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European Journal of Nuclear Medicine... Jul 2022Bacterial infection and antibiotic resistance are serious threats to human health. This study aimed to develop two novel radiotracers, F-NTRP and F-NCRP, that possess a...
PURPOSE
Bacterial infection and antibiotic resistance are serious threats to human health. This study aimed to develop two novel radiotracers, F-NTRP and F-NCRP, that possess a specific nitroreductase (NTR) response to image deep-seated bacterial infections using positron emission tomography (PET). This method can distinguish infection from sterile inflammation.
METHODS
F-NTRP and F-NCRP were synthesized via a one-step method; all the steps usually involved in tracer radiosynthesis were successfully adapted in the All-In-One automated module. After the physiochemical properties of F-NTRP and F-NCRP were characterized, their specificity and selectivity for NTR were verified in E. coli and S. aureus. The ex vivo biodistribution of the tracers was evaluated in normal mice. MicroPET-CT imaging was performed in mouse models of bacterial infection and inflammation after the administration of F-NTRP or F-NCRP.
RESULTS
Fully automated radiosynthesis of F-NTRP and F-NCRP was achieved within 90-110 min with overall decay-uncorrected, isolated radiochemical yields of 21.24 ± 4.25% and 11.3 ± 3.78%, respectively. The molar activities of F-NTRP and F-NCRP were 320 ± 40 GBq/μmol and 275 ± 33 GBq/µmol, respectively. In addition, F-NTRP and F-NCRP exhibited high selectivity and specificity for NTR response. PET-CT imaging in bacteria-infected mouse models with F-NTRP or F-NCRP showed significant radioactivity uptake in either E. coli- or S. aureus-infected muscles. The uptake for E. coli-infected muscles, 2.4 ± 0.2%ID/g with F-NTRP and 4.05 ± 0.49%ID/g with F-NCRP, was up to three times greater than that for uninfected control muscles. Furthermore, for both F-NTRP and F-NCRP, the uptake in bacterial infection was 2.6 times higher than that in sterile inflammation, allowing an effective distinction of infection from inflammation.
CONCLUSION
F-NTRP and F-NCRP are worth further investigation to verify their potential clinical application for distinguishing bacterial infection from sterile inflammation via their specific NTR responsiveness.
Topics: Animals; Bacterial Infections; Escherichia coli; Fluorine Radioisotopes; Humans; Inflammation; Mechlorethamine; Mice; Nitroreductases; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Staphylococcus aureus; Tissue Distribution; Tomography, X-Ray Computed
PubMed: 35122512
DOI: 10.1007/s00259-022-05710-2 -
Experimental Eye Research Jun 2023The vesicant sulfur mustard (SM) is a chemical warfare agent that causes acute and chronic injury to the cornea and proximal anterior segment structures. Despite...
The vesicant sulfur mustard (SM) is a chemical warfare agent that causes acute and chronic injury to the cornea and proximal anterior segment structures. Despite clinical evidence of SM-exposure causing unexplained retinal deficits, there have been no animal studies conducted to examine the retinal toxicity of this vesciant. The cardinal hallmark of retinal response to stressors or injury is the activation of reactive gliosis, a cellular process largely governed by Müller glia. Previously we showed that corneal exposure to sodium hydroxide elicits rapid induction of reactive gliosis and results in retinal degeneration in a dose-related manner. Based on this evidence, we hypothesized that the vesicant nitrogen mustard (NM), an analog of SM, may also elicit reactive gliosis. To test this idea, we developed a mouse model of NM ocular injury and investigated corneal and retinal effects focusing on citrullination, a posttranslational modification (PTM) of proteins. This PTM was recently linked to alkali injury and has also been shown to occur in retinal degenerative conditions. Here, we demonstrate that corneal exposure to 1% NM causes a synchronous activation of citrullination in both the cornea and retina with hypercitrullination becoming apparent temporally and manifesting with altered cellular expression characteristics. A key finding is that ocular citrullination occurs acutely as early as 1-h post-injury in both the cornea and retina, which underscores a need for expeditious interception of this acute corneal and retinal response. Moreover, exploiting dose response and temporal studies, we uncoupled NM-induced retinal citrullination from its induction of retinal gliosis. Our findings demonstrate that hypercitrullination is a common corneo-retinal mechanism that sensitizes the eye to NM injury and suggests that counteracting hypercitrullination may provide a suitable countermeasure to vesicant injury.
