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PubMed1994

International Commission for Protection Against Environmental Mutagens and Carcinogens. Working paper no. 6. Estimation of genetic risks of exposure to chemical mutagens: relevance of data on spontaneous mutations and of experience with ionizing radiation.

This paper examines the impact of advances in knowledge on the molecular biology of human Mendelian diseases on the estimation of genetic risks of exposure to ionizing radiation and to chemical mutagens. More specifically, it addresses the question of whether and to what extent naturally occurring Mendelian diseases can be used as a baseline for efforts in this area. Data on the molecular nature and mechanisms of origin of spontaneous mutations underlying naturally occurring Mendelian diseases and on radiation-induced mutations in experimental systems suggest that for ionizing radiation, naturally occurring Mendelian diseases may not constitute an entirely adequate frame of reference and that current risk estimates for this class of diseases are conservative; these estimates however provide a margin of safety in formulating radiation protection guidelines. Currently available data on mechanisms and specificities of action of chemical mutagens, molecular dosimetry, repair of chemically induced adducts in the DNA, adduct-mutation relationships etc., permit the tentative conclusion that naturally occurring Mendelian diseases may provide a better baseline for genetic risk estimation for chemical mutagens than for ionizing radiation. With both ionizing radiation and chemical mutagens, the question of which Mendelian diseases are potentially inducible will become answerable in the near future when more molecular data on human genetic diseases become available. It is therefore essential that risk estimators keep abreast of advances in human genetics and integrate these into their conceptual framework. However, induced Mendelian diseases (especially the dominant ones which are of more immediate concern) are likely to represent a very small fraction of the adverse genetic effects of induced mutations. More attention therefore needs to be devoted to studies on the heterozygous effects of induced mutations.

Animals↗
PubMed1995

Induction of transcription of "immediate early genes" by low-dose ionizing radiation.

The induction of transcription of specific genes after exposure to ionizing radiation has previously been reported after lethal doses of radiation (2-50 Gy). Little attention has been focused on expression of "immediate early genes" after low doses of ionizing radiation, where cell viability remains high. This dose range (0.25-2.0 Gy) is above the diagnostic dose level but at or below the doses typical for a single exposure in fractionated radiotherapy treatment of cancer. In this study, it was observed that doses in the range of 0.25-2.0 Gy induced different amounts of the mRNAs of the proto-oncogenes c-fos, c-jun, c-myc and c-Ha-ras at a given dose and time in Epstein-Barr virus-transformed human lymphoblastoid 244B cells. A maximum response was seen after a dose of 0.5 Gy for all but c-fos, which showed a maximum response after exposure to 0.25 Gy. Time-course studies demonstrated that, for all four proto-oncogenes, the induction was transient, reaching a maximum at 1 h and declining to the constitutive level at 4 h after irradiation. Using second-messenger specific inhibitors, the signaling pathways involved in the induction of these proto-oncogenes was also investigated. The results showed that all four of the proto-oncogenes induced after 0.5 Gy shared a common pathway of tyrosine kinase activation. Other signaling pathways included protein kinase C, reactive oxygen intermediates and calcium-dependent kinases; these were found to be differentially involved in the induction of transcription of the individual proto-oncogenes. In summary, this study suggests that low-dose ionizing radiation (0.25-2.0 Gy) can modulate expression of immediate early genes. Secondly, the activation of immediate early genes after low-dose exposure involves multiple second-messenger signaling pathways. Third, the magnitude of involvement of the different signaling pathways after low-dose radiation is different for each proto-oncogene expressed.

Cell Line, Transformed↗
PubMed2006

Ionizing radiation activates expression of FOXO3a, Fas ligand, and Bim, and induces cell apoptosis.

Genotoxic stress such as ionizing radiation can induce DNA damage and promote cell-cycle arrest or apoptosis through either a p53-dependent or -independent pathway. Recently, members of the FOXO Forkhead transcription factor family have been implicated in playing a role in both DNA repair and apoptosis in mammalian cells that promoted us to examine the role of FOXO transcription factors in ionizing radiation-induced apoptosis. Here, we show that ionizing radiation can promote FOXO3a (FKHRL1) transcriptional activity and protein expression level, and induce nuclear translocation of FOXO3a in Saos2, a p53-null osteosarcoma cell line. Ionizing radiation stimulates expression of apoptosis-inducing proteins such as Fas ligand and the Bcl-2 interacting mediator of cell death (Bim) leading to cellular apoptosis. The observed upregulation of proapoptotic genes and apoptosis in cells without p53 in response to ionizing radiation suggests a novel p53-independent mechanism underlying ionizing radiation-induced apoptosis in cancer cells.

