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Environmental Health Perspectives Nov 1992The vesicant agents of the unitary chemical munitions stockpile include various formulations of sulfur mustard [bis-(2-chloroethyl) sulfide; agents H, HD, and HT] and... (Review)
Review
The vesicant agents of the unitary chemical munitions stockpile include various formulations of sulfur mustard [bis-(2-chloroethyl) sulfide; agents H, HD, and HT] and small quantities of the organic arsenical Lewisite [dichloro(2-chlorovinyl) arsine; agent L]. These agents can be dispersed in liquid, aerosol, or vapor form and are capable of producing severe chemical burns upon direct contact with tissue. Moist tissues such as the eyes, respiratory tract, and axillary areas are particularly affected. Available data summarizing acute dose response in humans and laboratory animals are summarized. Vesicant agents are also capable of generating delayed effects such as chronic bronchitis, carcinogenesis, or keratitis/keratopathy of the eye under appropriate conditions of exposure and dose. These effects may not become manifest until years following exposure. Risk analysis derived from carcinogenesis data indicates that sulfur mustard possesses a carcinogenic potency similar to that of benzo[a]pyrene. Because mustard agents are alkylating compounds, they destroy individual cells by reaction with cellular proteins, enzymes, RNA, and DNA. Once begun, tissue reaction is irreversible. Mustard agents are mutagenic; data for cellular and laboratory animal assays are presented. Reproductive effects have not been demonstrated in the offspring of laboratory rats. Acute Lewisite exposure has been implicated in cases of Bowen's disease, an intraepidermal squamous cell carcinoma. Lewisite is not known to generate reproductive or teratogenic effects.
Topics: Animals; Arsenic Poisoning; Arsenicals; Cell Membrane Permeability; Chemical Warfare; DNA Damage; Dermatitis, Irritant; Female; Humans; Irritants; Keratitis; Lethal Dose 50; Lung Neoplasms; Male; Mustard Gas; Mutation; Pregnancy; Reproduction; Respiratory Tract Diseases
PubMed: 1486858
DOI: 10.1289/ehp.9298259 -
Journal of Leukocyte Biology Jun 2021Ethanol remains a confounder in postburn pathology, which is associated with an impaired intestinal barrier. Previously, we demonstrated that ethanol and burn injury...
Ethanol remains a confounder in postburn pathology, which is associated with an impaired intestinal barrier. Previously, we demonstrated that ethanol and burn injury reduce intestinal oxygen delivery (hypoxia) and alters microRNA (miR) expression in small intestinal epithelial cells. Hypoxia has been shown to influence expression of miRs and miR biogenesis components. Therefore, we examined whether hypoxia influences expression of miR biogenesis components (drosha, dicer, and argonaute-2 [ago-2]) and miRs (-7a and -150) and whether these changes impacted other parameters following ethanol and burn injury. Mice were gavaged with ethanol (∼2.9 g/kg) 4 h before receiving a ∼12.5% total body surface full thickness burn. Mice were resuscitated at the time of injury with normal saline with or without 5 mg/kg PX-478, a hypoxia-inducible factor-1α inhibitor. One day following injury mice were euthanized, and the expression of miRs and their biogenesis components as well as bacterial growth, tight junction proteins, intestinal transit, and permeability were assessed. Ethanol combined with burn injury significantly reduced expression of drosha, ago-2, miRs (-7a and -150), occludin, zonula occludens-1, claudin-4, zonula occludens-1, mucins-2 and -4, and intestinal transit compared to shams. Furthermore, there was an increase in intestinal permeability, total bacteria, and Enterobacteriaceae populations following the combined injury compared to shams. PX-478 treatment improved expression of drosha, ago-2, miRs (-7a and -150), occludin, claudin-4, zonula occludens-1, and mucin-2. PX-478 treatment also improved intestinal transit and reduced dysbiosis and permeability. These data suggest that PX-478 improves miR biogenesis and miR expression, and restores barrier integrity while reducing bacterial dysbiosis following ethanol and burn injury.
