Radiation-induced Genetic Damage Research Articles

Improving Cytogenetic Surveillance in Radiology Workers Exposed to Low-Dose Radiation in Africa: A Call to Action

Radiation exposure is an occupational hazard for diagnostic and interventional radiology workers, potentially leading to chromosomal damage and increased cancer risk. This review explores the status of cytogenetic monitoring of radiation exposure among radiology workers in Africa. Monitoring of Radiation Exposure in Diagnostic and Interventional Radiology Workers in Ghana and Africa provides a crucial examination of radiation safety practices within the Ghanaian and Africa healthcare sector. We recovered existing literature on the cytogenetic surveillance conducted on radiology workers in Ghana and Africa stressing on the impact and/or significance of cytogenetic monitoring programmes. In these studies, mostly mathematical modeling and physical methods were used to estimate and extrapolate risks of exposure to ionizing radiation. Additionally, we discuss the challenges and opportunities for implementing cytogenetic monitoring programmes in Africa particularly Ghana and provide recommendations for future research and occupational health policies. This review attempts to bridge the gap between physical and biological dosimetry in surveillance studies. It addresses the significant gap in cytogenetic monitoring among diagnostic and interventional radiology workers in Africa. It highlights the importance of cytogenetic surveillance for early detection of radiation-induced genetic damage, assesses the current practices, and provides a recommendation and a roadmap for establishing robust monitoring programmes. This work would contribute significantly to the understanding of occupational radiation safety issues in the healthcare sector of Africa. It also offers a comprehensive examination of the challenges and opportunities in implementing cytogenetic monitoring programmes.

Application of the Cytokinesis-Block Micronucleus Assay for High-Dose Exposures Using Imaging Flow Cytometry

The cytokinesis-block micronucleus assay is a well-established method to assess radiation-induced genetic damage in human cells. This assay has been adapted to imaging flow cytometry (IFC), allowing automated analysis of many cells, and eliminating the need to create microscope slides. Furthermore, to improve the efficiency of assay performance, a small-volume method previously developed was employed. Irradiated human blood samples were cultured, stained, and analyzed by IFC to produce images of the cells. Samples were run using both manual and 96-well plate automated acquisition. Multiple parameter-based image features were collected for each sample, and the results were compared to confirm that these acquisition methods are functionally identical. This paper details the multi-parametric analysis developed and the resulting calibration curves up to 10 Gy. The calibration curves were created using a quadratic random coefficient model with Poisson errors, as well as a logistic discriminant function. The curves were then validated with blinded, irradiated samples, using relative bias and relative mean square error. Overall, the accuracy of the dose estimates was adequate for triage dosimetry (within 1 Gy of the true dose) over 90% of the time for lower doses and about half the time for higher doses, with the lowest success rate between 5 and 6 Gy where the calibration curve reached its peak and there was the smallest change in MN/BNC with dose. This work describes the application of a novel multi-parametric analysis that fits the calibration curves and allows dose estimates up to 10 Gy, which were previously limited to 4 Gy. Furthermore, it demonstrates that the results from samples acquired manually and with the autosampler are functionally similar.

Merkel cell carcinoma: A review.

Merkel cell carcinoma has been a focus of active scientific investigation in recent years and new information on the topic has emerged. Although uncommon, this primary cutaneous neuroendocrine carcinoma, usually involving the head/neck of elderly individuals, has a poor prognosis. Within the past two decades, an increase in the incidence of the tumor and the discovery of its link to the Merkel cell polyomavirus have focused medical attention on the lesion. The resulting studies have improved our understanding of the biology of the neoplasm and contributed to clinical care. Specifically, two pathogenic subsets of the tumor have come to light, the majority due to Merkel cell polyomavirus and the minority caused by ultraviolet radiation-induced genetic damage. This dichotomy carries prognostic implications favoring the former subset. In addition, having capitalized on the known susceptibility of the tumor to immune influences, investigators have recently discovered its responsiveness to immune checkpoint inhibition. This revelation has constituted a therapeutic milestone at the clinical level. Herein we provide an overview of the topic, outline updates in the field and place an emphasis on dermatopathologic aspects of Merkel cell carcinoma.