Apoptosis↗
PubMed1995

C-jun and Egr-1 participate in DNA synthesis and cell survival in response to ionizing radiation exposure.

Exposure of mammalian cells to ionizing radiation results in the induction of the immediate early genes, c-jun and Egr-1, which encode transcription factors implicated in cell growth as well as the cellular response to oxidative stress. We studied the role of these immediate early genes in cell cycle kinetics and cell survival following x-irradiation of clones containing inducible dominant negatives to c-jun and Egr-1. The dominant negative constructs to c-jun (delta 9) and Egr-1 (WT/Egr) prevented x-ray induction of transcription through the AP-1 and Egr binding sites, respectively. Twenty percent of confluent, serum-deprived SQ20B human tumor cells, normal fibroblasts, and fibroblasts from patients with ataxia telangiectasia entered S phase within 5 h of irradiation. Clones containing inducible delta 9 and WT/Egr dominant negative constructs demonstrated attenuation of the percentage of cells exiting G1 phase and reduced survival following irradiation. These data indicate that the dominant negatives to the stress-inducible immediate early genes Egr-1 and c-jun prevent the onset of S phase and reduce the survival of human cells exposed to ionizing radiation.

Cell Cycle↗
PubMed1995

Combined effects of ionizing radiation and cycloheximide on gene expression.

We performed experiments to determine the effects of ionizing radiation exposure on expression of genes such as beta-actin, c-fos, histone H4, c-myc, c-jun, Rb, and p53 after exposure of Syrian hamster embryo (SHE) cells to the protein synthesis inhibitor cycloheximide. The purpose of these experiments was to determine the role of a labile protein in the radiation-induced response. The results revealed that when ionizing radiation (either fission-spectrum neutrons or gamma rays) was administered 15 min after cycloheximide treatment of SHE cells, the radiation exposure reduced cycloheximide-mediated gene induction of c-fos, histone H4, and c-jun. In addition, dose-rate differences were found when radiation exposure most significantly inhibited the cycloheximide response. Our results suggest that ionizing radiation does not act as a general protein-synthesis inhibitor and that the presence of a labile protein is required for the maintenance of specific gene transcription and mRNA accumulation after radiation exposure, especially at high dose-rates.

Actins↗
PubMed2006

Computational evaluation of changes in ionizing radiation dose distribution in tissues caused by EM applicators when external radiation and hyperthermia act simultaneously.

PURPOSE: The presented theoretical study investigates the influence of CFMA-like electromagnetic microstrip applicators (MAs) on ionizing radiation intensity and depth radiation dose distribution (DRDD) in irradiated tissues which are tightly covered with a MA. METHODS: It is shown that at relatively low photon energy (<200 keV) the MA does not affect noticeable the profile of the DRDD curve and does not lead to skin overdosing. Nevertheless, it significantly (up to 20-35%) decreases the low energy ionizing radiation intensity. For high energy photons (>1 MeV), on the contrary, the decrease of radiation intensity, caused by the MA, is small (3-10%), but the profile of the DRDD curve, calculated by means of the Monte-Carlo method, is significantly affected. RESULTS: The radiation dose maximum is shifted to the skin, resulting in possible skin overdosing. Radiation absorption characteristics of MA are calculated and compared with published parameters of EM horn and US applicators now in use for external simultaneous radiation and hyperthermia (ESRH) procedures. The MA provides the minor ionizing radiation absorption. Due to it and owing to their conformability with the tissue surface the MAs would not require any additional means or devices to be used for ESRH treatment procedures with any common ionizing radiation equipment. CONCLUSIONS: The necessity of development means for decreasing the time of radiation equipment occupation during ESRH procedures is pointed out.

Absorption↗
PubMed2000

Antitumor activity of combined treatment of human cancer cells with ionizing radiation and anti-epidermal growth factor receptor monoclonal antibody C225 plus type I protein kinase A antisense oligonucleotide.

