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Thomas H. Connor - One of the best experts on this subject based on the ideXlab platform.
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meta analysis of chromosomal aberrations as a biomarker of exposure in healthcare workers occupationally exposed to Antineoplastic drugs
Mutation Research-reviews in Mutation Research, 2017Co-Authors: Christine Roussel, Kristine L Witt, Peter B Shaw, Thomas H. ConnorAbstract:Many Antineoplastic drugs used to treat cancer, particularly alkylating agents and topoisomerase inhibitors, are known to induce genetic damage in patients. Elevated levels of chromosomal aberrations, micronuclei, and DNA damage have been documented in cancer patients. Elevations in these same biomarkers of genetic damage have been reported in numerous studies of healthcare workers, such as nurses and pharmacists, who routinely handle these drugs, but results vary across studies. To obtain an overall assessment of the exposure effect, we performed a meta-analysis on data obtained from peer-reviewed publications reporting chromosomal aberration levels in healthcare workers exposed to Antineoplastic drugs. A literature search identified 39 studies reporting on occupational exposure to Antineoplastic drugs and measurement of chromosomal aberrations in healthcare workers. After applying strict inclusion criteria for data quality and presentation, data from 17 studies included in 16 publications underwent meta-analysis using Hedges' bias-corrected g and a random-effects model. Results showed the level of chromosomal aberrations in healthcare workers exposed to Antineoplastic drugs was significantly higher than in controls. The standardized mean differences (difference of means divided by within sd) from all studies were pooled, yielding a value 1.006 (unitless) with p<0.001. Thus, in addition to the documented genotoxic effects of Antineoplastic drugs in cancer patients, this meta-analysis confirmed a significant association between occupational exposure to Antineoplastics during the course of a normal work day and increases in chromosomal aberrations in healthcare workers. Based on the studies reviewed, we were unable to accurately assess whether appropriate use of protective measures might reduce the incidence of genetic damage in healthcare workers. However, given the potential for increased cancer risk linked to increases in chromosomal aberrations, the results of this study support the need to limit occupational exposure of healthcare workers to Antineoplastic drugs as much as possible.
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reproductive health risks associated with occupational exposures to Antineoplastic drugs in health care settings a review of the evidence
Journal of Occupational and Environmental Medicine, 2014Co-Authors: Thomas H. Connor, Christina C Lawson, Martha Polovich, Melissa A McdiarmidAbstract:Objectives: Antineoplastic drugs are known reproductive and developmental toxicants. Our objective was to review the existing literature of reproductive health risks to workers who handle Antineoplastic drugs. Methods: As tructured literature review of 18 peer-reviewed, English language publications of occupational exposure and reproductive outcomes was performed. Results: Although effect sizes varied with study size and population, occupational exposure to Antineoplastic drugs seems to raise the risk of both congenital malformations and miscarriage. Studies of infertility and time to pregnancy also suggested an increased risk for subfertility.Conclusions: Antineoplastic drugs are highly toxic in patients receiving treatment, and adverse reproductive effects have been well documented in these patients. Health care workers with long-term, low-level occupational exposure to these drugs also seem to have an increased risk of adverse reproductive outcomes. Additional precautions to prevent exposure should be considered.
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Preventing occupational exposures to Antineoplastic drugs in health care settings
CA: A Cancer Journal for Clinicians, 2006Co-Authors: Thomas H. Connor, Mph Melissa A. McdiarmidAbstract:The toxicity of Antineoplastic drugs has been well known since they were introduced in the 1940s. Because most Antineoplastic drugs are nonselective in their mechanism of action, they affect noncancerous as well as cancerous cells, resulting in well-documented side effects. During the 1970s, evidence came to light indicating health care workers may be at risk of harmful effects from Antineoplastic drugs as a result of occupational exposure. Since that time, reports from several countries have documented drug contamination of the workplace, identified drugs in the urine of health care workers, and measured genotoxic responses in workers. Evidence also exists of teratogenic and adverse reproductive outcomes and increased cancers in health care workers. During the past 30 years, professional organizations and government agencies have developed guidelines to protect health care workers from adverse effects from occupational exposure to Antineoplastic drugs. Although many safety provisions were advanced to reduce worker exposure in the 1980s, recent studies have shown that workers continue to be exposed to these drugs despite safety policy improvements. In 2004, the National Institute for Occupational Safety and Health (NIOSH) published an alert reviewing the most recent information available and promoting a program of safe handling during their use.
Richard L. Momparler - One of the best experts on this subject based on the ideXlab platform.
