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PubMed1995

Isolation and characterization of a cell line resistant to 5-[3-(2-nitro-1-imidazoyl)-propyl]-phenanthridinium bromide (2-NLP-3), a DNA-intercalating hypoxic cell radiosensitizer and cytotoxin.

A DNA-targeted hypoxic cell radiosensitizer and cytotoxin, 5-[3-(2-nitro-1-imidazoyl)-propyl]-phenanthridinium bromide (2-NLP-3), has been shown previously to have increased efficacy over untargeted analogues in vitro. To further study the mechanism of action of this compound, a cell line, CHO-1000, derived from Chinese hamster ovary (CHO) AA8-4 cells was isolated. This cell line is capable of continuously growing in a concentration of 2-NLP-3 approximately 10-fold greater than that tolerated by wild-type CHO cells. The resistance of CHO-1000 to 2-NLP-3 was compared with that of the P-glycoprotein overexpressing, multidrug resistant Chinese hamster cell line CHR-C5 (C5). The resistance of CHO-1000 cells to the acute toxic effects of 2-NLP-3 under both hypoxic and aerobic exposure conditions was intermediate to that of the sensitive CHO wild-type cells and the resistant C5 cells. A similar pattern was seen for the hypoxic cell radiosensitizing ability of 2-NLP-3. 2-NLP-3 produced significant depletion of glutathione under both hypoxic and aerobic conditions in all three cell lines studied, and the degree of depletion was correlated with drug toxicity. CHO-1000 and C5 cells were significantly more resistant to colchicine and doxorubicin compared with wild-type cells. The toxicity pattern of 2-NLP-3 and its comparison phenanthridinium ion, P3, was not the same for CHO-1000 cells compared with C5 cells. Verapamil was an effective agent for reversing the hypoxic resistance to 2-NLP-3 in both CHO-1000 and C5 cells, but only a partial reversal of aerobic resistance was observed in CHO-1000 cells. These results indicate that the resistant phenotype of CHO-1000 is mediated to some degree by P-glycoprotein expression, but that other as yet unidentified factors are also involved.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1992

In search of a correlation between the electron affinity and the radiosensitizing activity of some glyoxylic compounds.

The electron affinity of some glyoxylic compounds with radiosensitizing properties was evaluated using different approaches. The half-wave reduction potentials were measured by polarography, and the molecular structures in solution were determined by NMR spectroscopy. The electron affinity of the unhydrated and hydrated molecules was theoretically evaluated by means of a semi-empirical quantum mechanical procedure, the MNDO. The possible correlations between these values and the radiosensitizing efficiency of these glyoxylic compounds is discussed.

Electrochemistry↗

PubMed1985

Effect of hypoxic cell radiosensitizers on glutathione level and related enzyme activities in isolated rat hepatocytes.

A comparative study of the effect of misonidazole and novel radiosensitizers on glutathione (GSH) levels and related enzyme activities in isolated rat hepatocytes was performed. Incubation of hepatocytes with 5 mM radiosensitizers led to a decrease in the intracellular GSH level. The most pronounced decrease in cellular GSH was evoked by 2,4-dinitroimidazole-1-ethanol (DNIE); after incubation for only 15 min, GSH was hardly detected. DNIE-mediated GSH loss was dependent upon its concentration. DNIE reacted with GSH nonenzymatically as well as with diethylmaleate, while misonidazole and 1-methyl-2-methyl-sulfinyl-5-methoxycarbonylimidazole (KIH-3) did not. Addition of partially purified glutathione S-transferase (GST) did not enhance DNIE-mediated GSH loss in a cell-free system. DNIE inhibited glutathione peroxidase (GSH-Px), GST, and glutathione reductase (GSSG-R) activities in hepatocytes, while misonidazole and KIH-3 did not. GSH-Px activity assayed with H2O2 as substrate was the most inhibited. Inhibition of GSH-Px activity assayed with cumene hydroperoxide as substrate and GST was less than that of GSH-Px assayed with H2O2 as substrate. GSSG-R activity was decreased by DNIE, but not significantly. Incubation of purified GSH-Px with DNIE resulted in a little change in the activity when assayed with H2O2 as substrate.

