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British Medical Journal Sep 1979
Topics: Adolescent; Adult; History, 20th Century; Hodgkin Disease; Humans; Lymphography; Nitrogen Mustard Compounds; Palliative Care; United Kingdom
PubMed: 91404
DOI: 10.1136/bmj.2.6190.587 -
Annals of Surgery Aug 1953
Topics: Aneurysm; Humans; Mechlorethamine; Nitrogen Mustard Compounds
PubMed: 13066011
DOI: 10.1097/00000658-195308000-00007 -
Journal of the Royal College of... Jan 1971
Review
Topics: Adult; Antineoplastic Agents; Asparaginase; Carmustine; Child; Cyclophosphamide; Cytarabine; Cytosine; Daunorubicin; Drug Therapy, Combination; Hodgkin Disease; Humans; Immunotherapy; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphoma; Male; Mechlorethamine; Mercaptopurine; Methotrexate; Nitrogen Mustard Compounds; Prednisolone; Prednisone; Procarbazine; Remission, Spontaneous; Vincristine
PubMed: 4950464
DOI: No ID Found -
Chemical Research in Toxicology Feb 2016N,N-Bis-(2-chloroethyl)-phosphorodiamidic acid (phosphoramide mustard, PM) and N,N-bis-(2-chloroethyl)-amine (nornitrogen mustard, NOR) are the two biologically active...
N,N-Bis-(2-chloroethyl)-phosphorodiamidic acid (phosphoramide mustard, PM) and N,N-bis-(2-chloroethyl)-amine (nornitrogen mustard, NOR) are the two biologically active metabolites of cyclophosphamide, a DNA alkylating drug commonly used to treat lymphomas, breast cancer, certain brain cancers, and autoimmune diseases. PM and NOR are reactive bis-electrophiles capable of cross-linking cellular biomolecules to form covalent DNA-DNA and DNA-protein cross-links (DPCs). In the present work, a mass spectrometry-based proteomics approach was employed to characterize PM- and NOR-mediated DNA-protein cross-linking in human cells. Following treatment of human fibrosarcoma cells (HT1080) with cytotoxic concentrations of PM, over 130 proteins were found to be covalently trapped to DNA, including those involved in transcriptional regulation, RNA splicing/processing, chromatin organization, and protein transport. HPLC-ESI(+)-MS/MS analysis of proteolytic digests of DPC-containing DNA from NOR-treated cells revealed a concentration-dependent formation of N-[2-[cysteinyl]ethyl]-N-[2-(guan-7-yl)ethyl]amine (Cys-NOR-N7G) conjugates, confirming that it cross-links cysteine thiols of proteins to the N7 position of guanines in DNA. Cys-NOR-N7G adduct numbers were higher in NER-deficient xeroderma pigmentosum cells (XPA) as compared with repair proficient cells. Furthermore, both XPA and FANCD2 deficient cells were sensitized to PM treatment as compared to that of wild type cells, suggesting that Fanconi anemia and nucleotide excision repair pathways are involved in the removal of cyclophosphamide-induced DNA damage.
Topics: Alkylating Agents; Cell Line, Tumor; Chromatography, High Pressure Liquid; DNA; DNA Adducts; Humans; Nitrogen Mustard Compounds; Peptides; Phosphoramide Mustards; Proteins; Proteomics; Spectrometry, Mass, Electrospray Ionization
PubMed: 26692166
DOI: 10.1021/acs.chemrestox.5b00430 -
Emergency Medicine Journal : EMJ Jun 2006There is no specific antidote for the treatment of casualties exposed to chlorine, phosgene, or mustards; therefore, management is largely supportive. Corticosteroid... (Review)
Review
There is no specific antidote for the treatment of casualties exposed to chlorine, phosgene, or mustards; therefore, management is largely supportive. Corticosteroid treatment has been given to casualties accidentally exposed to chlorine. Clinical data on efficacy are inconclusive as the numbers given steroids have been small and the indications for administration unclear. There have been no clinical controlled studies. There is a stronger evidence base from animal studies, particularly from porcine and rodent models. Lung injury induced by phosgene and mustard appears to be mediated by glutathione depletion, lipid peroxidation, free radical generation, and subsequent cellular toxicity. There is limited evidence to suggest that repletion of glutathione reduces and/or prevents lung damage by these agents. This may provide an opportunity for therapeutic intervention.
Topics: Animals; Bronchodilator Agents; Chemical Warfare Agents; Humans; Inhalation Exposure; Lung Diseases; Mustard Compounds; Phosgene; Porphyrins; Rats; Swine
PubMed: 16714497
DOI: 10.1136/emj.2003.011775 -
Biological & Pharmaceutical Bulletin Nov 2008The L-type amino acid transporter 1 (LAT1, SLC7A5) is an Na+-independent neutral amino acid transporter the expression of which is located in retinal endothelial cells....