Topics: Animals; Mice; Mechlorethamine; Irritants; Gliosis; Cornea; Eye Injuries; Retina; Mustard Gas; Retinal Diseases
PubMed: 37080381
DOI: 10.1016/j.exer.2023.109485 -
Journal of Drugs in Dermatology : JDD Aug 2020Langerhans cell histiocytosis (LCH) limited to the skin is rare in adult patients. Given the challenges of prospective clinical trials for this rare disease, there is...
Langerhans cell histiocytosis (LCH) limited to the skin is rare in adult patients. Given the challenges of prospective clinical trials for this rare disease, there is paucity in data to guide the management of cutaneous LCH. Topical nitrogen mustard is a possible treatment for cutaneous LCH with positive responses in five known adult cases in the literature. In this report, we present two adult patients with recalcitrant cutaneous LCH and no evidence of systemic involvement who had rapid and complete response on topical nitrogen mustard therapy. We provide support for topical nitrogen mustard as a treatment option for primary cutaneous LCH which may spare patients from requiring systemic immunosuppressive treatments. J Drugs Dermatol. 2020;19(8):803-805. doi:10.36849/JDD.2020.4943.
Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Alkylating Agents; Biopsy; Female; Histiocytosis, Langerhans-Cell; Humans; Mechlorethamine; Skin; Skin Diseases; Treatment Outcome
PubMed: 32845598
DOI: 10.36849/JDD.2020.4943 -
Veterinary and Comparative Oncology Sep 2023Multi-agent chemotherapy successfully induces remission in most naïve, high-grade canine lymphoma patients; however, disease recurrence is common. MOPP...
Multi-agent chemotherapy successfully induces remission in most naïve, high-grade canine lymphoma patients; however, disease recurrence is common. MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) is an effective rescue protocol used to re-induce remission, but is associated with gastrointestinal toxicity and can be a less desirable option for patients that previously failed vincristine-containing protocols. Therefore, alternative members of the vinca alkaloid family, such as vinblastine, could be potentially advantageous as substitutes for vincristine to reduce gastrointestinal toxicity and chemoresistance. The objective of this study was to report the clinical outcomes and toxicity of 36 dogs with relapsed or refractory multicentric lymphoma treated with a modified MOPP protocol whereby vincristine was replaced with vinblastine (MVPP). The overall response rate to MVPP was 25% with a median progression free survival of 15 days and a median overall survival of 45 days. MVPP at the prescribed doses resulted in modest and transient clinical benefit, but was well tolerated with no treatment delays or hospitalizations secondary to side effects. Given the minimal toxicity, dose intensification could be considered to improve clinical responses.
Topics: Animals; Dogs; Prednisone; Vinblastine; Mechlorethamine; Vincristine; Procarbazine; Neoplasm Recurrence, Local; Dog Diseases; Lymphoma; Antineoplastic Combined Chemotherapy Protocols; Lymphoma, Non-Hodgkin; Doxorubicin
PubMed: 37222086
DOI: 10.1111/vco.12913 -
Journal of Enzyme Inhibition and... Dec 2022Chromone has emerged as one of the most important synthetic scaffolds for antitumor activity, which promotes the development of candidate drugs with better activity. In...