Animals↗

PubMed1991

Enhancement of radiosensitizing effect of the nitroimidazole derivative RK28 on the proliferation of MethA tumor cells in combined use with diethyldithiocarbamate.

The radiosensitizing effect of the nitroimidazole derivative RK28 and diethyldithiocarbamate (DDC), which is an inhibitor of superoxide dismutase activity, was examined in vitro by using Meth A tumor cells. The radiosensitizing effect of 0.5 mM RK28 was observed in both of 10 Gy and 15 Gy irradiated groups. The addition of 5 x 10(-7) M DDC also enhanced the radiation-induced proliferation inhibition. Marked enhancement of the antiproliferative effect was observed in combined use of 0.2 mM or 0.5 mM RK28 with 2 x 10(-7) M or 5 x 10(-7) M DDC. These results suggest that enhanced oxygen effect could be expected through combined use of the ionizing irradiation with both of these agents.

Animals↗

PubMed1975

A comparison of chromosomal radiosensitivities of somatic cells of mouse and man.

A cell culture technique for quantitative analysis of radiation-induced chromosome aberrations in somatic cells has been developed and used for the comparison of chromosomal sensitivity of skin cells of mouse and man to 60Co-gamma-rays. This includes culture of irradiated tissues or cells in culture in arginine and isoleucine-deficient medium and subsequent refeeding with complete medium (CM). With this technique, radiation-induced chromosome aberrations can be analyzed selectively in the cells exposed in G1 phase and recovered at their first post-irradiation mitosis. When tested on the human embryonic cells, the dicentric yield was essentially the same whether they were skin cells irradiated in silu or cultured cells at various in vitro passages irradiated in vitro. In contrast, when studied in the skin cells irradiated in silu, mouse embryos and newborns were insensitive to the induction of dicentrics. In young mice on day II however, the sensitivity was at a level comparable to that in human embryonic cells and it was intermediate on day 4. Such embryonic insensitivity of the mouse cells was rapidly lost during serial transfer in vitro; and, when tested at 4th or later subculture generations, mouse and human cells were equally sensitive to the induction of dicentrics. These results suggest that the chromosomal radiosensitivity is essentially the same for mouse and human cells but can be modified by some biological factors, possibly DNA repair mechanisms, which differ between species as well as among the states of differentiation of particular cell types. Special attention was paid to the parellelism between the age-dependent changes in the chromosomal, mutational and carcinogenic radiosensitivities in the mouse. If this parallelism can be carried over to man, human pre-natal irradiation will not present any reduced genetic hazards.

Animals↗

PubMed1981

Rbe of densely ionizing radiation for wild-type and radiosensitive mutants of yeast.

Survival curves were obtained for haploid and diploid yeasts, Saccharomyces cerevisiae, of wild-type strains and radiosensitive mutants exposed to gamma-rays and alpha-particles. A correlation between the values of the relative biological effectiveness (RBE) of high-LET radiation and cell-repair capacity was found. The difference in radiosensitivities of the wild-type diploid strain and homozygous rad mutants incapable of recovery was significantly higher after low-LET radiation than after high-LET radiation. Possible reasons for the observed radiation responses to low- and high-LET exposure of yeast cells with various genotype are discussed.

Alpha Particles↗

PubMed1983

Influence of misonidazole on survival of wild-type and radiosensitive mutants of yeast.

Survival curves were obtained for haploid and diploid yeasts, Saccharomyces cerevisiae, of a wild-type strain and radiosensitive mutants exposed to gamma-rays in oxygenated and hypoxic conditions both in the absence and in the presence of misonidazole. Misonidazole enhanced the radiosensitivity only of hypoxic cells. A correlation between oxygen and misonidazole sensitization was observed. The data confirm that misonidazole mimics the sensitizing effect of oxygen. The degree of liquid-holding recovery of yeast cells was greater when the cells were irradiated in hypoxic conditions with than without misonidazole. Possible reasons for the observed radiation responses are discussed.

Dose-Response Relationship, Drug↗

PubMed1984

Enhanced radiosensitivity for the induction of translocations in mouse stem cell spermatogonia following treatment with cyclophosphamide or adriamycin.