The L-type amino acid transporter 1 (LAT1, SLC7A5) is an Na+-independent neutral amino acid transporter the expression of which is located in retinal endothelial cells. Due to its broad substrate selectivity, LAT1 has been proposed to mediate the transport of amino acid-related drugs across the blood-tissue barriers. Here, we have investigated the transport screening of amino acid-mustards using a conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB2) which expresses LAT1. We synthesized 5 amino acid-mustards: tyrosine-mustard, phenylglycine-mustard, alanine-mustard, ornithine-mustard, and lysine-mustard. LAT1-mediated [3H]L-phenylalanine (Phe) uptake by TR-iBRB2 cells was inhibited in a competitive manner by tyrosine-mustard and phenylglycine-mustard as well as melphalan (phenylalanine-mustard). Phenylglycine-mustard was able to induce the efflux of [3H]Phe preloaded into the TR-iBRB2 cells expressing LAT1 through the obligatory exchange mechanism, although tyrosine-mustard, alanine-mustard, ornithine-mustard, lysine-mustard, and melphalan did not induce any significant efflux. These findings suggest that phenylglycine-mustard is a better substrate for LAT1 than melphalan and other amino acid-mustards.
Topics: Amino Acids; Animals; Biological Transport; Cell Line; Dose-Response Relationship, Drug; Endothelial Cells; Large Neutral Amino Acid-Transporter 1; Mustard Compounds; Protein Binding; Rats; Retina; Substrate Specificity; Time Factors
PubMed: 18981585
DOI: 10.1248/bpb.31.2126 -
Blood Jun 1975Nitrogen mustard (NH2) and Nor-nitrogen mustard (Nor-HN2) both inhibit the polymerization of deoxyhemoglobin S in solution and in intact erythrocytes. Metabolic studies...
Nitrogen mustard (NH2) and Nor-nitrogen mustard (Nor-HN2) both inhibit the polymerization of deoxyhemoglobin S in solution and in intact erythrocytes. Metabolic studies were undertaken to determine the feasability of an extracorporeal treatment with these or related agents. Glucose utilization, hexose monophosphate shunt activity, methemoglobin reduction, and incubation with acetylphenylhydrazine for Heinz body formation were performed, as well as specific assays for hexokinase, pyruvate kinase, glucose-6-phosphate dehydrogenase, glutathione reductase, ATP, reduced glutathione (GSH), and survival of autologous mustard-treated cells in rabbits. HN2 was found to enter red cells rapidly and bind to intracellular contents. Metabolic studies revealed no significant inhibition or alteration of function by Nor-HN2 at 10 mg/ml of whole blood. Rabbit red cell survival was also normal. HN2, however, inhibited glutathione reductase and blocked the free sulfhydryl group of GSH by forming serveral addition products of alkylated GSH. Heinz body test with acetylphenylhydrazine became positive in HN2-treated cells, and rabbit red cell survival was shortened considerably in the concentration range used to inhibit sickling. Ascorbic acid stimulation of the hexose shunt pathway was inhibited by HN2, but methylene blue stimulation remained unaffected. 14-C-HN2 remains bound to red cells in vivo, and the disappearance of radioactivity is similar to that found with 14-C-DFP (disopropylfluorophosphate). Oxygen affinity of both HN2 and Nor-HN2 treated human red cells remains virtually the same as that found in control samples. It is concluded that Nor-HN2 may be a suitable agent for an extracorporeal therapy, and that each mustard needs to be evaluated individually for its antisickling effects and its suitability for extracorporeal use.
Topics: Animals; Carbon Radioisotopes; Cell Survival; Erythrocytes; Glucose; Glucosephosphate Dehydrogenase Deficiency; Glutathione Reductase; Hemoglobins; Humans; Isoflurophate; Nitrogen Mustard Compounds; Rabbits; Sulfhydryl Compounds
PubMed: 1125427
DOI: No ID Found -
Drugs in R&D Mar 2013Bendamustine is an alkylating agent with clinical activity against a variety of hematologic malignancies and solid tumors. To assess the roles of renal and hepatic drug...
BACKGROUND
Bendamustine is an alkylating agent with clinical activity against a variety of hematologic malignancies and solid tumors. To assess the roles of renal and hepatic drug elimination pathways in the excretion and metabolism of bendamustine, a mass balance study was performed in patients with relapsed or refractory malignancies.
METHODS
A single 60-minute intravenous dose of 120 mg/m(2), 80-95 μCi (14)C-bendamustine hydrochloride was administered to six patients, followed by collection of blood, urine, and fecal samples at specified time points up to day 8 or until the radioactivity of the 24-hour urine and fecal collections was below 1% of the administered dose (whichever was longer). Total radioactivity (TRA) was measured in all samples, and concentrations of unchanged bendamustine and its metabolites γ-hydroxy-bendamustine (M3), N-desmethyl-bendamustine (M4), and dihydroxy bendamustine (HP2) were determined in plasma and urine, using validated liquid chromatography-tandem mass spectrometry methods.