Topics: Alcoholic Intoxication; Animals; Argonaute Proteins; Biomarkers; Burns; Disease Susceptibility; Enzyme Inhibitors; Ethanol; Hypoxia-Inducible Factor 1, alpha Subunit; Intestinal Mucosa; Male; Mice; MicroRNAs; Mustard Compounds; Phenylpropionates; Protective Agents; RNA, Messenger; RNA, Ribosomal, 16S
PubMed: 32964503
DOI: 10.1002/JLB.3A0820-323RR -
Journal of Clinical Oncology : Official... Sep 2014Chemoimmunotherapy has been the standard of care for chronic lymphocytic leukemia (CLL). However, the introduction of B-cell receptor (BCR) kinase inhibitors such as... (Review)
Review
PURPOSE
Chemoimmunotherapy has been the standard of care for chronic lymphocytic leukemia (CLL). However, the introduction of B-cell receptor (BCR) kinase inhibitors such as ibrutinib has the potential to eliminate the role of chemotherapy in the treatment of CLL. How to best incorporate old and new therapies for CLL in this landscape is increasingly complex.
METHODS
This article reviews current data available to clinicians and integrates these data to provide a strategy that can be used to approach the treatment of CLL in the era of BCR signaling inhibitors.
RESULTS
Current strategies separate patients based on age or functional status as well as genetics [presence or absence of del(17)(p13.1)]. In the era of targeted therapy, this will likely continue based on current available data. Phase III studies support chemoimmunotherapy as the initial standard therapy for patients without del(17)(p13.1). Choice of chemotherapy (fludarabine plus cyclophosphamide, bendamustine, or chlorambucil) and anti-CD20 antibody (rituximab, ofatumumab, or obinutuzumab) varies based on regimen and patient status. For patients with del(17)(p13.1), no standard initial therapy exists, although several options supported by phase II clinical trials (methylprednisolone plus alemtuzumab or ibrutinib) seem better than chemoimmunotherapy. Treatment of relapsed CLL seems to be best supported by ibrutinib-based therapy. Completion of trials with ibrutinib and other new agents in the near future will offer opportunity for chemotherapy-free treatment across all groups of CLL.
CONCLUSION
Therapy for CLL has evolved significantly over the past decade with introduction of targeted therapy for CLL. This has the potential to completely transform how CLL is treated in the future.
Topics: Adenine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Chlorambucil; Cyclophosphamide; Drug Resistance, Neoplasm; Gene Deletion; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Nitrogen Mustard Compounds; Piperidines; Practice Patterns, Physicians'; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Vidarabine
PubMed: 25049322
DOI: 10.1200/JCO.2014.55.8262 -
The Cochrane Database of Systematic... Sep 2012Indolent B cell lymphoid malignancies include follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, lymphoplasmacytic lymphoma and marginal zone... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Indolent B cell lymphoid malignancies include follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, lymphoplasmacytic lymphoma and marginal zone lymphomas. Chronic lymphocytic leukaemia (CLL) is a lymphoid malignancy similar to small lymphocytic lymphoma (SLL) in its leukaemic phase.Indolent lymphoid malignancies including CLL are characterised by slow growth, a high initial response rate and a relapsing and progressive disease course. Advanced-stage indolent B cell lymphoid malignancies are often incurable. If symptoms or progressive disease occur, chemotherapy plus rituximab is indicated. No chemotherapy regimen has been shown to improve overall survival compared to a different regimen.Bendamustine is efficacious in the treatment of patients with indolent B cell lymphoid malignancies. A number of randomised controlled trials have examined the effect of bendamustine compared to other chemotherapy regimens in these patients. Improved disease control with no survival benefit is shown.
OBJECTIVES
To evaluate the efficacy of bendamustine therapy for patients with indolent B cell lymphoid malignancies including CLL.
