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Results for “Radiosensitivity”

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PubMed2006

Comparison of clonogenic assay with premature chromosome condensation assay in prediction of human cell radiosensitivity.

AIM: To determine whether the number of non-rejoining G2-chromatid breaks can predict the radiosensitivity of human cell lines. METHODS: Cell lines of human ovary carcinoma cells (HO8910), human hepatoma cells (HepG2) and liver cells (L02) were irradiated with a range of doses and assessed both of cell survival and non-rejoining G2-chromatid breaks at 24 h after irradiation. Cell survival was documented by a colony assay. Non-rejoining G2-chromatid breaks were measured by counting the number of non-rejoining G2 chromatid breaks at 24 h after irradiation, detected by the prematurely chromosome condensed (PCC) technique. RESULTS: A linear-quadratic survival curve was observed in three cell lines, and HepG2 was the most sensitive to gamma-radiation. A dose-dependent linear increase was observed in radiation-induced non-rejoining G2-PCC breaks measured at 24 h after irradiation in all cell lines, and HepG2 was the most susceptible to induction of non-rejoining G2-PCC breaks. A close correlation was found between the clonogenic radiosensitivity and the radiation-induced non-rejoining G2-PCC breaks (r = 0.923). Furthermore, survival-aberration correlations for two or more than two doses lever were also significant. CONCLUSION: The number of non-rejoining G2 PCC breaks holds considerable promise for predicting the radiosensitivity of normal and tumor cells when two or more than two doses lever is tested.

Cell Line, Tumor↗

PubMed2006

Down-regulation of survivin expression by small interfering RNA induces pancreatic cancer cell apoptosis and enhances its radiosensitivity.

AIM: To investigate the inhibitory effect of small interfering RNA (siRNA) on the expression of survivin in pancreatic cancer cell line PC-2 and the role of siRNA in inducing PC-2 cell apoptosis and enhancing its radiosensitivity. METHODS: A siRNA plasmid expression vector against survivin was constructed and transfected into PC-2 cells with Lipofectamine 2000. The down regulation of survivin expression was detected by semi-quantitative RT-PCR and immunohistochemical SP method and the role of siRNA in inducing PC-2 cell apoptosis and enhancing its radiosensitivity was detected by flow cytometry. RESULTS: The sequence-specific siRNA efficiently and specifically down-regulated the expression of survivin at both mRNA and protein levels. The expression inhibition ratio was 81.25% at mRNA level detected by semi-quantitative RT-PCR and 74.24% at protein level detected by immunohistochemical method. Forty-eight hours after transfection,apoptosis was induced in 7.03% cells by siRNA and in 14.58% cells by siRNA combined with radiation. CONCLUSION: The siRNA plasmid expression vector against survivin can inhibit the expression of survivin in PC-2 cells efficiently and specifically. Inhibiting the expression of survivin can induce apoptosis of PC-2 cells and enhance its radiosensitivity significantly. RNAi against survivin is of potential value in gene therapy of pancreatic cancer.

Apoptosis↗

PubMed2002

DNA-PKcs subunits in radiosensitization by hyperthermia on hepatocellular carcinoma hepG2 cell line.

AIM: To investigate the role of DNA-PKcs subunits in radiosensitization by hyperthermia on hepatocellular carcinoma HepG(2) cell lines. METHODS: Hep G(2) cells were exposed to hyperthermia and irradiation. Hyperthermia was given at 45.5 degrees C. Cell survival was determined by an in vitro clonogenic assay for the cells treated with or without hyperthermia at various time points. DNA DSB rejoining was measured using asymmetric field inversion gel electrophoresis (AFIGE). The DNA-PKcs activities were measured using DNA-PKcs enzyme assay system. RESULTS: Hyperthermia can significantly enhance irradiation-killing cells. Thermal enhancement ratio as calculated at 10 % survival was 2.02. The difference in radiosensitivity between two treatment modes manifested as a difference in the alpha components and the almost same beta components, which alpha value was considerably higher in the cells of combined radiation and hyperthermia as compared with irradiating cells (1.07 Gy(-1) versus 0.44 Gy(-1)). Survival fraction showed 1 logarithm increase after an 8-hour interval between heat and irradiation, whereas DNA-PKcs activity did not show any recovery. The cells were exposed to heat 5 minutes only, DNA-PKcs activity was inhibited at the nadir, even though the exposure time was lengthened. Whereas the ability of DNA DSB rejoining was inhibited with the increase of the length of hyperthermic time. The repair kinetics of DNA DSB rejoining after treatment with Wortmannin is different from the hyperthermic group due to the striking high slow rejoining component. CONCLUSION: Determination with the cell extracts and the peptide phosphorylation assay, DNA-PKcs activity was inactivated by heat treatment at 45.5 degrees C, and could not restore. Cell survival is not associated with the DNA-PKcs inactivity after heat. DNA-PKcs is not a unique factor affecting the DNA DSB repair. This suggests that DNA-PKcs do not play a crucial role in the enhancement of cellular radiosensitivity by hyperthermia.

