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Results for “Radiosensitivity”

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PubMed2002

DNA topoisomerase activities in Chinese hamster radiosensitive mutants after X-ray treatment.

In the last years the attractive hypothesis of a possible involvement of mammalian topoisomerases in DNA repair has been proposed, given their molecular mechanism of action. So far, using asynchronous cultures a lot of controversial results have been reported, without taking into account the frequently dramatic fluctuations of topoisomerase activities depending upon the cell cycle stage and proliferation rate (mainly for topoisomerase II). We have addressed this question making use of G1 synchronous cultures of the Chinese hamster radiosensitive mutants xrs 5 (defective in DNA double strand breaks rejoining) and irs 2 (which shows radioresistant DNA synthesis), as well as their parental lines CHO K1 and V79 respectively, which show a normal radiosensitivity. Cells were irradiated with 5 Gy of X-rays and the activities of topoisomerases I and II in nuclear extracts were studied for comparison with non-irradiated controls in both the mutants and parental cell lines. Our results clearly show a modulation of the topoisomerase activities after irradiation, that varies depending upon the mutation that the different lines bear. While this hypothesis needs further testing, an interesting idea is that DNA topoisomerases might be involved in the cellular response to radiation damage, either through a direct participation in the repair mechanisms or in a preparative step to allow repair to proceed.

Animals↗

PubMed1998

In vitro chromosomal radiosensitivity in common variable immune deficiency.

Common variable immune deficiency (CVID) is characterized by low immunoglobulin levels and recurrent infections in patients with a period of normal immune function several years after birth. It is associated with diarrhea, malabsorption, bronchiectasis, and lymphoreticular malignancies. Radiation-induced chromosome instability may contribute to the high degree of susceptibility to neoplasia. Peripheral blood lymphocyte cultures were obtained from six patients with CVID and the healthy control group matched by age and sex. The groups did not differ in the frequency of spontaneous chromosome aberrations. After exposure to X-ray radiation, mitotic indices were found to be significantly low and incidence of chromosomal alterations were high in the CVID group. We conclude that chromosomes of cells from patients with CVID are significantly more radiosensitive than those of controls. Thus these patients must be protected from unnecessary X-ray examinations and in case of radiosensitive tumour, the dose of irradiation should be carefully monitored.

Adolescent↗

PubMed2000

Ataxia-telangiectasia: phenotype/genotype studies of ATM protein expression, mutations, and radiosensitivity.

Previous studies on a limited number of ataxia-telangiectasia (A-T) patients with detectable levels of intracellular ATM protein have suggested a genotype/phenotype correlation. We sought to elucidate this possible correlation by comparing ATM protein levels with mutation types, radiosensitivity, and clinical phenotype. In this study, Western blot analysis was used to measure ATM protein in lysates of lymphoblastoid cell lines (LCLs) from 123 unrelated A-T patients, 10 A-T heterozygotes, and 10 patients with phenotypes similar to A-T. Our Western blot protocol can detect the presence of ATM protein in as little as 1 microg of total protein; at least 25 microg of protein was tested for each individual. ATM protein was absent in 105 of the 123 patients (85%); most of these patients had truncating mutations. The remaining subset of 18 patients (15%) had reduced levels of normal-sized ATM protein; missense mutations were more common in this subset. We used a colony survival assay to characterize the phenotypic response of the LCLs to radiation exposure; patients with or without detectable ATM protein were typically radiosensitive. Nine of 10 A-T heterozygotes also had reduced expression of ATM, indicating that both alleles contribute to ATM protein production. These data suggest that although ATM-specific mRNA is abundant in A-T cells, the abnormal ATM protein is unstable and is quickly targeted for degradation. We found little correlation between level of ATM protein and the type of underlying mutation, the clinical phenotype, or the radiophenotype.

Age of Onset↗

PubMed1988

Correlation between polymerase beta activity and thermal radiosensitization in Chinese hamster ovary cells.

The enhancement of the radiosensitivity of CHO cells was determined for various single and multiple heat treatments followed by X-irradiation at 0 degrees C to prevent repair during exposure. Furthermore, the reduction in the activity of DNA polymerase beta was determined after the same heat treatments. The thermal enhancement ratios for cell killing, calculated on the 10% survival level for the various experimental conditions, showed a clear-cut correlation with the activity of DNA polymerase beta measured by the end of the various heat treatments. These results indicate that the thermal radiosensitization observed in many biological systems might be associated with the transient loss of polymerase beta activity.