The effects of pretreatment of mouse spermatogonial stem cells with cyclophosphamide (100 and 200 mg/kg) and adriamycin (2.5, 5 and 7 mg/kg) on the induction of chromosomal translocations by high doses (800 or 900 rad) of X-rays applied 24 h later, were studied by spermatocyte analysis. The results indicate that both compounds were able to alter the chromosomal radiosensitivity of surviving stem cells. It is concluded that depletion of differentiating and differentiated spermatogonia is sufficient for triggering stem cells into a more radiosensitive phase.

Animals↗

PubMed1994

Radiosensitive target in the early mouse embryo exposed to very low doses of ionizing radiation.

We exposed mouse preimplantation embryos in vitro to either tritiated water (HTO) or tritiated thymidine (TdR) to determine whether the radiosensitive target was nuclear or extranuclear for embryonic cell proliferation disadvantage in the mouse embryo chimera assay. 8-cell embryos were incubated in either HTO or TdR for 2 h and paired with non-irradiated control embryos to form chimeras. Chimeras were cultured for an average of 20.2 h to allow for 2-3 cell cycles and then partially dissociated to obtain the number of progeny cells contributed by the two partner embryos for each chimera. These values were expressed as a "proliferation ratio" (number of cells from the irradiated embryo: total number of cells in the chimera). A ratio significantly less than 0.50 indicates that the experimental embryo expressed an embryonic cell proliferation disadvantage, which is the endpoint of this assay. The activity concentrations of HTO and TdR were adjusted so that both would deliver comparable mean absorbed nuclear doses during the combined initial 2-h irradiation incubation and subsequent 20.2 h chimera incubation periods. Although nuclear doses were comparable under these conditions, the extranuclear dose delivered by the uniformly distributed HTO was about 100 times greater than the extranuclear dose delivered by TdR for each given nuclear dose. Consequently, obtaining mean TdR proliferation ratios < or = mean HTO proliferation ratios would be evidence for a nuclear target while obtaining mean HTO proliferation ratios < mean TdR proliferation ratios would be evidence for an extranuclear target. TdR consistently produced lower mean proliferation ratios over a range of doses from 0.14 Gy to 0.43 Gy. Therefore, we conclude that the radiosensitive target for this endpoint is nuclear.

Animals↗

PubMed1994

Post-irradiation DNA synthesis inhibition and G2 phase delay in radiosensitive body cells from non-Hodgkin's lymphoma patients: an indication of cell cycle defects.

In the present study, both post-irradiation DNA synthesis and G2 phase accumulation were analyzed in lymphoblastoid cell lines (LCLs) and fibroblast cell strains derived from (Saudi) patients with non-Hodgkin's lymphoma (NHL), ataxia telangiectasia (AT), AT heterozygotes and normal subjects. A comparison of the percent DNA synthesis inhibition (assayed by 3H-thymidine uptake 30 min after irradiation), and a 24 h post-irradiation G2 phase accumulation determined by flow cytometry placed the AT heterozygotes and the NHL patients in an intermediate position between the normal subjects (with maximum DNA synthesis inhibition and minimum G2 phase accumulation) and the AT homozygotes (with minimum DNA synthesis inhibition and maximum G2 accumulation). The similarity between AT heterozygotes and the NHL patients with respect to the two parameters studied after irradiation was statistically significant. The data indicating a moderate abnormality in the control of cell cycle progression after irradiation in the LCLs and fibroblasts from NHL patients may explain the enhanced cellular and chromosomal radiosensitivity in these patients reported by us earlier. In addition to demonstrating a link between cell cycle abnormality and radiosensitivity as a possible basis for cancer susceptibility, particularly in the NHL patients, the present studies emphasized the usefulness of the assay for 24 h post-irradiation G2 phase accumulation developed by Lavin et al. (1992) in characterizing AT heterozygote-like cell cycle anomaly in cancer patients irrespective of whether they carried the AT gene or any other affecting the cell cycle.

Ataxia Telangiectasia↗

PubMed1996

The molecular nature of spontaneous mutations at the hprt locus in the radiosensitive CHO mutant xrs-5.