SEARCH METHODS
We electronically searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 2), MEDLINE (1966 to May 2012), EMBASE (1974 to November 2011), LILACS (1982 to May 2012), databases of ongoing trials (accessed 30 April 2012) and relevant conference proceedings. We searched references of identified trials and contacted the first author of each included trial.
SELECTION CRITERIA
Randomised controlled trials that compared a bendamustine-containing regimen to other chemotherapy with or without immunotherapy.
DATA COLLECTION AND ANALYSIS
Two authors independently appraised the quality of each trial and extracted data from included trials. We estimated and pooled hazard ratios (HR) and risk ratios (RR) with 95% confidence intervals (CI).
MAIN RESULTS
We included five trials randomising 1343 adult patients in the systematic review. Allocation and blinding were unclear in three trials and adequate in two. Incomplete outcome data and selective reporting were adequate in all trials. Trials varied in the type of lymphoid malignancy, bendamustine regimen and the comparator regimen. In the three trials that included patients with follicular lymphoma, mantle cell lymphoma and other indolent lymphomas the comparator treatment was cyclophosphamide, a combination of cyclophosphamide, vincristine, doxorubicin and prednisone, and fludarabine. Two trials included only patients with CLL and compared bendamustine to chlorambucil, and to fludarabine. We did not conduct a meta-analysis due to the clinical heterogeneity among trials. Bendamustine had no statistically significant effect on the overall survival of patients with indolent B cell lymphoid malignancies in any of the included trials (trials of moderate quality). Progression-free survival was statistically significantly improved with bendamustine treatment compared to other chemotherapy in three of the four trials that reported on it. One trial demonstrated a non statistically significant improvement of PFS. The risk of grade 3 or 4 adverse events was similar when bendamustine was compared to CHOP and fludarabine, and higher when compared to chlorambucil. Compared to chlorambucil quality of life was unaffected by bendamustine treatment (one trial, no meta-analysis).
AUTHORS' CONCLUSIONS
As none of the currently available chemotherapeutic protocols for induction therapy in indolent B cell lymphoid malignancies confer a survival benefit and due to the improved progression-free survival in each of the included trials, and a similar rate of grade 3 or 4 adverse events, bendamustine may be considered for the treatment of patients with indolent B cell lymphoid malignancies. However, the unclear effect on survival and the higher rate of adverse events compared to chlorambucil in patients with CLL/SLL does not support the use of bendamustine for these patients.The effect of bendamustine combined with rituximab should be evaluated in randomised clinical trials with more homogenous populations and outcomes for specific subgroups of patients by type of lymphoma should be reported. Any future trial should evaluate the effect of bendamustine on quality of life.
Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Cyclophosphamide; Doxorubicin; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Lymphoma, Follicular; Lymphoma, Mantle-Cell; Nitrogen Mustard Compounds; Prednisone; Recurrence; Vincristine; Waldenstrom Macroglobulinemia
PubMed: 22972131
DOI: 10.1002/14651858.CD009045.pub2 -
IARC Monographs on the Evaluation of... 1990
Review
Topics: Alkylating Agents; Animals; Carcinogens; Humans; Molecular Structure; Nitrogen Mustard Compounds
PubMed: 2292796
DOI: No ID Found -
Journal of Chromatography. B,... Jul 2019Sulfur and nitrogen mustards are internationally banned vesicants listed as Schedule 1 chemical agents in the Chemical Weapons Convention. These compounds are highly...