Radioprotective effect of olanzapine as an anti-psychotic drug against genotoxicity and apoptosis induced by ionizing radiation on human lymphocytes.

Olanzapine (OLA), is prescribed as an anti-psychotic medicine in schizophrenia patients. In this study, the protective effect of OLA against genotoxicityand apoptosis induced by ionizing radiation in human healthy lymphocytes was evaluated. At first, the antioxidant activities of OLA were assayed by two different methods as free radical scavenging with DPPH (2,2-diphenyl-1-picryl-hydrazyl) and ferric reducing power methods. In in vitro experiment, human blood samples were treated with OLA at various concentrations (0.25-20μM) for 3h and then were exposed to X-ray at a dose of 150cGy. The genotoxicity was assessed in binucleated human lymphocytes with micronuclei assay. The apoptotic lymphocytes were assessed by flow cytometry in OLA treated and/or irradiated lymphocytes. OLA exhibited free radical scavenging and reducing power activities more than ascorbic acid. The results showed that the lymphocytes treated with OLA and later exposed to IR presented lower frequencies of micronuclei and apoptosis compared to the control sample which was irradiated and not treated to OLA. The maximum radioprotection was observed at 20μM of OLA with 83% of efficacy. The present studysuggested the protective role for OLA in protection radiation-induced genetic damage and apoptosis induced by ionizing irradiation in human normal cells.

In vitro Protective Effect of Rutin and Quercetin against Radiation-induced Genetic Damage in Human Lymphocytes.

Purpose of the Study:Rutin (RUT) and quercetin (QRT) which are dietary compounds were investigated for their ability to protect against ionizing radiation (IR)-induced genotoxicity in human lymphocytes.Materials and Methods:The radiation antagonistic potential of RUT and QRT was assessed by alkaline comet and cytokinesis-block micronucleus (CBMN) assay.Results:Treatment of lymphocytes with RUT and QRT (25 μg/ml) prior exposure to 2 Gy gamma radiation resulted in a significant reduction of frequency of micronuclei as compared to the control set of cells evaluated by CBMN assay. Similarly, treatment of lymphocytes with RUT and QRT before radiation exposure showed significant decrease in the DNA damage as assessed by comet parameters, such as percent tail DNA and olive tail moment.Conclusion:The study demonstrates the protective effect of RUT and QRT against IR-induced DNA damage in human lymphocytes, which may be partly attributed to scavenging of IR-induced free radicals and also by the inhibition of IR-induced oxidative stress.

Genome-Wide Deletion Screening with the Array CGH Method in Mouse Offspring Derived from Irradiated Spermatogonia Indicates that Mutagenic Responses are Highly Variable among Genes.

Until the end of the 20th century, mouse germ cell data on induced mutation rates, which were collected using classical genetic methods at preselected specific loci, provided the principal basis for estimates of genetic risks from radiation in humans. The work reported on here is an extension of earlier efforts in this area using molecular methods. It focuses on validating the use of array comparative genomic hybridization (array CGH) methods for identifying radiation-induced copy number variants (CNVs) and specifically for DNA deletions. The emphasis on deletions stems from the view that it constitutes the predominant type of radiation-induced genetic damage, which is relevant for estimating genetic risks in humans. In the current study, deletion mutations were screened in the genomes of F1 mice born to unirradiated or 4 Gy irradiated sires at the spermatogonia stage (100 offspring each). The array CGH analysis was performed using a "2M array" with over 2 million probes with a mean interprobe distance of approximately 1 kb. The results provide evidence of five molecularly-confirmed paternally-derived deletions in the irradiated group (5/100) and one in the controls (1/100). These data support a calculation, which estimates that the mutation rate is 1 × 10-2/Gy per genome for induced deletions; this is much lower than would be expected if one assumes that the specific locus rate of 1 × 10-5/locus per Gy (at 34 loci) is applicable to other genes in the genome. The low observed rate of induced deletions suggests that the effective number of genes/genomic regions at which recoverable deletions could be induced would be only approximately 1,000. This estimate is far lower than expected from the size of the mouse genome (>20,000 genes). Such a discrepancy between observation and expectation can occur if the genome contains numerous genes that are far less sensitive to radiation-induced deletions, if many deletion-bearing offspring are not viable or if the current method is substandard for detecting small deletions.