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inhibition of cytidine deaminase by zebularine enhances the Antineoplastic action of 5 aza 2 deoxycytidine
Cancer Chemotherapy and Pharmacology, 2009Co-Authors: Maryse Lemaire, Louise F. Momparler, Noël J.-m. Raynal, Mark L. Bernstein, Richard L. MomparlerAbstract:Cytidine (CR) deaminase is a key enzyme in the catabolism of cytosine nucleoside analogues, since their deamination results in a loss of their pharmacological activity. In this report we have investigated the importance of CR deaminase with respect to the Antineoplastic action of inhibitors of DNA methylation, 5-aza-2′-deoxycytidine (5-AZA-CdR) and zebularine. Zebularine has a dual mechanism of action, since it can also inhibit CR deaminase. The objective of our study was to investigate the importance of zebularine as an inhibitor of CR deaminase with respect to the Antineoplastic action of 5-AZA-CdR. Using an in vitro clonogenic assay, we investigated the Antineoplastic action of 5-AZA-CdR and zebularine, alone and in combination on wild type 3T3 murine fibroblasts and corresponding V5 cells transduced with CR deaminase gene to express a very high level of CR deaminase activity. The V5 cells were much less sensitive to 5-AZA-CdR than the wild type 3T3 cells. The addition of zebularine significantly enhanced the Antineoplastic action of 5-AZA-CdR on V5 cells, but not 3T3 cells. Enzymatic analysis on CR deaminase purified from the V5 cells showed that zebularine is a competitive inhibitor of the deamination of 5-AZA-CdR. These in vitro observations are in accord with our in vivo study in mice with L1210 leukemia, which showed that zebularine increased the antileukemic activity of 5-AZA-CdR. Pharmacokinetic analysis also showed that zebularine increased the plasma level of 5-AZA-CdR during an i.v. infusion in mice. Our results indicate that the major mechanism by which zebularine enhances the Antineoplastic action of 5-AZA-CdR is by inhibition of CR deaminase. These findings provide a rationale to investigate 5-AZA-CdR in combination with zebularine in patients with advanced leukemia.
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effect of histone deacetylase inhibitor laq824 on Antineoplastic action of 5 aza 2 deoxycytidine decitabine on human breast carcinoma cells
Cancer Chemotherapy and Pharmacology, 2006Co-Authors: Annie Hurtubise, Richard L. MomparlerAbstract:Purpose: Epigenetic silencing of tumor suppressor genes (TSGs) by aberrant DNA methylation and chromatin deacetylation provides interesting targets for chemotherapeutic intervention by inhibitors of these events. 5-Aza-2′-deoxycytidine (decitabine, 5AZA-CdR) is a potent demethylating agent, which can reactivate TSGs silenced by aberrant DNA methylation. LAQ824 (LAQ) is a novel inhibitor of histone deacetylase (HDAC) that shows Antineoplastic activity and can activate genes that produce cell cycle arrest. Both 5AZA-CdR and LAQ as single agents are currently under clinical investigation in patients with cancer. Previous reports indicate that the “cross-talk” between inhibitors of DNA methylation and HDAC can result in a synergistic activation of silent TSGs. These observations suggest that combination of these inhibitors may be an effective form of epigenetic therapy for breast cancer. The objective of our study was to determine if the combination of 5AZA-CdR and LAQ would show additive or synergistic Antineoplastic activity on human MDA-MB-231 and MCF-7 breast carcinoma cells. The Antineoplastic activity of these agents was evaluated by clonogenic assay and inhibition of DNA synthesis. Results: The combination produced greater Antineoplastic activity for the MDA-MB-231 tumor cells than either agent alone. For the MCF-7 tumor cells, there were signs of antagonism between 5AZA-CdR and LAQ when administered simultaneously. When a sequential schedule (first 5AZA-CdR followed by LAQ) was used, there were no signs of antagonism of the Antineoplastic action for the MCF-7 tumor cells. The mechanism of this interaction is probably due to the reduction of progression of MCF-7 tumor cells into S phase by LAQ. This would interfere with the Antineoplastic action of 5AZA-CdR, since it is an S phase specific agent. Conclusions: These studies demonstrated the importance of the schedule of administration of 5AZA-CdR and LAQ and may have application for future clinical trials on the treatment of breast cancer with these agents.
Michael T Heneka - One of the best experts on this subject based on the ideXlab platform.