Carcinoma, Hepatocellular↗

PubMedDate not supplied

In vivo efficacy and pharmacokinetics of a new hypoxic cell radiosensitizer doranidazole in SUIT-2 human pancreatic cancer xenografted in mouse pancreas.

A new 2-nitroimidazole radiosensitizer doranidazole is now undergoing clinical evaluation in combination with intraoperative radiotherapy for unresectable pancreatic cancer. However, there have been no laboratory data on its effect against pancreatic cancer. This study was undertaken to clarify the efficacy and pharmacokinetics of doranidazole in a human pancreatic cancer SUIT-2 xenografted in the pancreas of nude mice. The tumor-bearing mice were irradiated to the upper abdomen using electron beams with or without prior administration of doranidazole. The tumors were excised 3-6 days later and their weight was measured. Doranidazole given alone had no antitumor effect, but it had radiosensitizing effects when 100, 150, or 200 mg/kg of the drug was combined with single 5 Gy irradiation. The tumor/serum ratios for doranidazole concentration were 0.3-0.4, but the concentrations in the tumor were similar to those in the surrounding normal pancreas. At doses of 100 mg/kg or higher, concentrations of doranidazole in the pancreatic tumor appeared to be sufficient to obtain definite radiosensitization.

Animals↗

PubMedDate not supplied

BrdUrd-induced radiosensitization of two human tumour cell lines at iso-levels of incorporation.

Bromodeoxyuridine (BrdUrd)-induced radiosensitization of two different tumour cell lines was compared at equal levels of thymidine replacement. Human lung carcinoma cells (SW-1573) and human colorectal carcinoma cells (RKO) were grown for 48 h in the presence of respectively 1 microM BrdUrd and 4 microM of BrdUrd in order to obtain equal levels of BrdUrd into the DNA. In SW cells the level of thymidine replacement by BrdUrd was 6.7+/-0.5% and in RKO cells this was 7.1+/-0.8. Cell survival after irradiation with single doses up to 8 Gy, was determined with clonogenic assay. The magnitude of BrdUrd-induced radiosensitization was determined by analyzing radiation-dose survival curves with the linear-quadratic formula [S(D)/S(0)=exp-(alphaD+betaD2)]. In the SW cells BrdUrd radiosensitization led to a significant increase of the linear parameter, alpha, determining the initial slope of the survival curves, by a factor of about 2. In the RKO cells BrdUrd increased the value of alpha by a factor 1.4. This suggests that repair of potentially lethal damage (PLD) is inhibited. In both cell lines the quadratic term, beta, strongly influencing the high dose region of the survival curves, was not altered by sensitization by BrdUrd. The increase of alpha is of interest for clinical applications as BrdUrd sensitizes tumour cells after low doses of radiation.

Bromodeoxyuridine↗

PubMedDate not supplied

Prediction of radiosensitivity in human esophageal squamous cell carcinomas with heme oxygenase-1: a clinicopathological and immunohistochemical study.

The lack of an accurate system to predict the response to radiotherapy for individual cancer lesions remains a major clinical problem. The aim of this study was to establish whether heme oxygenase-1 (HO-1) may be useful in predicting radiosensitivity of esophageal cancers. We evaluated biopsy specimens from 13 esophageal squamous cell cancer patients. Of these, 8 patients had tumors responding to radiotherapy, and the remainder were considered radioresistant. Expression of HO-1 was assayed using a standard immunoperoxidase technique. Clinicopathological parameters were also analyzed as factors potentially contributing to radiosensitivity. Seven of 13 patients (53.8%) showed cytoplasmic staining for HO-1 in cancer tissues. The local treatment failure rate was 0% for HO-1 positive patients, as opposed to 83.3% for HO-1-negative patients (p=0.012). In contrast, tumor size, stage, and histologic grade were not significantly different between radiotherapy responders and non-responders to radiation therapy. No relationship was observed between HO-1 expression and clinicopathologic features. The results of the current study suggest that expression of HO-1 may be a useful indicator of radiosensitivity for esophageal cancer patients.