Effect of Phyllostachys parvifolia leaf extract on ionizing radiation-induced genetic damage: A preliminary in vitro cytogenetic study

The ionizing radiation is a known carcinogen as well as cancer therapeutic agent however, the side effect on normal tissue is a limiting factor and inadequate doses necessitates search for an ideal radioprotective agent. Bamboo species are rich source of antioxidants hence have therapeutic value in many free radical mediated diseases. This is the first report regarding in vitro protective effect of bamboo leaf extract against radiation induced genetic damage in human peripheral blood lymphocytes by cytokinesis blocked micronuclei (CBMN) assay. Fresh whole blood was exposed to 5Gy of cobalt-6o gamma radiation with or without 30 min pre-treatment with 3 μl and 5 μl of hydro alcoholic leaf extract of Phyllostachys parvifolia. In addition to whole extract the effect of potential active compound orientin was also assessed. The frequency of radiation induced micronuclei decreased significantly in a dose dependent manner following treatment with whole extract as well as orientin. The extent of reduction in micronuclei frequency was higher with whole bamboo leaf extract as compared to orientin alone.

Radiosensitivity in patients suffering from chronic kidney disease

Purpose: Patients suffering from chronic kidney disease (CKD) exhibit a high incidence of cancer, as well as high levels of genetic damage. We hypothesized that these patients show genomic instability detected as an increased chromosomal radiosensitivity in front of the genetic damage induced by ionizing radiation.Material and methods: The background levels of genetic damage and the net genetic damage after in vitro irradiation with 0.5 Gy were analyzed using the micronucleus (MN) assay in peripheral blood lymphocytes. A total number of 552 individuals (179 controls and 373 CKD patients) were included in the study.Results: The net radiation-induced genetic damage was significantly higher in CKD patients than in controls; but no differences between those patients submitted to hemodialysis and those in pre-dialytic stages were detected. A positive correlation was observed between basal and net micronucleus frequencies in CKD patients what would indicate an underlying genetic background modulating DNA damage levels.Conclusions: Our results indicate that CKD patients present genomic instability, measured as an increased chromosomal radiosensitivity in front of ionizing radiation.

Comparison of radiation-induced damage between CT angiography and conventional coronary angiography

Objective Both computed tomography (CTA) and conventional angiography (CCA) can provide direct visualization of the coronary arteries. The aim of the present study was to compare the radiation exposure between CTA and CCA and to search whether this amount of radiation causes signifi cant DNA damage.Method Seventy-two patients who underwent CTA or CCA were enrolled prospectively. We recorded the radiation dosage that was used during the procedures and calculated the eff ective dose (ED). We determined the sister chromatid exchange (SCE) level from the blood samples which were drawn from the patients before and after the procedures. The change in SCE is used as the measure of DNA damage induced by the radiation.Results The patients in the CTA (n = 36) and CCA groups (n = 36) had similar baseline characteristics. The ED was higher in CTA examinations compared to CCA examinations (14.2 ± 2.7 vs 6.4 ± 3.1, P< 0.001). The SCE level increased signifi cantly after both angiography methods (P < 0.001). When the change in SCE after angiography was compared, we did not fi nd a signifi cant diff erence among the groups (2.73 ± 1.6 vs 2.54 ± 1.22, P= NS).Conclusion Although the patients who underwent CTA were exposed to a greater amount of radiation, the radiation-induced genetic damage was similar with both types of the procedures.