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Antineoplastic effects of peroxisome proliferatoractivated receptor γ agonists
Lancet Oncology, 2004Co-Authors: Christian Grommes, Gary E Landreth, Michael T HenekaAbstract:Summary Peroxisome proliferator-activated receptors (PPAR) are members of a superfamily of nuclear hormone receptors. Activation of PPAR isoforms elicits both Antineoplastic and anti-inflammatory effects in several types of mammalian cells. PPARs are ligand-activated transcription factors and have a subfamily of three different isoforms: PPARα, PPARγ, and PPARβ/δ. All isoforms heterodimerise with the 9-cisretinoic acid receptor RXR, and play an important part in the regulation of several metabolic pathways, including lipid biosynthesis and glucose metabolism. Endogenous ligands of PPARγ include long-chain polyunsaturated fatty acids, eicosanoid derivates, and oxidised lipids. Newly developed synthetic ligands include thiazolidinediones—a group of potent PPARγ agonists and antidiabetic agents. Here, we review PPARγ-induced Antineoplastic signalling pathways, and summarise the Antineoplastic effects of PPARγ agonists in different cancer cell lines, animal models, and clinical trials.
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Antineoplastic effects of peroxisome proliferatoractivated receptor γ agonists
Lancet Oncology, 2004Co-Authors: Christian Grommes, Gary E Landreth, Michael T HenekaAbstract:Peroxisome proliferator-activated receptors (PPAR) are members of a superfamily of nuclear hormone receptors. Activation of PPAR isoforms elicits both Antineoplastic and anti-inflammatory effects in several types of mammalian cells. PPARs are ligand-activated transcription factors and have a subfamily of three different isoforms: PPAR alpha, PPAR gamma, and PPAR beta/delta. All isoforms heterodimerise with the 9-cis-retinoic acid receptor RXR, and play an important part in the regulation of several metabolic pathways, including lipid biosynthesis and glucose metabolism. Endogenous ligands of PPAR gamma include long-chain polyunsaturated fatty acids, eicosanoid derivates, and oxidised lipids. Newly developed synthetic ligands include thiazolidinediones-a group of potent PPAR gamma agonists and antidiabetic agents. Here, we review PPAR gamma-induced Antineoplastic signalling pathways, and summarise the Antineoplastic effects of PPAR gamma agonists in different cancer cell lines, animal models, and clinical trials.
Dongguk Shin - One of the best experts on this subject based on the ideXlab platform.
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chemotherapy induced oral mucositis is associated with detrimental bacterial dysbiosis
Microbiome, 2019Co-Authors: Boyoung Hong, Linda Choquette, Amanda K Dupuy, Angela Thompson, Andrew L Salner, Pujan Joshi, Takanori Sobue, Peter K. Schauer, Joseph A Burleson, Dongguk ShinAbstract:Gastrointestinal mucosal injury (mucositis), commonly affecting the oral cavity, is a clinically significant yet incompletely understood complication of cancer chemotherapy. Although Antineoplastic cytotoxicity constitutes the primary injury trigger, the interaction of oral microbial commensals with mucosal tissues could modify the response. It is not clear, however, whether chemotherapy and its associated treatments affect oral microbial communities disrupting the homeostatic balance between resident microorganisms and the adjacent mucosa and if such alterations are associated with mucositis. To gain knowledge on the pathophysiology of oral mucositis, 49 subjects receiving 5-fluorouracil (5-FU) or doxorubicin-based chemotherapy were evaluated longitudinally during one cycle, assessing clinical outcomes, bacterial and fungal oral microbiome changes, and epithelial transcriptome responses. As a control for microbiome stability, 30 non-cancer subjects were longitudinally assessed. Through complementary in vitro assays, we also evaluated the antibacterial potential of 5-FU on oral microorganisms and the interaction of commensals with oral epithelial tissues. Oral mucositis severity was associated with 5-FU, increased salivary flow, and higher oral granulocyte counts. The oral bacteriome was disrupted during chemotherapy and while antibiotic and acid inhibitor intake contributed to these changes, bacteriome disruptions were also correlated with Antineoplastics and independently and strongly associated with oral mucositis severity. Mucositis-associated bacteriome shifts included depletion of common health-associated commensals from the genera Streptococcus, Actinomyces, Gemella, Granulicatella, and Veillonella and enrichment of Gram-negative bacteria such as Fusobacterium nucleatum and Prevotella oris. Shifts could not be explained by a direct antibacterial effect of 5-FU, but rather resembled the inflammation-associated dysbiotic shifts seen in other oral conditions. Epithelial transcriptional responses during chemotherapy included upregulation of genes involved in innate immunity and apoptosis. Using a multilayer epithelial construct, we show mucositis-associated dysbiotic shifts may contribute to aggravate mucosal damage since the mucositis-depleted Streptococcus salivarius was tolerated as a commensal, while the mucositis-enriched F. nucleatum displayed pro-inflammatory and pro-apoptotic capacity. Altogether, our work reveals that chemotherapy-induced oral mucositis is associated with bacterial dysbiosis and demonstrates the potential for dysbiotic shifts to aggravate Antineoplastic-induced epithelial injury. These findings suggest that control of oral bacterial dysbiosis could represent a novel preventive approach to ameliorate oral mucositis.