Age Factors↗

PubMedDate not supplied

mda-7 (IL-24) Inhibits growth and enhances radiosensitivity of glioma cells in vitro via JNK signaling.

Despite therapeutic interventions including surgery, chemotherapy and radiotherapy, glioblastoma multiforme (GBM) has a very poor prognosis and novel therapies are required. MDA-7 (IL-24), when expressed via a recombinant replication defective adenovirus, Ad.mda-7, has profound anti-proliferative and cytotoxic effects in a variety of tumor cells, but not in non-transformed cells. The present studies examined the combined impact of Ad.mda-7 and ionizing radiation on the proliferation and survival of GBM cells. Ad.mda-7 reduced the proliferation of rodent and human glioma cells in MTT assays and in colony formation assays. The anti-proliferative effects of Admda-7 were enhanced by radiation in a greater than additive fashion. In vitro, this cellular change correlated with enhanced cell numbers in G1/G0 and G2/M phases of the cell cycle, implying Ad.mda-7 radiosensitizes tumor cells in a cell cycle-independent manner. The radiosensitizing effects were not observed in cultures of non-transformed primary astrocytes. The enhanced reduction in growth correlated with increased necrosis and DNA degradation. Ad.mda-7 enhanced p38 and ERK1/2 activity but did not alter JNK or Akt activity. Irradiation of cells expressing MDA-7 suppressed ERK1/2 activity and dramatically enhanced JNK1/2 activity without altering either Akt or p38 activity. Inhibition of JNK1/2, but not p38, signaling abolished the radiosensitizing properties of MDA-7. Inhibition of neither ERK1/2 nor PI3K signaling enhanced the anti-proliferative effects of Ad.mda-7, whereas combined inhibition of both pathways enhanced cell killing, suggesting that ERK and PI3K signaling can be protective against MDA-7 lethality.

Adenoviridae↗

PubMed1995

[A study on radiosensitivity cell line SSM-1 derived human oral malignant melanoma].

In order to study the efficiency of radiation therapy for human oral malignant melanoma, radiosensitivity for SSM-1 cell line derived from oral malignant melanoma was investigated by colony formation rate, survival curve, light microscopic observation, ultrastructual observation and immunocytochemical study with HMB-45. Survival curve of the SSM-1 cells was higher than that of cutaneous melanoma cell lines for radiosensitivity. Uniform masses of SSM-1 cells were found even with high dose irradiation. Giant cells and multiple nuclei cells were found after high dose irradiation. By ultrastructural observation, various nucleoi, chromatins and nucleus structures were found after low dose irradiation. Immunocytochemically, hot nodules of SSM-1 cells were found to have HMB-45 antibody, and the hot nodules increased after irradiation, suggesting increased number of melanosomes. By ultrastructural observation, the number of melanosomes was found to have increased after low dose irradiation. Radiosensitivity of SSM-1 cell line derived from oral malignant melanoma was higher than that of cutaneous melanoma cell lines, and the results of this study might support that radiotherapy is helpful for oral malignant melanoma.

Cell Survival↗

PubMed2005

[Radiosensitizing effect of hyperfractionated radiation].

To determine whether hyperfractionated treatment has benefits in the radiation therapy, two melanoma cell lines were irradiated with eight 0.5 Gy fractions as well as one single 4 Gy in vitro. The radiation was performed in air and in hypoxia as well. Cells were also irradiated in the presence of dibromodulcitol, a bifunctional alkylating agent with a weak radiosensitizer effect. The aim of the study was to examine whether hyperfractionation can influence the radiosensitizing effect of the bioreductive agent. Survival of the cells was determined immediately and 24 hours after various treatments by cell counting in hemocytometer and clonogenic assay. The number of the apoptotic cells was determined by the TUNEL assay and was followed up to 72 hours after treatment. Hypoxic cells had higher sensitivity than normoxic cells after 0.5 Gy irradiation. Radiosensitizing enhancement of DBD was higher with fractionated irradiation. The number of the apoptotic cells was significantly higher after hyperfractionated treatments than after single dose treatment combinations. Our results showed the significance of the hyperfractionated irradiation with 0.5 Gy per fraction in vitro.