Animals↗

PubMed1993

Radiosensitive populations and recovery in X-ray-induced apoptosis in the developing cerebellum.

Sprague-Dawley rats received a single dose of 2 Gy X-rays at the age of 1 or 3 days and were killed at different intervals. Dying cells with the morphological characteristics of apoptosis appeared in the external and internal granular layers (EGL and IGL) and white matter (WM) of the cerebellum, mainly 3-6 h after irradiation, and decreased thereafter to reach normal values between 48 h and 5 days later. This process was curbed by the injection of cycloheximide at a dose of 1 microgram/g body weight. In addition, the number of mitoses in EGL rapidly decreased after irradiation and did not reach normal values until a few days later. Proliferating cell nuclear antigen (PCNA)-immunoreactive cells, which were chiefly found in EGL but also in IGL and WM, dramatically decreased in number from 3 to 48 h after irradiation. PCNA-immunoreactive cells reappeared and reached age-matched values in the following days. Hu (considered as an early neuronal marker) and vimentin immunocytochemistry disclosed that Hu-nonreactive cells in the upper level of EGL, Hu-immunoreactive cells in the inner level of EGL, Bergmann glia and many astrocytes in WM, as well as many non-typified cells in WM, were radiosensitive populations, whereas Purkinje cells were not. The present results indicate that irradiation at P1 or P3 blocks mitosis in EGL and kills sensitive cells mainly in the late G1 and S phases of the cell cycle, probably by apoptosis through a protein synthesis-mediated process. Radiosensitive cells are germinal cells and neuroblasts in EGL, Bergmann glia, astrocytes in WM, and non-typified cells, probably glial cell precursors, in WM. Surviving cells in EGL and PCNA-immunoreactive cells in other cortical layers and white matter reconstitute the cerebellum following a single dose of X-rays.

Animals↗

PubMed1995

The radiosensitivity of uveal melanoma cells and the cell survival curve.

BACKGROUND: No study of the radiosensitivity of uveal melanoma cells and their survival curve has been published. The purpose of this study was to investigate the sensitivity to different single radiation doses of SP6.5, a human uveal melanoma cell line. METHODS: Cells were irradiated with cobalt-60 at doses from 0 to 1200 cGy. Radiosensitivity was measured by three methods: soft-agar bilayer assay, tritiated thymidine incorporation, and bromodeoxyuridine (BrdU) incorporation. RESULTS: The soft-agar bilayer assay, by assessing the colony-forming units, showed that the D1 value was 470 cGy, the Dq value was 400 cGy, and the n value exceeded 10, thus indicating a broad, shoulder and relative radioresistance. The doubling time as estimated by [3H]thymidine incorporation was unaffected at doses below 600 cGy, another indication of radioresistance. BrdU incorporation revealed no significant increase between 0 and 1000 cGy, indicating that the cell cycle was not interrupted. CONCLUSION: Cell survival, doubling time, and cell phases are parameters of growth kinetics, and the results suggest that SP6.5 is radioresistant and virtually unaffected by single radiation doses lower than 600 cGy. Our data parallel published data for cutaneous melanomas.

Aged↗

PubMed1993

Histochemistry with Helix pomatia agglutinin in human germ cell tumors: detection of nongerminomatous components and correlation between HPA reactivity and radiosensitivity in germinomas.

Binding sites of Helix pomatia agglutinin (HPA) were examined in 32 patients with intracranial human germ cell tumors. HPA reactivity was found in vascular endothelial cells and erythrocytes of patients with blood type A or AB. HPA-positive neoplastic cells were seen in one yolk sac carcinoma in a patient with blood group A, and in embryonal carcinomas and teratomas irrespective of blood group type. Although in 10 out of 18 germinomas neoplastic cells were totally negative for HPA, another 8 germinomas showed HPA-positive neoplastic cells which were distributed sporadically or in an area and independent of blood group types. HPA-negative germinoma patients showed a very good response to radiotherapy, whereas 4 out of 8 HPA-positive tumors showed poor radiosensitivity, with a residual lesion seen on computed tomography even after the total radiation dose of 40-50 Gy. These findings suggest that HPA-positive neoplastic cells in germinomas indicate components of differentiation of non-germinomatous germ cells. HPA-positive germinomas might be less radiosensitive than HPA-negative germinomas.