Evaluation of the in vivo genotoxic effects of gamma radiation on the peripheral blood leukocytes of head and neck cancer patients undergoing radiotherapy

The present study aimed to evaluate the genotoxic effects of ionizing radiation on non-target cells of Head and Neck Squamous Cell Carcinoma (HNSCC) patients exposed to various cumulative doses of gamma rays during radiotherapy. The ten patients (P1–P10) were treated with cobalt 60 gamma radiation (External Beam Radiotherapy) for a period of five to six weeks with a daily fraction of 2Gy for 5 days each week. The genotoxic effects of radiation (single strand breaks – SSBs) in these patients were analyzed using the alkaline single cell gel electrophoresis (SCGE) technique, with the Olive Tail Moment (OTM) as the critical parameter. A sample of each patient's peripheral blood before starting with radiotherapy (pre-therapy) served as the control, and blood collected at weekly time intervals during the course of the radiotherapy served as treated (10, 20, 30, 40, 50 and 60Gy) samples. In vivo radiosensitivity of these patients, as indicated by SSB's after the cumulative radiation doses at the various times, was assessed using Student's t-test. Significant DNA damage relative to the individual patient's pre-therapy baseline data was observed in all patients. Inter-individual variation of the genotoxic effects was analyzed using two-way ANOVA. The correlation between doses for the means of smoker and non-smoker patients was calculated using the Pearson test. The results of this study may indicate the need to reduce the daily radiotherapy dose further to prevent genotoxic effects on non-target cells, thus improving safety. Furthermore, these results may indicate that the estimation of DNA damage following exposure to a gamma radiation, as measured by the comet assay in whole blood leukocytes, can be used to screen human populations for radiation-induced genetic damage at the molecular level.

Genomic instability in chronic renal failure patients

Patients suffering chronic renal failure (CRF) exhibit a high incidence of cancer, as well as high levels of genetic damage. We hypothesized that these patients show genomic instability as measured by increased radiosensitivity to the induction of genetic damage. The background levels of genetic damage and the net genetic damage after in vitro irradiation with 0.5 Gy were analyzed using the micronucleus assay in peripheral blood lymphocytes of 174 CRF patients and 53 controls. The net radiation-induced genetic damage was significantly higher in CRF patients with respect to controls. Among CRF patients, the levels of genetic damage were higher in those with prior incidence of cancer than in those without cancer; in addition, those CRF patients undergoing hemodialysis presented with higher levels of genetic damage than those in the advanced Stages (4-5) of the pathology. A positive association was observed between basal and net micronucleus frequency among CFR patients. However, no association was found between net genetic damage and parameters linked to the different stages of the pathology, such as urine creatinine levels and glomerular filtration rate. Our results indicate that CRF patients show increased radiosensitivity and that the degree of radiosensitivity is associated with the progression of the pathological stage of the disease.

Protection against X-ray radiation-induced cellular damage of human peripheral blood lymphocytes by an aminothiazole derivative of dendrodoine

The present study was aimed to evaluate the radioprotective efficacy of dendrodoine analog (DA), an aminothiazole derivative against X-ray radiation-induced cellular damage in cultured human peripheral blood lymphocytes. Different concentrations of DA (2, 4, 6, 8, 10 μg/ml or 6.15, 12.29, 18.44, 24.59, 30.73 μM) were pre-incubated with lymphocytes for 30 min prior to irradiation [4 Gy] and the micronuclei (MN) scoring and comet assay were performed to fix the effective concentration of DA against 4 Gy irradiation-induced cellular damage. The results indicated that among all the concentrations, 6 μg/ml concentration of DA showed optimum protection by effectively decreasing the MN frequencies and comet attributes. Based on the above results, 6 μg/ml concentration of DA was fixed as the effective dose to further investigate its radioprotective efficacy. This was carried out by pre-incubating the lymphocytes with 6 μg/ml concentration of DA followed by exposure of the lymphocytes to different doses (1, 2, 3 and 4 Gy) of radiation and investigating the radiation-induced genetic damage (MN, comet assay, DNA fragmentation assay) and biochemical changes (changes in the level of enzymic and non-enzymic antioxidants, lipid peroxidation). The results indicated a dose-dependent increase in both genetic damage and thiobarbituric acid reactive substances (TBARS), accompanied by a significant decrease in the antioxidant status in the irradiated groups compared to DA treated groups which modulated the toxic effects through its antioxidant potential. Thus the current study shows DA to be an effective radioprotector against X-ray radiation induced in vitro cellular damage in lymphocytes.