Chromone has emerged as one of the most important synthetic scaffolds for antitumor activity, which promotes the development of candidate drugs with better activity. In this study, a series of nitrogen mustard derivatives of chromone were designed and synthesised, in order to discover promising anti-breast tumour candidates. Almost all target derivatives showed antiproliferative activity against MCF-7 and MDA-MB-231 cell lines. In particular, methyl ()-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-(5-(((6-methoxy-4-oxo-4-chromen-3-yl)methyl)amino)-5-oxopentanamido)propanoate showed the most potent antiproliferative activity with IC values of 1.83 and 1.90 μM, respectively, and it also exhibited certain selectivity between tumour cells and normal cells. Further mechanism exploration against MDA-MB-231 cells showed that it possibly induced G2/M phase arrest and apoptosis by generating intracellular ROS and activating DNA damage. In addition, it also inhibited MDA-MB-231 cells metastasis, invasion and adhesion. Overall, methyl ()-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-(5-(((6-methoxy-4-oxo-4-chromen-3-yl)methyl)amino)-5-oxopentanamido)propanoate showed potent antitumor activities and relatively low side effects, and deserved further investigation.
Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Chromones; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Female; Humans; Mechlorethamine; Molecular Structure; Structure-Activity Relationship
PubMed: 34957906
DOI: 10.1080/14756366.2021.2018685 -
Signal Transduction and Targeted Therapy Jan 2021Nitrogen mustard (NM) causes severe vesicating skin injury, which lacks effective targeted therapies. The major limitation is that the specific mechanism of NM-induced...
Nitrogen mustard (NM) causes severe vesicating skin injury, which lacks effective targeted therapies. The major limitation is that the specific mechanism of NM-induced skin injury is not well understood. Recently, autophagy has been found to play important roles in physical and chemical exposure-caused cutaneous injuries. However, whether autophagy contributes to NM-induced dermal toxicity is unclear. Herein, we initially confirmed that NM dose-dependently caused cell death and induced autophagy in keratinocytes. Suppression of autophagy by 3-methyladenine, chloroquine, and bafilomycin A1 or ATG5 siRNA attenuated NM-induced keratinocyte cell death. Furthermore, NM increased transient receptor potential vanilloid 1 (TRPV1) expression, intracellular Ca content, and the activities of Ca/calmodulin-dependent kinase kinase β (CaMKKβ), AMP-activated protein kinase (AMPK), unc-51-like kinase 1 (ULK1), and mammalian target of rapamycin (mTOR). NM-induced autophagy in keratinocytes was abolished by treatment with inhibitors of TRPV1 (capsazepine), CaMKKβ (STO-609), AMPK (compound C), and ULK1 (SBI-0206965) as well as TRPV1, CaMKKβ, and AMPK siRNA transfection. In addition, an mTOR inhibitor (rapamycin) had no significant effect on NM-stimulated autophagy or cell death of keratinocytes. Finally, the results of the in vivo experiment in NM-treated skin tissues were consistent with the findings of the in vitro experiment. In conclusion, NM-caused dermal toxicity by overactivating autophagy partially through the activation of TRPV1-Ca-CaMKKβ-AMPK-ULK1 signaling pathway. These results suggest that blocking TRPV1-dependent autophagy could be a potential treatment strategy for NM-caused cutaneous injury.
Topics: AMP-Activated Protein Kinase Kinases; Adenine; Animals; Autophagy; Autophagy-Related Protein 5; Autophagy-Related Protein-1 Homolog; Blister; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Cell Death; Chloroquine; Humans; Keratinocytes; Macrolides; Mechlorethamine; Mice; RNA, Small Interfering; Sirolimus; Skin; Skin Diseases; TOR Serine-Threonine Kinases; TRPV Cation Channels
PubMed: 33487631
DOI: 10.1038/s41392-020-00389-z -
The Journal of Small Animal Practice Jul 2019To compare the progression-free survival of dogs with high-grade T-cell lymphoma treated with either a cyclophosphamide, doxorubicin, vincristine and prednisone-based or...
OBJECTIVES
To compare the progression-free survival of dogs with high-grade T-cell lymphoma treated with either a cyclophosphamide, doxorubicin, vincristine and prednisone-based or a modified mechlorethamine, vincristine, prednisone and procarbazine chemotherapy protocol.