ABO Blood-Group System↗

PubMed1982

Intercellular communication, three-dimensional cell contact and radiosensitivity.

When electrically coupled mammalian cells are cultured as spherical clones (spheroids) and exposed to ionizing radiation they are less radiosensitive than monolayers of the same cell line. Investigations into the possible role of coupling (gap junctions) and three-dimensional contact in the expression of this phenomenon revealed 1) a correlation between cell coupling and the activity of adenylate cyclase in monolayers, 2) a sharp drop of cyclase activity in spheroids of coupled cells compared to monolayers, and 3) a decrease of coupling with age ("maturation") of the spheroids. These results suggest profound physiological alterations in communicating cells induced under conditions of tight three-dimensional contact as a possible cause for the reduced radiosensitivity of spheroids.

Adenylyl Cyclases↗

PubMed1984

Radiosensitivity of vertebral bone marrow CFU-S surviving in mice internally contaminated with 239Pu or 241Am.

The radiosensitivity of pluripotent hemopoietic stem cells was studied in ICR "Swiss" mice (28 g/mouse) given i.v. 198.6 kBq 239Pu/kg as citrate complex or 208.6 kBq 241 Am/kg as nitrate at the age of 10 weeks. The bone marrow cells were examined at the early and late phases of radionuclide contamination. To obtain data for survival curves and D0 of stem cells the CFU-S assay was used and the donor vertebral marrow cells were exposed to the complementary X-irradiation either early after injection to the heavily irradiated recipients or to the "in vitro" irradiation given before the transplantation. To determine the iron uptake in splenic erythroid progeny the recipients given marrow cells unexposed to the X-rays received 37 kBq 59Fe 6 h before they were killed and the relative activity per colony was calculated. The radiation effect of the used actinides on the bone marrow cells resulted in decreased cellularity and seriously altered both relative and absolute CFU-S numbers. The radiosensitivity of CFU-S increased in all intervals examined (D0 from 0.60 to 0.86 Gy, in controls 0.97 to 1.06 Gy) and was more expressed when the CFU-S were exposed to the X-rays immediately after the bone marrow cell transplantation to the heavily irradiated hosts. The stem cell pool appeared, especially at older age, to be affected also in its ability to produce erythrocytic progeny.

Americium↗

PubMed1984

The effect of superoxide dismutase on the radiosensitivity of bacterial spores at various oxygen concentrations.

Superoxide dismutases are considered to be essential protective agent against radiation injury. Experiments were carried out to investigate the effect of extracellularly added SOD on the radiosensitivity of Bacillus megaterium spores. 120 micrograms/ml SOD had no effect on the radiosensitivity of Bacillus megaterium spores at different oxygen concentrations. Relative enzyme activity obtained at various oxygen concentrations indicating the lack of oxygen effect in the radiation-induced inactivation of SOD.

Bacillus megaterium↗

PubMed1991

Combined chemo- and radiosensitivity testing with ifosfamide and ACNU in human lung cancer cell lines.

The combination of radiotherapy and cytostatic drugs is of interest in the treatment of several solid tumors. In these preclinical investigations we tested whether ifosfamide and ACNU are able to enhance radiation effects. The experiments were performed by using the MTT assay. Two small cell and 2 non small cell lung cancer cell lines were involved. Ifosfamide, ACNU or both drugs together were tested in 6 different concentrations adjusted to the peak blood level. During the 1 hour drug incubation time, the cell lines were either irradiated with a single dose of 4 Gy or not. The main results were that ACNU possessed only little cytostatic activity in the cell lines under examination. In contrast, ifosfamide caused a dose related cytostatic activity in all cell lines. Concentrations of 26 micrograms/ml (NCC-SCLC H 82) or 10-12 micrograms/ml (3 other cell lines) were able to reduce the surviving cell fraction to less than 50% (IC50). While ACNU showed no clear outlined radiosensitizing properties, ifosfamide reinforced the radiation effects in 3 out of 4 cell lines indicating radiosensitizing properties of this drug. Synergistic effects of ifosfamide and ACNU have not been noticed. These preclinical investigations may constitute the basis for combined ifosfamide and irradiation therapy in future clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1987

Effect of oridonin, a Rabdosia diterpenoid, on radiosensitization with misonidazole.

