mice disclosed that mature lymphocytes are not required for the development of lethal radiation enteritis or the microbiota-associated enhancement of endothelial radiosensitivity [24].
• In addition, however, we find that loss of p21 in the context of an atm-deficient mouse leads to a delay in thymic lymphomagenesis and an increase in acute radiation sensitivity in vivo (the latter principally because of effects on the gut epithelium) [25].
• The radiation sensitivity of LAK (lymphokine-activated killer) cells and their precursors, the bulk of which are NK cells, is undetermined [26].
• Selective inhibition of Ras, phosphoinositide 3 kinase, and Akt isoforms increases the radiosensitivity of human carcinoma cell lines [27].

Associations of Radiation Tolerance with chemical compounds

• We were able to achieve restoration of their radiosensitivity and sensitivity to 5-fluorouracil and irinotecan by reexpression of SPARC in tumor xenografts [28].
• Thymidine analogues and hydroxyurea also appear to produce clinically relevant increases in radiation sensitivity [29].
• Metronidazole: effect on radiosensitivity of tumor and normal tissues in mice [30].
• Glutathione deficiency and radiosensitivity in AIDS patients [31].
• Increase in pO2 and radiosensitivity of tumors by Fluosol-DA (20%) and carbogen [32].

Gene context of Radiation Tolerance

• Rif1 inhibition resulted in radiosensitivity and a defect in the intra-S-phase checkpoint [33].
• The significant radiosensitivity of Artemis-deficient cells demonstrates the importance of this component of DSB repair to survival [34].
• Mre11 deficiency also causes increased radiosensitivity and strongly reduced targeted integration frequencies [35].
• However, yku70 mutations enhance the radiosensitivity of rad52 strains, which are deficient in homologous recombination [36].
• These studies have also defined an element of the radiation sensitivity caused by loss of Rad17 function which is not associated with the radiation-induced G2 arrest defect seen in the rad17.d null mutant cells [37].

Analytical, diagnostic and therapeutic context of Radiation Tolerance

• The presence of EGF in the cell culture either after irradiation (during the clonogenic assay period) or continuously before, during, and after irradiation enhanced the radiosensitivity of the cells and reduced their plating efficiency (PE) [20].
• The findings demonstrate that HDGF may play an important role in radiosensitivity, and it could be a novel marker predicting effectiveness of radiotherapy in clinical cases [38].
• Antisense ATM gene therapy: a strategy to increase the radiosensitivity of human tumors [39].
• Dextran sulfate injection mobilized normal numbers of CFU-GM into the blood early after transplantation, and spontaneously circulating CFU-GM in a later phase did not differ from blood progenitors of normal animals with respect to radiation sensitivity and sedimentation velocity [40].
• Although the growth of SCLC cells in a clonogenic assay may be of value in chemotherapy selection, the established cell lines provide a model for studying mechanisms of drug and radiation sensitivity; and drug metabolism [41].

References