MATERIALS AND METHODS
In this retrospective study, cases were selected based on histologic or cytologic diagnosis of lymphoma, T-cell phenotype, hypercalcaemia, or both, and no previous chemotherapy for lymphoma. Treatment was not randomly allocated.
RESULTS
Seventy-three dogs were included in this study: 50 in the cyclophosphamide, doxorubicin, vincristine and prednisone group and 23 in the mechlorethamine, vincristine, prednisone and procarbazine group. The median progression-free survival was 133 days for dogs in the cyclophosphamide, doxorubicin, vincristine and prednisone group and 97 days for dogs in the mechlorethamine, vincristine, prednisone and procarbazine group. When golden retrievers (n = 16) were evaluated -separately, progression-free survival was longer in the cyclophosphamide, doxorubicin, vincristine and prednisone versus mechlorethamine, vincristine, prednisone and procarbazine treatment group (median PFS 154 days versus 70.5 days, respectively).
CLINICAL SIGNIFICANCE
The progression-free survival time for dogs with multi-centric T-cell lymphoma treated with a modified mechlorethamine, vincristine, prednisone and procarbazine protocol was similar to that of dogs treated with cyclophosphamide, doxorubicin, vincristine and prednisone. Further studies, including those evaluating golden retrievers separately, are needed to confirm these findings.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cyclophosphamide; Dog Diseases; Dogs; Doxorubicin; Hypercalcemia; Lymphoma; Prednisone; Retrospective Studies; T-Lymphocytes; Vincristine
PubMed: 30790291
DOI: 10.1111/jsap.12986 -
Inhalation Toxicology Mar 2020Sulfur mustards are toxic agents used as a chemical warfare in the twentieth century. Exposure to nitrogen mustards (NM), their more water-soluble analogs, is...
Sulfur mustards are toxic agents used as a chemical warfare in the twentieth century. Exposure to nitrogen mustards (NM), their more water-soluble analogs, is associated with respiratory, dermatological, neurological, and systemic symptoms whose severity depends on dose and length of contact. Long-term effects of acute inhalation have been related to the development of chronic lung injury and pulmonary fibrosis whose precise mechanisms and potential antidotes are yet to be discovered. We have developed a model of NM-induced pulmonary fibrosis by intratracheally instilling mechlorethamine hydrochloride into C57Bl/6J male mice. Following mechlorethamine exposure, strong early and milder late inflammatory responses were observed. Initially, the number of white blood cells and levels of protein and pro-inflammatory cytokines in the bronchoalveolar lavage fluid (BALF) increased, followed by increases in the number of macrophages and the levels of transforming growth factor-β (TGF-β), a pro-fibrotic mediator. Analysis of lung homogenates revealed increased phosphorylation of pro-fibrotic biomarkers, serine/threonine-selective protein kinases (p-ERK), and heat shock protein 90 (P-HSP90) at 10 and 30 days after exposure. Total collagen expression and deposition of extracellular matrix proteins also increased. Lung function measurements demonstrated the presence of both obstructive and restrictive disease in agreement with evidence of increased lower airway peribronchial collagen deposition and parenchymal fibrosis. We conclude that the mouse represents a useful model of NM-induced acute lung injury and chronic pulmonary fibrosis, the latter driven by the overexpression of TGF-β, p-ERK, and P-HSP90. This model may prove useful in the pre-clinical development of antidotes and other countermeasures.
Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Chemical Warfare Agents; Chronic Disease; Cytokines; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; HSP90 Heat-Shock Proteins; Leukocyte Count; Lung; Macrophages; Male; Mechlorethamine; Mice, Inbred C57BL; Pulmonary Fibrosis; Transforming Growth Factor beta
PubMed: 32362214
DOI: 10.1080/08958378.2020.1757791 -
Acta Dermato-venereologica Jun 2022Chlormethine is a bifunctional cytotoxic alkylating agent that binds to DNA, resulting in cell death (apoptosis). Chlormethine (also known as mechlorethamine) gel (CL...