RESULTS
The mean recovery of TRA in excreta was 76% of the radiochemical dose. Approximately half of the administered dose was recovered in urine and a quarter in feces. Less than 5% of the administered dose was recovered in urine as unchanged bendamustine. Bendamustine clearance from plasma was rapid, with a half-life of ~40 minutes. Plasma concentrations of M3, M4, and HP2 were very low relative to bendamustine concentrations. Plasma levels of TRA were higher and more sustained as compared with plasma concentrations of bendamustine, M3, M4, and HP2, suggesting the presence of one or more longer-lived (14)C-bendamustine-derived compounds. Fatigue (50%) and vomiting (50%) were the most frequent treatment-related adverse events. A grade 3/4 absolute lymphocyte count decrease occurred in all patients at some point during the study.
CONCLUSION
Bendamustine is extensively metabolized, with subsequent excretion in both urine and feces. Accumulation of bendamustine is not anticipated in cancer patients with renal or hepatic impairment, because of the dose administration schedule and short half-life.
Topics: Aged; Antineoplastic Agents, Alkylating; Bendamustine Hydrochloride; Carbon Radioisotopes; Female; Humans; Infusions, Intravenous; Male; Metabolic Clearance Rate; Middle Aged; Neoplasm Recurrence, Local; Neoplasms; Nitrogen Mustard Compounds; Recurrence
PubMed: 23322528
DOI: 10.1007/s40268-012-0001-5 -
Cancer Feb 2009Alkylating agents form the basis of most combination treatment regimens for low-grade lymphoproliferative disorders. Bendamustine is a unique alkylating agent that has... (Review)
Review
Alkylating agents form the basis of most combination treatment regimens for low-grade lymphoproliferative disorders. Bendamustine is a unique alkylating agent that has distinctive preclinical activity in cell lines resistant to other alkylators. Furthermore, clinical activity has been demonstrated in patients with alkylating agent resistant disease. Recently, larger studies have been organized to study the clinical effects of bendamustine further. In indolent B-cell non-Hodgkin lymphoma that is resistant to rituximab, bendamustine induced a remission in 77% of patients. Myelosuppression was identified as the most common toxicity. In 2 studies of similar populations of patients, the combination of bendamustine and rituximab induced remission 90% of patients with a median progression-free survival of 23-24 months. The overall remission rate was 59% in a prospective, randomized study of untreated patients with chronic lymphocytic leukemia, which was significantly greater than the rate of 26% in the chlorambucil control arm (P < 0.001). Combined with rituximab, bendamustine induces a remission in 67% of patients with relapsed or refractory chronic lymphocytic leukemia. Bendamustine is an active agent for the treatment of low-grade lymphoproliferative disorders and more study is needed to determine which dose and schedule is optimal, and which patients will derive the greatest benefit from its use.
Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Lymphoproliferative Disorders; Nitrogen Mustard Compounds
PubMed: 19117340
DOI: 10.1002/cncr.24057 -
Chemical Research in Toxicology Jan 2017Biomarker-driven drug selection plays a central role in cancer drug discovery and development, and in diagnostic strategies to improve the use of traditional...
Biomarker-driven drug selection plays a central role in cancer drug discovery and development, and in diagnostic strategies to improve the use of traditional chemotherapeutic drugs. DNA-modifying anticancer drugs are still used as first line medication, but drawbacks such as resistance and side effects remain an issue. Monitoring the formation and level of DNA modifications induced by anticancer drugs is a potential strategy for stratifying patients and predicting drug efficacy. In this perspective, preclinical and clinical data concerning the relationship between drug-induced DNA adducts and biological response for platinum drugs and combination therapies, nitrogen mustards and half-mustards, hypoxia-activated drugs, reductase-activated drugs, and minor groove binding agents are presented and discussed. Aspects including measurement strategies, identification of adducts, and biological factors that influence the predictive relationship between DNA modification and biological response are addressed. A positive correlation between DNA adduct levels and response was observed for the majority of the studies, demonstrating the high potential of using DNA adducts from anticancer drugs as mechanism-based biomarkers of susceptibility, especially as bioanalysis approaches with higher sensitivity and throughput emerge.
Topics: Animals; Antineoplastic Agents; Biomarkers; DNA Adducts; Humans; Hypoxia; Nitrogen Mustard Compounds; Oxidoreductases; Platinum Compounds; Precision Medicine; Prodrugs
PubMed: 27936622
DOI: 10.1021/acs.chemrestox.6b00380