Sulfur and nitrogen mustards are internationally banned vesicants listed as Schedule 1 chemical agents in the Chemical Weapons Convention. These compounds are highly reactive electrophiles that form stable adducts to a variety of available amino acid residues on proteins upon exposure. We present a quantitative exposure assay that simultaneously measures agent specific protein adducts to cysteine for sulfur mustard (HD) and three nitrogen mustards (HN1, HN2, and HN3). Proteinase K was added to a serum or plasma sample to digest protein adducts and form the target analyte, the blister agent bound to the tripeptide cysteine-proline-phenylalanine (CPF). The mustard adducted-tripeptide was purified by solid phase extraction and analyzed using isotope dilution LC-MS/MS. Product ion structures were identified using high-resolution product ion scan data for HD-CPF, HN1-CPF, HN2-CPF, and HN3-CPF. Thorough matrix comparison, analyte recovery, ruggedness, and stability studies were incorporated during method validation to produce a robust method. The method demonstrated long term-stability, precision (RSD < 15%), and intra- and inter-day accuracies > 85% across the reportable range of 3.00-200 ng/mL for each analyte. Compared to previously published assays, this method quantitates both sulfur and nitrogen mustard exposure biomarkers, requires only 10 μL of sample volume, and can use either a liquid sample or dried sample spot.
Topics: Biomarkers; Chromatography, High Pressure Liquid; Cysteine; Environmental Exposure; Humans; Mustard Compounds; Reproducibility of Results; Serum Albumin; Tandem Mass Spectrometry
PubMed: 31082684
DOI: 10.1016/j.jchromb.2019.05.005 -
Toxicology and Applied Pharmacology Jan 2009The biochemical sequelae to chloroethyl mustard exposure correspond very well to toxic processes initiated by free radicals. Additionally, mustard solutions contain...
The biochemical sequelae to chloroethyl mustard exposure correspond very well to toxic processes initiated by free radicals. Additionally, mustard solutions contain spontaneously formed cyclic onium ions which produce carbon free radicals when reduced electrochemically. Therefore, we hypothesized that the onium ions of sulfur or nitrogen mustards might produce carbon free radicals upon being reduced enzymatically, and that these radicals might constitute a metabolic activation. We set out to document radical production using an in vitro metabolic system and electron paramagnetic resonance (EPR). Our system consisted of NADPH, one of several pyridine nucleotide-driven flavoprotein reductases, cytochrome c as a terminal electron acceptor, various sulfur or nitrogen mustards and the spin trap alpha-[4-pyridyl-1-oxide]-N-tert-butylnitrone in buffer. Reactions were started by adding the reductase to the other materials, vortexing and immediately transferring the mixture to a 10 mm EPR flat cell. Repeated scans on a Bruker ESP 300E EPR spectrometer produced a triplet of doublets with hyperfine splitting constants of a(N)=15.483 G and a(H)=2.512 G. The outcome supported our hypothesis that carbon-centered free radicals are produced when mustard-related onium ions are enzymatically reduced. The EPR results varied little with the chloroethyl compound used or with porcine or human cytochrome P450 reductase, the reductase domain of rat brain neuronal nitric oxide synthase or rat liver thioredoxin reductase. Our results offer new insight into the basis for mustard-induced vesication and the outcome of exposure to different mustards. The free radical model provides an explanation for similarities in the lesions arising from mustard exposure and energy-based lesions such as those from heat, ultraviolet and nuclear radiation as well as damage across tissue types such as skin, eyes or airway epithelium.
Topics: Animals; Brain; Chemical Warfare Agents; Cytochromes c; Electron Spin Resonance Spectroscopy; Free Radicals; Humans; Liver; Mustard Gas; NADP; NADPH-Ferrihemoprotein Reductase; Nitric Oxide Synthase; Nitrogen Mustard Compounds; Pyridines; Rats; Spin Trapping; Swine; Thioredoxin-Disulfide Reductase
PubMed: 18977373
DOI: 10.1016/j.taap.2008.10.002 -
Bioscience Reports Apr 2023Directed enzyme prodrug therapy is a highly promising anti-cancer strategy. However, the current technology is limited by inefficient prodrug activation and the...