Apoptosis↗

PubMed1999

Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck.

We examined effects of the anti-epidermal growth factor receptor monoclonal antibody C225 on proliferation, cell cycle phase distribution, apoptosis, and radiosensitivity in squamous cell carcinoma (SCC) cell lines derived from head and neck cancer patients. Exposure to C225 in culture inhibits SCC proliferation in a time-dependent manner, and the degree of growth inhibition, compared to controls, ranges from 20 to 75%. Flow cytometry analysis demonstrates that C225 treatment induces accumulation of cells in G1, which is accompanied by a 2-3-fold decrease in the percentage of cells in S phase. C225 exposure also induces apoptosis in SCC populations, as demonstrated by flow cytometry analysis using dual stainings of merocyanine 540 and Hoechst 33342. Western blot analysis indicates that C225 exposure induces accumulation of hypophosphorylated retinoblastoma protein and increases expression of p27KIP1. An increase in Bax expression and concurrent decrease in Bcl-2 expression are observed when SCC cells are exposed to C225. Examination of C225 effects on radiation response in SCCs demonstrates enhancement in radiosensitivity and amplification of radiation-induced apoptosis. These effects are observed in both single-dose and fractionated radiation experiments. C225 represents a promising growth-inhibitory agent that can influence cellular proliferation, apoptosis, and radiosensitivity in SCCs of the head and neck.

Antibodies, Monoclonal↗

PubMed1999

Correlation between unirradiated cell TP53 protein levels and radiosensitivity in MOLT-4 cells.

MOLT-4 cells undergo apoptosis after X irradiation. A radiosensitive variant, MOLT-4N1, and a radioresistant variant, MOLT-4N2, have been studied with respect to their radiosensitivity and its relationship to the levels of TP53 protein (formerly known as p53). X irradiation induces apoptosis in both cell lines with the following difference: The induction of apoptosis in MOLT-4N2 cells occurred later than in MOLT-4N1 cells as determined by the morphological changes and DNA fragmentation. The levels of cell death measured by the dye exclusion test coincided with the levels of apoptosis in both cell lines, suggesting that radiation-induced cell killing is determined by the induction of apoptosis. Unirradiated MOLT-4N1 cells contained a significantly higher intracellular level of TP53 protein and a much higher level of TP53 mRNA compared to MOLT-4N2 cells. X irradiation led to an accumulation of TP53 protein in both cell lines that was greater in MOLT-4N1 cells. This accumulation of TP53 protein preceded changes in DNA degradation and ladder formation and in nuclear morphology. These results strongly suggest that the radiosensitivity of MOLT-4 cells correlates well with the unirradiated control levels of TP53 mRNA and TP53 protein, and that the quantitative levels of TP53 protein must reach a threshold for the cells to undergo apoptosis.

Adult↗

PubMed1999

Combined immunodeficiency associated with increased apoptosis of lymphocytes and radiosensitivity fibroblasts.

Severe immunodeficiency characterized by lymphopenia was found in two siblings, one of whom was examined in detail. The calcium flux, pattern of tyrosine phosphorylation of proteins, and interleukin 2 (IL-2) production and proliferation in response to mitogens suggested that the peripheral blood T cells activated normally. The peripheral blood T cells were shown to have an activated phenotype with increased expression of CD45RO+ and CD95/Fas. Increased spontaneous apoptosis occurred in unstimulated lymphocyte cultures. The elevated apoptosis was not due to alterations in expression or to mutations in Bcl-2, Bcl-X(L), or Flip, nor could the spontaneous apoptosis be prevented by blocking Fas, suggesting that it was independent of Fas signaling. This is the first inherited combined immunodeficiency associated with impaired lymphocyte survival. Fibroblasts derived from the patient showed appreciable radiosensitivity in clonal assays, but apoptosis was not elevated. Our results show that the fibroblasts represent a new radiosensitive phenotype not associated with cell cycle checkpoint defects, V(D)J recombination defects, or elevated chromosome breakage. We suggest that the affected gene plays a role in an undetermined damage response mechanism that results in elevated spontaneous apoptosis in lymphoid cells and radiosensitivity in fibroblasts.

Apoptosis↗

PubMed1999

Response of human tumor cells of varying radiosensitivity and radiocurability to fractionated irradiation.