Abstract 254: A HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis

Abstract There is a gap between the initial formation of cells carrying radiation-induced genetic damage and their contribution to cancer development. Herein we reveal a previously uncharacterized gene FATS through a genome-wide approach and demonstrate its essential role in regulating the abundance of p21 in surveillance of genome integrity. A large exon coding the NH2-terminal domain of FATS, deleted in spontaneous mouse lymphomas, is much more frequently deleted in radiation-induced mouse lymphomas. Its human counterpart is a fragile site gene at a previously identified loss of heterozygosity (LOH) site. FATS is essential for maintaining steady-state level of p21 protein and sustaining DNA damage checkpoint. Furthermore, the NH2-terminal FATS physically interacts with HDAC1 to enhance the acetylation of endogenous p21, leading to the stabilization of p21. Our results reveal a molecular linkage between p21 abundance and radiation-induced carcinogenesis. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 254.

Modulation of Radiation-Induced Genetic Damage by HCMV in Peripheral Blood Lymphocytes from a Brain Tumor Case-Control Study.

Human cytomegalovirus (HCMV) infection occurs early in life and viral persistence remains through life. An association between HCMV infection and malignant gliomas has been reported, suggesting that HCMV may play a role in glioma pathogenesis and could facilitate an accrual of genotoxic damage in the presence of γ-radiation; an established risk factor for gliomas. We tested the hypothesis that HCMV infection modifies the sensitivity of cells to γ-radiation-induced genetic damage. We used peripheral blood lymphocytes (PBLs) from 110 glioma patients and 100 controls to measure the level of chromosome damage and cell death. We evaluated baseline, HCMV-, γ-radiation and HCMV + γ-radiation induced genetic instability with the comprehensive Cytokinesis-Blocked Micronucleus Cytome (CBMN-CYT). HCMV, similar to radiation, induced a significant increase in aberration frequency among cases and controls. PBLs infected with HCMV prior to challenge with γ-radiation led to a significant increase in aberrations as compared to baseline, γ-radiation and HCMV alone. With regards to apoptosis, glioma cases showed a lower percentage of induction following in vitro exposure to γ-radiation and HCMV infection as compared to controls. This strongly suggests that, HCMV infection enhances the sensitivity of PBLs to γ-radiation-induced genetic damage possibly through an increase in chromosome damage and decrease in apoptosis.

An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis

There is a gap between the initial formation of cells carrying radiation-induced genetic damage and their contribution to cancer development. Herein, we reveal a previously uncharacterized gene FATS through a genome-wide approach and demonstrate its essential role in regulating the abundance of p21 in surveillance of genome integrity. A large exon coding the NH2-terminal domain of FATS, deleted in spontaneous mouse lymphomas, is much more frequently deleted in radiation-induced mouse lymphomas. Its human counterpart is a fragile site gene at a previously identified loss of heterozygosity site. FATS is essential for maintaining steady-state level of p21 protein and sustaining DNA damage checkpoint. Furthermore, the NH2-terminal FATS physically interacts with histone deacetylase 1 (HDAC1) to enhance the acetylation of endogenous p21, leading to the stabilization of p21. Our results reveal a molecular linkage between p21 abundance and radiation-induced carcinogenesis.