Hans Kromhout - One of the best experts on this subject based on the ideXlab platform.
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inhalation and dermal exposure to eight Antineoplastic drugs in an industrial laundry facility
International Archives of Occupational and Environmental Health, 2007Co-Authors: W Fransman, Daan Huizer, Jochen Tuerk, Hans KromhoutAbstract:Objectives The aims of the study were to quantify levels of dermal and inhalation exposure to Antineoplastic drugs in an industrial laundry service in the Netherlands and to test the removal efficiency of the washing procedure for removal of Antineoplastic drugs.
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nurses with dermal exposure to Antineoplastic drugs reproductive outcomes
Epidemiology, 2007Co-Authors: W Fransman, Nel Roeleveld, Susan Peelen, W De Kort, Hans Kromhout, Dick HeederikAbstract:BACKGROUND: Nurses and other hospital workers are exposed to Antineoplastic drugs during daily activities. Previous studies suggest that Antineoplastic drugs at occupational exposure levels may be toxic to reproduction, but these studies are not consistent or conclusive. METHODS: Self-administered questionnaires were completed by 4393 exposed and nonexposed nurses employed between 1990 and 1997 (79% response). Questions were asked about pregnancy outcome, work-related exposures, and lifestyle. Exposure to Antineoplastic drugs was estimated using task-based dermal exposure measurements and self-reported task frequencies. Time to pregnancy was modeled using survival analysis, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for other reproductive outcomes using multiple logistic regression analysis. Associations were further explored by nonparametric regression modeling. RESULTS: Nurses highly exposed to Antineoplastic drugs took longer to conceive than referent nurses (adjusted hazard ratio = 0.8; CI = 0.6-0.9). Exposure to Antineoplastic drugs was associated with premature delivery (OR per unit increase in ln[exposure] = 1.08; CI = 1.00-1.17) and low birth weight (OR per unit increase in ln[exposure] = 1.11; 1.01-1.21). Penalized smoothed spline plots corroborated these log-linear relations. Spontaneous abortion, stillbirth, congenital anomalies, and sex of offspring appeared not to be related to exposure to Antineoplastic drugs. CONCLUSION: Antineoplastic drugs may reduce fertility and increase poor neonatal outcomes among occupationally exposed oncology nurses. © 2007 Lippincott Williams & Wilkins, Inc.
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exposure to Antineoplastic drugs outside the hospital environment
Annals of Occupational Hygiene, 2006Co-Authors: Tim Meijster, W Fransman, R Veldhof, Hans KromhoutAbstract:Objectives The objectives were (i) to identify occupational populations outside hospitals working with Antineoplastic drugs, (ii) to determine the size of the populations 'at risk', (iii) to identify major determinants and routes of exposure outside hospitals and (iv) to estimate exposure levels and frequencies relative to levels found in hospitals. Methods The survey consisted of two phases; (i) identification of activities with potential exposure to Antineoplastic drugs by literature review, interviews, questionnaires and workplace visits, (ii) exploratory measurements of exposure and surface contamination in selected sectors. Results Eight sectors were identified with potential exposure to Antineoplastic drugs: pharmaceutical industry, pharmacies, universities, veterinary medicine, nursing homes, home care, laundry facilities, and waste treatment. Four sectors were of primary concern: veterinary medicine, home care, nursing homes and industrial laundries. The populations potentially exposed in these sectors vary considerably (from several tens to thousands of workers), as do their levels of exposure. Exposure measurements collected in the veterinary medicine sector showed that workers are indeed exposed to Antineoplastic drugs and, in some cases (on gloves after administration), levels were 15 times higher than levels measured during administration in hospitals. Workers sorting contaminated hospital laundry in industrial laundry facilities were exposed to Antineoplastic drugs through inhalation. For the home care and nursing homes sectors the highest exposure levels were found when cleaning toilets and washing treated patients. These two sectors are expected to have the largest exposed population (5,000-10,000 individuals). Conclusions This study has resulted in a comprehensive overview of populations with potential exposure to Antineoplastic drugs. Exposure levels can potentially be high compared with the hospital environment, because exposure routes are complex and awareness of the hazard (and therefore use of protective measures) is low. The number of individuals outside hospitals in The Netherlands exposed to Antineoplastic drugs is estimated to be between 5,000 and 15,000.