The radiosensitization brought about by oridonin, one of the Rabdosia diterpenoids, alone or in combination with misonidazole, was investigated in Chinese hamster V79 cells. The enhancement ratio of 1.92 was obtained when 0.01 mM oridonin and 1 mM misonidazole were administered to hypoxic cells under radiation. The enhancement ratios of oridonin and misonidazole for hypoxic cells were 1.16 and 1.59 respectively. Hence, a supra-additive effect was obtained by the combined treatment with these two drugs. Under aerobic conditions, no effect of 0.01 mM oridonin on the radiosensitization caused by misonidazole was observed.

Animals↗

PubMedDate not supplied

Renal elimination of the hypoxic cell radiosensitizer misonidazole in Wistar rats: influence of some drugs on its excretion.

The hypoxic cell radiosensitizing drug, misonidazole (Miso) (Ro 07-0582) and its demethylated metabolite were administered to Wistar rats at different dose levels to examine their renal elimination. The data were consistent with a model in which Miso is eliminated mainly after biotransformation into desmethylmisonidazole (Demiso) which is eliminated according to its renal clearance. The study of Miso renal elimination process shows a tubular reabsorption. So we analyzed the interaction of various drugs on urinary 24 hours elimination of this radiosensitizer. Following results were observed: Furosemide and acetazolamide do not change the rate of renal elimination of the drug; Soludactone increases the elimination level of unmetabolized Miso (p less than 0.01); Under probenecid treatment, the elimination of Miso and its O-demethylated derivative are increased; On the other hand, after a pretreatment with phenobarbital, the urinary level of desmethylmisonidazole is strongly increased (p less than 0.001).

Animals↗

PubMed2003

Significant increase in residual DNA damage as a possible mechanism of radiosensitization by gemcitabine.

PURPOSE: To investigate the effect of gemcitabine (dFdC), a promising radiosensitizing nucleoside analog, on the induction and repair of DNA double-strand breaks (dsbs) after ionizing radiation (RT) in a pancreatic tumor cell line. MATERIAL AND METHODS: BxPC3 pancreatic tumor cells were treated using different concentrations of gemcitabine with and without subsequent irradiation. DNA dsbs were detected by constant-field gel electrophoresis under neutral conditions. RESULTS: With the addition of gemcitabine (0.5-1,000 micromol/l for 2 h prior to RT) to RT (0-75 Gy), a considerable and dose-dependent increase of remaining DNA damage after 24 h (5.4-fold for 0.5 micromol/l dFdC, 12.2-fold for 1,000 micromol/l dFdC at 25 Gy) was noted. Enhancement factors were inversely correlated with increasing X-ray dose (7.8-fold for 0.5 micromol/l at 1 Gy decreasing to 1.6-fold at 75 Gy). Conversely, the induction of DNA dsbs was not affected. Gemcitabine alone lead to a slight increase of initial DNA dsbs and only a modest elevation of residual DNA damage. CONCLUSION: These findings strengthen the hypothesis of DNA repair inhibition as a major mechanism of radiosensitization by gemcitabine.

Antimetabolites, Antineoplastic↗

PubMed2000

p53: biology and role for cellular radiosensitivity.

PURPOSE: p53 is the most commonly mutated gene in human tumors with large impact on cellular biology and response to radiation. Many excellent reviews are available on various aspects but for several years none about the role of p53 for radiosensitivity. The latter is the aim of the present paper. METHODS: Review of the literature. RESULTS: p53 is a regulator of apoptosis mainly in hematopoetic tissue. In normal tissue and solid tumors presumably other functions have more impact on the cellular response. p53 controls cell-cycle progression after irradiation and also DNA-repair, namely homologous and non-homologous recombination. Mutations of p53 alter these functions which may be responsible for an enhanced cellular and tumor radioresistance. At present only few reports were able to show that under tightly controlled conditions loss of p53 wild-type function leads to enhanced radioresistance. A general proof is still lacking. CONCLUSIONS: The emerging picture in the year 2000 shows p53 as a central protein in a multi-enzyme multi-function network which is far from being fully understood. Although p53 appears to be a major regulator it is certainly not the unreplaceable component the loss of which uniformly determines radioresistance. Only further understanding of modifiers and co-operators in the cell and in the specific tissue context will elucidate p53's role for radiosensitivity and radiotherapy.