The cytotoxic effects of radiation delivered in daily fractions of 2.0 Gy were examined in plateau phase cultures of human tumor cells of varying in vitro radiosensitivity, derived from tumors of varying radiocurability. Among the eight cell lines examined, three types of responses to fractionated irradiation were observed. In the group composed of tumor cell lines that were radioresistant in culture (D0 > 2 Gy) and derived from known local radiation failures or from tumor histologies associated with radiation failure, a gradual linear reduction in surviving fraction versus total dose was observed. In a second group, composed of cell lines that were radiosensitive in culture (D0 approximately 1 Gy) but derived from known radiation failures, the surviving fraction initially declined and began to plateau after 6 Gy (three fractions of 2 Gy). In the third group, composed of radiosensitive cell lines derived from tumors associated with high radiocurability, a rapid decline in surviving fraction versus total dose was observed. The in vitro response of human tumor cells to fractionated irradiation delivered at clinically relevant doses appears to be independent of in vitro X-ray sensitivity and p53 status but related to clinical radiocurability, suggesting a possible role in predicting tumor response to radiotherapy.

Cyclin-Dependent Kinase Inhibitor p21↗

PubMed1999

Radiosensitization by gemcitabine.

Gemcitabine is a potent radiosensitizer in both laboratory studies and in the clinic. Initial laboratory studies showed that gemcitabine radiosensitizes a wide variety of rodent and human tumor cells in culture. Maximum radiosensitization occurs in cells that demonstrate concurrent redistribution into S phase and d-adenosine triphosphate pool depletion. Although the mechanism of sensitization is not yet clear, recent evidence from our laboratory suggests that gemcitabine lowers the threshold for radiation-induced apoptosis. Our preclinical data were used to design gemcitabine dose-escalation trials in combination with standard radiation for patients with unresectable head and neck cancer and pancreatic cancer. In head and neck cancer, we have found that gemcitabine doses far below the maximum tolerated dose for the drug when used alone significantly potentiate the toxicity of treatment. Comparatively, normal tissue sensitization has not been as marked in the treatment of pancreatic tumors. These findings have led us to conduct experiments using an animal model to improve the therapeutic index of treatment. We conclude that gemcitabine is a promising radiation sensitizer that will need to be developed cautiously if excessive normal tissue toxicity is to be avoided.

Animals↗

PubMed2000

Preclinical toxicity and efficacy study of a 14-day schedule of oral 5-iodo-2-pyrimidinone-2'-deoxyribose as a prodrug for 5-iodo-2'-deoxyuridine radiosensitization in U251 human glioblastoma xenografts.

In anticipation of an initial clinical Phase I trial in patients with high-grade gliomas of p.o. administered 5-iodo2-pyrimidinone-2'-deoxyribose (IPdR) given daily for 14 days as a prodrug for 5-iodo-2'-deoxyuridine (IUdR)-mediated tumor radiosensitization, we determined the systemic toxicities and the percentage IUdR-DNA incorporation in normal athymic mouse tissues and a human glioblastoma xenograft (U251) after this dosing schedule of IPdR. Using a tumor regrowth assay of s.c. U251 xenografts, we also compared radiosensitization with this IPdR-dosing schedule to radiation therapy (XRT) alone (2 Gy/day for 4 days) or to XRT after continuous infusion IUdR for 14 days at the maximum tolerated dose in mice (100 mg/kg/day). Athymic mice with and without U251 s.c. xenografts tolerated 750 or 1500 mg/kg/day of p.o. IPdR (using gastric lavage) for 14 days without weight loss or activity level changes during treatment and for a 28-day posttreatment observation period. The percentage IUdR-DNA incorporation in U251 tumor cells was significantly higher after p.o. IPdR (750 and 1500 mg/kg/day) for 14 days (3.1 +/- 0.2% and 3.7 +/- 0.3%, respectively) than continuous infusion IUdR for 14 days (1.4 +/- 0.1%). Compared to XRT alone, a significant sensitizer enhancement ratio (SER) was found with the combination of p.o. IPdR (1500 mg/kg/d) + XRT (SER = 1.31; P = 0.05) but not for the combination of continuous infusion IUdR + XRT (SER = 1.07; P = 0.57) in the U251 xenografts. The percentage IUdR-DNA incorporation after IPdR at 1500 mg/kg/day for 14 days in normal bone marrow, normal small intestine, and normal liver were 1.2 +/-0.2%, 3.3 +/- 0.3%, and 0.2 +/- 0.1%, respectively. We conclude that a 14-day p.o. schedule of IPdR at up to 1500 mg/kg/day results in no significant systemic toxicity in athymic mice and is associated with significant radiosensitization using this human glioblastoma multiforme xenograft model. Based on these data and our previously published data using shorter IPdR dosing schedules, which also demonstrate an improved therapeutic index for IPdR compared to IUdR, an initial clinical Phase I and pharmacokinetic study of p.o. IPdR daily for 14 days is being designed.