Recent studies have suggested that selective inhibition of mitogenic pathways may improve the antitumor activity of ionizing radiation. The epidermal growth factor receptor (EGFR) is overexpressed and is involved in autocrine growth control in the majority of human carcinomas. Protein kinase A type I (PKAI) plays a key role in neoplastic transformation and is overexpressed in cancer cells in which an EGFR autocrine pathway is activated. We used two specific inhibitors of EGFR and PKAI that are under clinical evaluation in cancer patients: C225, an anti-EGFR chimeric human-mouse monoclonal antibody (MAb); and a mixed-backbone antisense oligonucleotide targeting the PKAI RIalpha subunit (PKAI AS). We tested in human colon cancer (GEO) and ovarian cancer (OVCAR-3) cell lines the antiproliferative activity of MAb C225 and/or PKAI AS in combination with ionizing radiation. In vivo antitumor activity was evaluated in nude mice bearing established GEO xenografts. Dose-dependent inhibition of soft agar growth was observed in both cancer cell lines with ionizing radiation, C225, or PKAI AS oligonucleotide. A cooperative antiproliferative effect was obtained when cancer cells were treated with ionizing radiation followed by MAb C225 or PKAI AS oligonucleotide. This effect was observed at all doses tested in both GEO and OVCAR-3 cancer cell lines. A combination of the three treatments at the lowest doses produced an even greater effect than that observed when two modalities were combined. Treatment of mice bearing established human GEO colon cancer xenografts with radiotherapy (RT), MAb C225, or PKAI AS oligonucleotide produced dose-dependent tumor growth inhibition that was reversible upon treatment cessation. A potentiation of the antitumor activity was observed in all mice treated with RT in combination with MAb C225 or PKAI AS oligonucleotide. Long-term GEO tumor growth regression was obtained following treatment with ionizing radiation in combination with MAb C225 plus PKAI AS oligonucleotide, which produced a significant improvement in survival compared with controls (P < 0.001), the RT-treated group (P < 0.001), or the group treated with MAb C225 plus PKAI AS oligonucleotide (P < 0.001). All mice of the RT + MAb C225 + PKAI AS group were alive 26 weeks after tumor cell injection. Furthermore, 50% of mice in this group were alive and tumor-free after 35 weeks. This study provides a rationale for evaluating in cancer patients the combination of ionizing radiation and selective drugs that block EGFR and PKAI pathways.

Animals↗
PubMedDate not supplied

On the combination of photodynamic therapy with ionizing radiation.

Ehrlich ascites carcinoma growth and cell damage have been examined after photodynamic therapy (PDT), radiotherapy (RT) and combined treatment. Haematoporphyrin dimethyl ether (HPde) is used as a photosensitizer for PDT and tested as a radiosensitizer for RT. For PDT a non-coherent light source (370 < lambda < 680 nm) equipped with filters is used. gamma-Irradiation consists of 60Co irradiation at a dose of 2 Gy. Both PDT and RT induce a significant delay and inhibition in tumour growth (33 and 38%, respectively). Nevertheless cell damage after these treatments is different: after PDT the cell membrane integrity is damaged and no serious chromosomal aberrations are observed; whereas after gamma-irradiation there is no cell membrane integrity damage, but more significant DNA injuries are observed. It seems evident that HPde is able to act as a photosensitizer as well as a radiosensitizer. Combining PDT and RT produces an additive effect, not dependent on the sequence in which the two treatments are given, when a 1 h time window is used.

Animals↗
PubMedDate not supplied

[Interactions of carboplatin, cisplatin, and ionizing radiation on a human cell line of ovarian cancer].

AIM OF THE STUDY: Cisplatin (CDDP) and radiotherapy are frequently used concomitantly in the treatment of various malignant conditions. Because of its toxicity, cisplatin tends to be replaced by carboplatin (CBDCA) in several indications. Available data regarding the combined effects of cisplatin and carboplatin with ionising radiation are contradictory. MATERIALS AND METHODS: Various concentrations of cisplatin and carboplatin and various timing of association with radiation have been tested in vitro in a human ovarian cancer cell line. The parental cell line (AOvC-0) and a cisplatin-resistant stable subline (AOvC-CDDP/0) (De Pooter et al., Canc Res, 1991) were exposed to carboplatin (2.5, 5 and 10 M) and to CDDP (1, 2.5 and 5 M), 16 h and 4 h before and 4 h and 16 h after irradiation, respectively. Cell survival was evaluated by a classical clonogenic assay. RESULTS: Exposure of AOvC-0 to 5 M CBDCA and of AOvC-CDDP/0 to 10 M CBDCA, before or shortly after radiation exposure, increased cell lethality in a clear supra-additive way, with the highest DEF in the shoulder region of the survival curve and at radiation doses relevant to clinical radiotherapy. In the sensitive cell line, 5 M carboplatin resulted in an additional lethality equivalent to 4.5 Gy; in the resistant cells, 10 M carboplatin was equivalent to 3.6 Gy. Replacing carboplatin by cisplatin in an identical set-up demonstrated exclusively simple additivity (DEF = 1). CONCLUSION: These data suggest that carboplatin and cisplatin delivered at equitoxic doses interact with radiation in a different way and that, in the present set-up, only carboplatin enhanced the effects of radiation. Carboplatin might consequently be a better candidate than cisplatin in some concomitant combinations with radiotherapy.

Carboplatin↗