The radiosensitive mutant xrs-5, a derivative of the Chinese hamster ovary (CHO) K1 cell, is defective in DNA double-strand break rejoining ability and in V(D)J recombination. The radiosensitivity and defective repair phenotype are complemented by the 80-kDa subunit of the Ku protein. We determined the nature of the mutations that develop spontaneously at the hprt locus in this cell line using both multiplex PCR deletion screening and DNA sequencing. Ninety-two independent spontaneous mutants were analyzed and the results were compared to the mutation spectrum of 64 previously analyzed hprt spontaneous mutants isolated from the parental CHO-K1 cell line. More than 50% of the spontaneous xrs-5 mutants had lost one or more exons while less than 25% of spontaneous CHO-K1 mutants had lost one or more exons. Most of the deletions in xrs-5 cells involved the loss of multiple exons while single exon deletions predominated in CHO-K1. There was also a nonrandom distribution of breakpoints in both CHO-K1 and xrs-5. Most of the deletion breakpoints were 3' to exon 9, around exons 4-6, or near exon 1. Although the frequency of base substitutions was lower in xrs-5, the spectrum of base substitutions was qualitatively similar to that of CHO-K1. There was no significant difference in the spontaneous mutant frequency in xrs-5 and CHO-K1. The results suggest that in certain regions of the hprt gene, base alterations can be converted to large deletions, and that alterations in the Ku protein complex can influence this process.

Animals↗

PubMed1985

Comparison of the radiosensitivity of interleukin-2 production between species, between tissues, and between young and old individuals.

The radiosensitivity of interleukin-2 (IL-2) production was assessed of (a) peripheral blood mononuclear cells (PBMC) of young humans, dogs, and mice (C57BL/6); (b) PBMC and splenic cells of young mice; and (c) PBMC of young and old humans and the splenic cells of young and old mice. The results indicate that (a) large differences in radiosensitivity exist between the PBMC of humans, dogs, and mice (e.g., the radiation doses which resulted in 37% remaining IL-2 activity (D37) of human, dog, and mouse PBMC were 3771, greater than 10,000, and 1398 rads, respectively); (b) only a small difference exists between the PBMC and splenic cells of mice; and (c) no difference exists between the PBMC of young and old humans and between splenic cells of young and old mice. Topological abnormalities, as judged by scanning electron microscopic analysis, could not be detected in dog PBMC after their exposure to 1800 rads, but could be detected in mouse PBMC after their exposure to 400 rads.

Adult↗

PubMed1991

Simplified quantitative estimation in vitro of lymphocyte radiosensitivity applied to patients with chronic lymphocytic leukaemia.

Lymphocyte survival changes observed at 1, 2 and 3 days as responses to 3 doses of ionising radiation in vitro (40, 100, and 500 cGy) are analysed by computer according to a simple (single cell population) mathematical model. Intrinsic radiosensitivity, the susceptibility to lethal injury, which is expressed as the D37 value (the radiation dose permitting 37% survival), is estimated separately from the kinetics of subsequent death of lethally-irradiated cells (expressed as their half-life, or t1/2 value). Among the 35 patients with B-cell CLL studied (15 were never treated), both parameters varied widely and independently of one another. t1/2 ranged from 9-200 h and above, D37 from 14-500 cGy or above. Twenty-three patients were deemed 'radiosensitive' (D37 below 110 cGy). D37 level did not correlate with treatment status, mode of treatment, clinical staging (Rai) or lymphocyte count. With some exceptions, D37 remained relatively constant for individual patients with increasing duration of disease or alterations in treatment status. The assay method may prove useful as an aid in predicting response to low-dose splenic irradiation (SI) in CLL.

B-Lymphocytes↗

PubMed1985

G2 chromosomal radiosensitivity of ataxia-telangiectasia heterozygotes.