Directed enzyme prodrug therapy is a highly promising anti-cancer strategy. However, the current technology is limited by inefficient prodrug activation and the dose-limiting toxicity associated with the prodrugs being tested; to overcome these limitations, the dinitrobenzamide mustard prodrugs, PR-104A and SN27686, have been developed. The present study will assess both of these prodrugs for their potential uses in a novel magnetic-nanoparticle directed enzyme prodrug therapy strategy by determining their kinetic parameters, assessing the products formed during enzymatic reduction using HPLC and finally their ability to cause cell death in the ovarian cancer cell line, SK-OV-3. It was shown for the first time that the dinitrobenzamide mustard prodrugs are able to be reduced by the genetically modified nitroreductases, NfnB-cys and YfkO-cys, and that these enzyme/prodrug combinations can induce a significant cell death in the SK-OV-3 cell line, highlighting the potential for both enzyme/prodrug combinations for use in magnetic-nanoparticle directed enzyme prodrug therapy.
Topics: Humans; Prodrugs; Nitrogen Mustard Compounds; Neoplasms; Antineoplastic Agents, Alkylating; Antineoplastic Agents
PubMed: 37067816
DOI: 10.1042/BSR20230627 -
F&S Science May 2022To investigate the antitumor effects of the selective hypoxia-inducible factor-1 (HIF-1) inhibitors echinomycin and PX-478 on uterine fibroids.
OBJECTIVE
To investigate the antitumor effects of the selective hypoxia-inducible factor-1 (HIF-1) inhibitors echinomycin and PX-478 on uterine fibroids.
DESIGN
Experimental study using in vitro primary culture systems and an in vivo mouse xenograft model.
SETTING
Academic university center.
PATIENT(S)
Women with uterine fibroids who underwent hysterectomy or myomectomy.
INTERVENTION(S)
Administration of the selective HIF-1 inhibitors echinomycin and PX-478 to the media of the primary cultured uterine fibroid cells and to nonobese diabetic/severe combined immunodeficient mice bearing fibroid xenografts consisting of the primary cultured fibroid cells and type Ⅰ collagen gels beneath the kidney capsule.
MAIN OUTCOME MEASURE(S)
Cell proliferation was measured by Cell Counting Kit-8 assay. Apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay and by measuring caspase 3 and 7 activities. The xenografts were evaluated by gross appearance, surface area, and histology. The Ki-67 index was measured to evaluate proliferation of the xenografts.
RESULT(S)
Both echinomycin and PX-478 inhibited cell proliferation and induced apoptosis in fibroid cells cultured under hypoxia and normoxia. Enlargement of the fibroid xenografts was significantly attenuated. The Ki-67 index significantly decreased after the administration of the HIF-1 inhibitors in the xenograft model. Eight of 27 xenografts treated with the HIF-1 inhibitors contained calcification and hyalinizing components from 3 days after the grafting to 2 weeks, suggesting that the HIF-inhibitors induce degeneration of the fibroid xenografts.
CONCLUSION(S)
The selective HIF-1 inhibitors echinomycin and PX-478 show antitumor effects against uterine fibroids both in vitro and in vivo. These findings support the potential use of HIF-1 inhibitors for the treatment of uterine fibroids.
Topics: Animals; Echinomycin; Female; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Ki-67 Antigen; Leiomyoma; Mice; Mustard Compounds; Phenylpropionates
PubMed: 35560016
DOI: 10.1016/j.xfss.2022.01.005 -
Dermatology Online Journal Nov 2012The term "flagellate erythema" after bleomycin therapy was described as bleomycin-induced linear hyperpigmentation. Since then, this pattern has not been related to any...
BACKGROUND
The term "flagellate erythema" after bleomycin therapy was described as bleomycin-induced linear hyperpigmentation. Since then, this pattern has not been related to any other chemotherapeutic regimen.
OBSERVATION
We report a rare patient with chronic lymphocytic leukemia who developed "flagellate dermatitis" induced by bendamustine.
CONCLUSION
Chemotherapy induced "Flagellate Dermatitis" is a rare finding reported only after bleomycin therapy. We describe the first case with this characteristic eruption pattern after administration of bendamustine.
Topics: Antineoplastic Agents, Alkylating; Bendamustine Hydrochloride; Drug Eruptions; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Nitrogen Mustard Compounds
PubMed: 23217953
DOI: No ID Found