Administration, Oral↗

PubMed1998

[The comparison of radiosensitivity between uterine cervical squamous carcinoma and adenocarcinoma].

OBJECTIVE: To compare the radiosensitivity of uterine cervical squamous carcinoma and adenocarcinoma. METHODS: The shrinkage of tumor and the radiation-induced damage were compared between cervical squamous carcinoma and adenocarcinoma after twice afterloading radiotherapy. Proliferating cell nuclear antigen index (PI), detected immunohistochemically, was compared before and after radiotherapy between the two tumors. RESULTS: Patients of squamous carcinoma with tumor shrinkage 50% or more accounted for 70% (21/30) and patients of adenocarcinoma accounted for 27% (4/15), which was statistically significant (P < 0.01). The radiation-induced damage grade II b-III accounted for 60% (18/30) in squamous carcinoma and for 20% (3/15) in adenocarcinoma, which was statistically significant (P < 0.05); PI decreased from 53.50% +/- 4.34% to 39.30% +/- 4.02% after radiotherapy in squamous carcinoma (P < 0.001), while PI decreased from 35.47% +/- 3.83% to 31.80% +/- 3.06% in adenocarcinoma (P > 0.05). CONCLUSIONS: The radiosensitivity of cervical squamous carcinoma is higher than that of adenocarcinoma. The decrease of PI after radiotherapy may be a biological basis of radiosensitivity for uterine cervical squamous carcinoma.

Adenocarcinoma↗

PubMed2000

Biological basis of radiation sensitivity. Part 2: Cellular and molecular determinants of radiosensitivity.

Recent studies have elucidated some of the molecular and cellular mechanisms that determine the sensitivity or resistance to ionizing radiation. These findings ultimately may be useful in devising new strategies to improve the therapeutic ratio in cancer treatment. Despite the rapid advances in knowledge of cellular functions that affect radiosensitivity, we still cannot account for most of the clinically observed heterogeneity of normal tissue and tumor responses to radiotherapy, nor can we accurately predict which individual tumors will be controlled locally and which patients will develop more severe normal tissue damage after radiotherapy. However, several candidate genes for which deletion or loss of function mutations may be associated with altered cellular radiosensitivity (e.g., ATM, p53, BRCA1, BRCA2, DNA-PK) have been identified. Some of the differences in normal tissue sensitivity to radiation may stem from mutations with milder effects, heterozygosity, or polymorphisms of these genes. Finally, molecular mechanisms linking genetic instability, radiosensitivity, and predisposition to cancer are being unraveled.

Apoptosis↗

PubMed2000

Radiosensitivity in Nijmegen Breakage Syndrome cells is attributable to a repair defect and not cell cycle checkpoint defects.

Cells derived from Nijmegen Breakage Syndrome (NBS) patients display radiosensitivity and cell cycle checkpoint defects. Here, we examine whether the radiosensitivity of NBS cells is the result of a repair defect or whether it can be attributed to impaired checkpoint arrest. We report a small increased fraction of unrejoined double strand breaks and, more significantly, increased chromosome breaks in noncycling NBS cells at 24 h after irradiation. One of the NBS lines examined (347BR) was atypical in showing a nearly normal checkpoint response. In contrast to the mild checkpoint defect, 347BR displays marked y-ray sensitivity similar to that shown by other NBS lines. Thus, the gamma-ray sensitivity correlates with the repair defect rather than impaired checkpoint control. Taken together, the results provide direct evidence for a repair defect in NBS cells and are inconsistent with the suggestion that the radiosensitivity is attributable only to impaired checkpoint arrest. 347BR also displays elevated spontaneous damage that cannot be attributed to impaired G2-M arrest, suggesting a function of Nbsl in decreasing or limiting the impact of spontaneously arising double strand breaks.

Abnormalities, Multiple↗