Chlormethine is a bifunctional cytotoxic alkylating agent that binds to DNA, resulting in cell death (apoptosis). Chlormethine (also known as mechlorethamine) gel (CL gel) was approved in the European Union in 2017 and was first used in 2019. The aim of the study is to examine evidence regarding the efficacy and safety of chlormethine gel in everyday clinical experience from a cutaneous lymphoma centre. Twenty-three patients with stage IA-IIB mycosis fungoides received chlormethine gel between September 2020 and May 2021. All patients started by applying the gel daily and were monitored every month. At 1, 3, 6 and 9 months, 0%, 43.47%, 56.52% and 65.22% of patients, respectively, achieved an overall response. Five out of 23 patients (21.73%) achieved near complete response at a mean time of 6 months. Chlormethine gel was given as monotherapy in 12 patients (52.17%), and in addition to systemic treatments (methotrexate and peginterferon alpha-2a) in 11 patients (47.82%). Adverse events (AE) were recorded in 43.47% of patients, but only 3 discontinued treatment, due to dermatitis. Scale down of the treatment to application 3-times per week led to better patient compliance. This study shows that chlormethine gel is effective and safe in patients with mycosis fungoides with different types of skin lesions.
Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Humans; Mechlorethamine; Mycosis Fungoides; Skin Diseases; Skin Neoplasms
PubMed: 35199177
DOI: 10.2340/actadv.v102.1095 -
The Journal of Pharmacology and... Jan 2024The chemical warfare agent sulfur mustard and its structural analog nitrogen mustard (NM) cause severe vesicating skin injuries. The pathologic mechanisms for the skin...
The chemical warfare agent sulfur mustard and its structural analog nitrogen mustard (NM) cause severe vesicating skin injuries. The pathologic mechanisms for the skin injury following mustard exposure are poorly understood; therefore, no effective countermeasure is available. Previous reports demonstrated the protective activity of carvedilol, a US Food and Drug Administration (FDA)-approved -blocker, against UV radiation-induced skin damage. Thus, the current study evaluated the effects of carvedilol on NM-induced skin injuries in vitro and in vivo. In the murine epidermal cell line JB6 Cl 41-5a, -blockers with different receptor subtype selectivity were examined. Carvedilol and both of its enantiomers, R- and S-carvedilol, were the only tested ligands statistically reducing NM-induced cytotoxicity. Carvedilol also reduced NM-induced apoptosis and p53 expression. In SKH-1 mice, NM increased epidermal thickness, damaged skin architecture, and induced nuclear factor B (NF-B)-related proinflammatory genes as assessed by RT Profiler PCR (polymerase chain reaction) Arrays. To model chemical warfare scenario, 30 minutes after exposure to NM, 10 M carvedilol was applied topically. Twenty-four hours after NM exposure, carvedilol attenuated NM-induced epidermal thickening, Ki-67 expression, a marker of cellular proliferation, and multiple proinflammatory genes. Supporting the in vitro data, the non--blocking R-enantiomer of carvedilol had similar effects as racemic carvedilol, and there was no difference between carvedilol and R-carvedilol in the PCR array data, suggesting that the skin protective effects are independent of the -adrenergic receptors. These data suggest that the -blocker carvedilol and its enantiomers can be repurposed as countermeasures against mustard-induced skin injuries. SIGNIFICANCE STATEMENT: The chemical warfare agent sulfur mustard and its structural analog nitrogen mustard cause severe vesicating skin injuries for which no effective countermeasure is available. This study evaluated the effects of US Food and Drug Administration (FDA)-approved -blocker carvedilol on nitrogen mustard-induced skin injuries to repurpose this cardiovascular drug as a medical countermeasure.
Topics: Animals; Mice; Mechlorethamine; Carvedilol; Chemical Warfare Agents; Mustard Gas; Skin; Adrenergic beta-Antagonists
PubMed: 37827703
DOI: 10.1124/jpet.123.001663