Five lines of skin fibroblasts from individuals heterozygous for ataxia-telangiectasia (A-T), compared with six cell lines from age-matched normal controls, show a much higher frequency of chromatid breaks and gaps following x-irradiation during the G2 phase of the cell cycle. The magnitude of this difference suggests that G2 chromatid radiosensitivity could provide the basis for an assay to detect A-T heterozygotes. Though clinically normal, A-T heterozygotes share a high risk of cancer with A-T homozygotes and constitute approximately 1% of the human population. Further, we propose that G2 chromosomal radiosensitivity, which appears to result from a DNA repair deficiency, may be associated with a genetic predisposition to cancer.

Ataxia Telangiectasia↗

PubMed1993

Cellular radiosensitivity of patients with different types of neurofibromatosis.

Skin fibroblast cell strains were developed from nine Saudi patients with different types of neurofibromatosis (NF) and nine healthy subjects (controls), and their radiosensitivity was compared following chronic exposure to gamma-radiation at a dose rate of 0.0076 Gy/min (1 Gy = 100 rads). Cells from both normal appearing skin and café-au-lait spots of the different NF patients (7 out of 9) clearly showed increased radiosensitivity, with D10 (dose resulting in 10% survival) values of 2.0-4.4 Gy for the former and 3.0-4.8 Gy for the latter, compared to the normal controls (with D10 values of 6.1-10.6 Gy). These data provide further evidence of an association of enhanced cellular sensitivity to chronic irradiation with NF regardless of the classes they belong to. Hypersensitivity to specific carcinogens may, thus, be a factor responsible for the increased propensity to cancer in these patients.

Adult↗

PubMedDate not supplied

A search for radiosensitive mouse mutants by use of the micronucleus technique.

In order to identify radiosensitive mutations in mice, 26 genetically well defined mutations in 26 different combinations of homozygous, hemizygous or heterozygous conditions, together with normal mice and mutagen-sensitive MS/Ae mice were analysed for the induction of micronuclei by X-rays in bone-marrow cells. For each mutant two doses of 0.5 and 1.0 Gy, two sampling times of 18 and 27 h after irradiation and unirradiated controls were studied. Using our criteria, homozygous contrasted allele of steel (Slcon), scabby (scb), viable dominant spotting (Wv), quaking (qk), fidget (fi) and postaxial hemimelia (px), heterozygous lurcher (Lc), hemizygous gyro (Gy), the compounds Slcon/grizzle-belly (SlgbH) and Wv/rump-white (Rw) and MS/Ae mice, were regarded as radiosensitive, with Slcon/Slcon the highest in rank order. Homozygous wabbler-lethal (wl) and wasted (wst) showed hyposensitivity which for the latter may be connected with enhanced cell killing.

Animals↗

PubMed1995

The relative radiosensitivity of TK6 and WI-L2-NS lymphoblastoid cells derived from a common source is primarily determined by their p53 mutational status.

The lymphoblastoid cell lines WI-L2-NS and TK6 were derived from a non-clonal pool of cells taken from a human spleen. Despite their common background they exhibit marked differences in radiosensitivities; D0 values of 93 and 67 cGy have been reported for WI-L2-NS and TK6 cells respectively. We show here that this differential radiosensitivity is due to a decreased ability of the WI-L2-NS cell line to undergo radiation-induced apoptosis. Further, the WI-L2-NS cell line overexpresses the p53 gene product as a result of a mutation in codon 237 of the p53 gene. These data indicate that WI-L2-NS cells through disruption of normal p53 function are unable to engage the radiation-induced apoptosis program and so are relatively radioresistant.

Apoptosis↗

PubMed1988

Radiosensitivity related to neuroendocrine and endodermal differentiation in lung carcinoma lines.

A panel of human lung carcinoma lines was studied with respect to hormone production and intermediate filament expression to distinguish between endodermal and neuroendocrine differentiation. An index of the degree of neuroendocrine differentiation of each line was derived from the presence or absence of hormone production, cytokeratins, neurofilaments and an embryonic endodermal cell marker, which allowed identification of three groups showing high, intermediate or low neuroendocrine expression. This grouping correlated well with the in vitro radiosensitivity of the lines, those expressing pure neuroendocrine features being significantly more radiosensitive than those with an endodermal phenotype, with the intermediate group having intermediate sensitivity. Use of such an index might predict those patients likely to benefit from the use of radiotherapy in their management.

Adenocarcinoma↗