Cell Cycle↗

PubMed2000

P53 status plays no role in radiosensitizing effects of SN-38, a camptothecin derivative.

PURPOSE: Topoisomerase inhibitors including camptothecin are being studied as potential radiosensitizers. CPT-11 is a derivative of camptothecin and is clinically available. In this study, we investigated the effects of SN-38 (an active metabolite of CPT-11) on four nonirradiated and irradiated murine fibroblast cell lines with different p53 statuses to clarify the role of p53 in the radiosensitizing activity of SN-38. MATERIALS AND METHODS: Four fibroblast cell lines, MT158, MT158/neo, MT158/wtp53 and MT158/mp53 with the same genetic background but with different p53 statuses, were used. Exponentially growing cells were treated with SN-38 (200 nM) and incubated with the drug for 30 min. Cells were then irradiated (0 to 12 Gy) and further incubated with the drug for 2 h. The cell survival rate was determined using a conventional clonogenic assay. The effects of the treatments on the cell cycle were analyzed with a flow cytometric assay. Apoptosis after these treatments was also detected by an annexin V assay. RESULTS: There were no significant differences in sensitivity to radiation or SN-38 treatment among these cell lines. The combined treatment of irradiation and SN-38 showed supraadditive effects in all four cell lines independent of their p53 status. Transient arrest in G2 with a decreased percentage of cells in both the S and G1 phases was observed 8 h after treatment with either SN-38 alone, radiation or their combination, regardless of the p53 status. No significant differences in frequency of apoptosis were observed between treatment and control groups in two cell lines with or without wild-type p53. CONCLUSION: The combination of irradiation and SN-38 treatment showed supraadditive effects in all four cell lines tested, and the p53 status did not play a role in the combination effect.

Antineoplastic Agents, Phytogenic↗

PubMed1998

Radiation-induced genetic instability: no association with changes in radiosensitivity or cell cycle checkpoints in C3H 10T1/2 mouse fibroblasts.

We investigated various phenotypic characteristics of radiation-induced morphologically transformed C3H 10T1/2 mouse fibroblasts. The cells were treated with 8 Gy x-rays, and type II/III foci were isolated. Cell lines were developed from these foci, and subsequently clones were established from these focal lines. The clones were examined for DNA content, radiosensitivity and inducible cell cycle arrests. Besides the morphological changes associated with the transformed state, the major difference between the isolated focal lines or derived clones and the parental C3H 10T1/2 line was one of ploidy. The transformed cells often displayed aneuploid and multiple polyploid populations. No change in the radiosensitivity of the transformed cells was observed. Furthermore, the two major radiation- and staurosporine-induced G1 and G2 cell cycle arrests observed in the parental cell line were also observed in the morphological transformants, suggesting that checkpoint function was normal.

Aneuploidy↗

PubMed2001

The exogenous wild-type p14ARF gene induces growth arrest and promotes radiosensitivity in human lung cancer cell lines.

The cyclin-dependent kinase inhibitor p16INK4a encoded by the INK4A/CDKN2A/MTS1 gene is a frequent target of 9p21 inactivation in human lung cancers. The p14ARF transcript, which is an alternative spliced form of this locus, is also altered or deleted in a proportion of human lung cancers and has been shown to inhibit cell cycle progression as an endogenous cellular regulator of the p53 protein, raising the possibility that it might constitute an additional lung tumor suppressor gene at the 9p21 locus. To test the candidacy of p14ARF as a lung cancer suppressor and assess the role it plays in radiosensitivity, we transfected the wild-type p14ARF gene into four cell lines which had various endogenous gene backgrounds of INK4A-/p53+/RB+ (A549 and H460), INK4A+/p53+/RB- (H446) as well as p14ARF+/p53-/RB+ (Calu-1). We found that transfection of p14ARF is related to an obvious growth inhibition in all wtp53 cell lines, regardless of INK4A/ARF and RB status. Although it has been shown that p53-induced G1 checkpoint in response to DNA damage by ionizing radiation is p14ARF-independent, we found the radiosensitivity of two p14ARF-deficient cell lines was increased after p14ARF gene transfer. The results indicated that cell cycle redistribution after acquiring the exogenous gene might be the main explanation for the enhanced sensitization. An increased radiation-induced apoptotic proportion in one cell line also suggested a fortified p53 function that might be triggered by the restored p14ARF protein.

Cell Cycle↗