Gastrostomy in oropharyngeal cancer patients with ERCC4 ( XPF) germline variants

ERCC4 (XPF) plays a role in both recombinant DNA repair and nucleotide excision repair, which involve repairing radiation-induced genetic damage. We hypothesized that two ERCC4 single-nucleotide polymorphisms are associated with normal-tissue toxicity in patients treated with radiotherapy for oropharyngeal squamous cell carcinoma (OPSCC). A retrospective review of the medical records of 130 patients with OPSCC who were prospectively recruited into a molecular epidemiologic study was performed to determine whether a long-term percutaneous feeding gastrostomy (LPFG) tube (a tube required for more than 180 days) had been used during and after definitive radiotherapy. We determined the genotype of the ERCC4 G1244A and T2505C polymorphisms using standard polymerase chain reaction-restriction fragment-length polymorphism techniques on DNA extracted from peripheral blood lymphocytes. Of 130 patients, 100 (77%) were evaluable for the ERCC4 G1244A polymorphism in exon 8, and 122 (94%) were evaluable for the ERCC4 T2505C polymorphism in exon 11. The ERCC4 G1244A polymorphism was associated with a decreased need for LPFG, but this was not statistically significant (adjusted odds ratio = 0.53; 95% confidence interval, 0.10-2.78). Sixteen (32%), 9 (14%), and 1 (10%) of patients with the wild-type homozygous TT genotype of ERCC4 T2505C, the heterozygous TC genotype, and the homozygous CC polymorphic genotype, respectively, required LPFG. These results suggest that the ERCC4 2505C allele was associated with a reduced need for LPFG (adjusted odds ratio = 0.20; 95% confidence interval, 0.06-0.67). Furthermore, the need for LPFG was reduced by having more than 1 ERCC4 2505C allele and further for having both the ERCC4 1244A and 2505C polymorphic alleles, but this was not statistically significant. In addition, the actual time of gastrostomy dependence was associated with the T2505C polymorphism based on the Kaplan-Meier method (p = 0.03). Our findings suggest that the ERCC4 T2505C polymorphism may be associated with improved recovery from radiation treatment toxicity in patients with OPSCC. Further study with larger sample sizes and prospective measure of radiotherapy-induced toxicity is warranted.

Effect of depth on radiation-induced cell damage in a water phantom

Summary Aim The paper describes the effect of medium depth on radiation-induced genetic damage to SK-mel cultured cells placed inside a water phantom as measured by the number of cells with micronuclei formed and apoptoses seen in these cells. Materials/Methods The energy of photon radiation used was 6 MV; cells placed at various depths were irradiated with the same dose (5 Gy). Results/Conclusions Depending on medium depth, differences were noted in the number of damaged cells: ca.30% more affected cells were seen at a depth of 25 cm as compared to a depth of 5 cm. With increasing depth also the radiation energy spectrum changes. This is probably responsible for the observed effect. It should be taken into consideration in both clinical practice and in treatment planning.

Genetic effects of radiotherapy for childhood cancer.

Radiation-induced heritable diseases have not been demonstrated in humans and estimates of genetic risks for protection purposes are based on mouse experiments. The most comprehensive epidemiologic study is of the Japanese atomic bomb survivors and their children, which found little evidence for inherited defects attributable to parental radiation. Studies of workers exposed to occupational radiation or of populations exposed to environmental radiation appear too small and exposures too low to convincingly detect inherited genetic damage. In contrast, survivors of childhood cancer form the largest group of people exposed to high doses of ionizing radiation before reproduction and offer unique advantages for studying trans-generation effects. A wide range of gonadal doses are possible, several comparison groups are readily available (including siblings), and there is a strong willingness among cancer survivors to participate in health studies. Cancer patients also have detailed medical records that facilitate both the accurate estimation of gonadal doses and the assessment of potentially confounding factors, such as intercurrent illness, personal and family medical histories, lifestyle characteristics such as tobacco use, and circumstances at delivery. An international study is nearing completion of over 25,000 survivors of childhood cancer in the United States and Denmark who gave birth to or fathered over 6,000 children. Doses to gonads are being reconstructed from radiotherapy records with 46% over 100 mSv and 16% over 1,000 mSv. Adverse pregnancy outcomes being evaluated include major congenital malformations, cytogenetic abnormalities, stillbirths, miscarriages, neonatal deaths, total deaths, leukemia and childhood cancers, altered sex ratio, and birth weight. The main analyses are based on dose-response evaluations. Blood studies of trios (cancer survivor, spouse or partner and offspring) have been initiated to evaluate mechanistic evidence for the transmission of any radiation-induced genetic damage such as minisatellite mutations. Markers of cancer susceptibility such as chromosomal radiosensitivity and genotype profile will also be examined. In the United States series to date, 4,214 children were born to cancer survivors among whom 157 (3.7%) genetic diseases were reported in contrast to 95 (4.1%) reported conditions among 2,339 children born to sibling controls. In the Denmark series the comparable figures were 82 (6.1%) birth defects among 1,345 children of cancer survivors and 211 (5.0%) among 4,225 children of sibling controls. Coupled with prior studies, these preliminary findings, if sustained by ongoing dose-response analyses, provide reassurance that cancer treatments including radiotherapy do not carry much if any risk for inherited genetic disease in offspring conceived after exposure.

A single low dose of X-rays induces high frequencies of genetic instability (aneuploidy) and heritable damage (apoptosis), dependent on cell type and p53 status

We harvested and analyzed cells from four different non-transformed cell lines surviving a single X-ray exposure. Evidence of radiation-induced karyotype instability was observed in 100% of C3H 10T1/2 fibroblast clones and 11.3% of V79 fibroblast clones. Heritable damage: predisposition to apoptosis, but not karyotype instability, was induced in TK6 (p53 wt/wt) and WTK1 (p53 mut/mut) human B-lymphoblastoid cell clones. The studies indicate: (1) genetic instability and/or heritable damage are induced in cells exposed to radiation at a high frequency, and induction of genetic instability is not limited to morphologically transformed cells [Radiat. Res. 138 (1994) S105; Radiat. Environ. Biophys. 36 (1998) 255]; (2) sensitivity to genetic instability and heritable damage depend on cell type; (3) checkpoint stringency and p53 status significantly influence the frequency of radiation-induced genetic instability and heritable damage; (4) in some cell lines, damage induced by low doses of radiation (below 2 Gy) leads to heritable cytotoxic and genotoxic effects in 100% of cells exposed. The data suggest that mammalian cells misinterpret damage induced by ionizing radiation as if it were a physiological cell signal. This contrasts strongly with the response of mammalian cells to damage induced by other types of DNA-toxic agents where damage-specific repair mechanisms are activated.

Polymorphisms of drug metabolizing enzymes and markers of genotoxicity to identify patients with Hodgkin's lymphoma at risk of treatment‐related complications

Survivors of childhood Hodgkin's lymphoma (HL) have an increased risk of developing treatment-related complications, especially second malignant neoplasms, as a result of treatment regimens incorporating chemotherapy and radiation therapy. Second cancers include leukemias that generally occur in the first two decades after therapy, and adult-type solid tumors that generally exhibit continued increasing incidence throughout subsequent follow-up. Identified clinical risk factors for second cancers include age at the time of treatment and intensity and type of therapy, with particularly strong associations between the use of radiotherapy and subsequent breast cancer, and alkylator chemotherapy dose-intensity and risk of secondary leukemia. However, second cancers affect a minority of patients, and there is probably great variability in individual susceptibility for this complication. Common genetic polymorphisms in drug-metabolizing enzymes that result in impaired detoxification of chemotherapy or inefficient repair of drug- or radiation-induced genetic damage may lead to increased risk of a second cancer. Studies of the potential role of polymorphisms in the genes encoding the glutathione S-transferases, cytochrome P450 3A4, NAD(P)H:quinone oxidoreductase and myeloperoxidase in the etiology of treatment-related complications are reviewed. Biological markers of drug- and radiation-induced genetic damage may also identify patients at higher risk of immediate and delayed side effects of therapy. The Children's Oncology Group (COG) is examining the roles of polymorphisms in drug metabolizing enzymes and biological markers of genotoxicity in predicting the treatment-related outcomes of patients with HL. These investigations may ultimately allow the use of pharmacogenetically guided therapy to improve the outcome of HL therapy and reduce the risk of therapy-related complications, especially secondary malignancies.