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Current Opinion in Pharmacology Aug 2018DNA crosslinking agents make up a broad class of chemotherapy agents that target rapidly dividing cancer cells by disrupting DNA synthesis. These drugs differ widely in... (Review)
Review
DNA crosslinking agents make up a broad class of chemotherapy agents that target rapidly dividing cancer cells by disrupting DNA synthesis. These drugs differ widely in both chemical structure and biological effect. In cells, crosslinking agents can form multiple types of DNA lesions with varying efficiencies. Inter-strand crosslinks (ICLs) are considered to be the most cytotoxic lesion, creating a covalent roadblock to replication and transcription. Despite over 50 years in the clinic, the use of crosslinking agents that specialize in the formation of ICLs remains limited, largely due to high toxicity in patients. Current ICL-based therapeutics have focused on late-stage and drug-resistant tumors, or localized treatments that limit exposure. In this article, we review the development of clinical crosslinking agents, our understanding of how cells respond to different lesions, and the potential to improve ICL-based chemotherapeutics in the future.
Topics: Antineoplastic Agents; Cross-Linking Reagents; DNA; Furocoumarins; Humans; Mechlorethamine; Mitomycins; Neoplasms
PubMed: 29679802
DOI: 10.1016/j.coph.2018.04.004 -
Journal of the American Academy of... Dec 1991Topical mechlorethamine hydrochloride is commonly used in the treatment of mycosis fungoides and has been formulated in both aqueous and ointment vehicles. Two concerns... (Clinical Trial)
Clinical Trial
Topical mechlorethamine hydrochloride is commonly used in the treatment of mycosis fungoides and has been formulated in both aqueous and ointment vehicles. Two concerns regarding the topical application of mechlorethamine hydrochloride relate to the adequacy of skin coverage that can be attained by the patient and the extent to which others in the patient's household might be exposed to the drug. In this study six patients applied either aqueous or ointment vehicles containing a fluorescent dye. Subsequent examination of the skin under a Wood's lamp revealed a significant percentage of body surface area to be missed during application; several areas were noted to be missed most commonly. These observations have led to specific alterations in instructions given to patients regarding drug application. Examination of the surrounding environment showed minimal evidence of contamination.
Topics: Administration, Cutaneous; Adult; Aged; Arm; Back; Body Surface Area; Clothing; Environmental Exposure; Fluorescent Dyes; Foot; Hand; Household Articles; Humans; Leg; Mechlorethamine; Middle Aged; Mycosis Fungoides; Ointments; Skin Neoplasms; Solutions
PubMed: 1844356
DOI: 10.1016/0190-9622(91)70307-n -
Archives of Dermatology Jul 1980Solutions of mechlorethamine hydrochloride used to treat patients with mycosis fungoides and psoriasis are stable for many months, especially when they are refrigerated....
Solutions of mechlorethamine hydrochloride used to treat patients with mycosis fungoides and psoriasis are stable for many months, especially when they are refrigerated. This fact should make the use of this treatment more convenient. On the other hand, the risk of cancer induction from such use should be appreciated.
Topics: Animals; Cell Division; Drug Stability; Drug Storage; Humans; In Vitro Techniques; Mechlorethamine; Ointments; Psoriasis; Solutions; Temperature
PubMed: 7396542
DOI: No ID Found -
Chemphyschem : a European Journal of... Dec 2017The reactivity of nitrogen mustard mechlorethamine (mec) with purine bases towards formation of mono- (G-mec and A-mec) and dialkylated (AA-mec, GG-mec and AG-mec)...
The reactivity of nitrogen mustard mechlorethamine (mec) with purine bases towards formation of mono- (G-mec and A-mec) and dialkylated (AA-mec, GG-mec and AG-mec) adducts has been studied using density functional theory (DFT). To gain a complete overview of DNA-alkylation processes, direct chloride substitution and formation through activated aziridinium species were considered as possible reaction paths for adduct formation. Our results confirm that DNA alkylation by mec occurs via aziridine intermediates instead of direct substitution. Consideration of explicit water molecules in conjunction with polarizable continuum model (PCM) was shown as an adequate computational method for a proper representation of the system. Moreover, Runge-Kutta numerical kinetic simulations including the possible bisadducts have been performed. These simulations predicted a product ratio of 83:17 of GG-mec and AG-mec diadducts, respectively.
Topics: Alkylation; DNA; Mechlorethamine; Purines; Quantum Theory
PubMed: 28981213
DOI: 10.1002/cphc.201700937 -
Journal of Cellular and Molecular... Apr 2022Nitrogen mustard (NM) is an alkylating vesicant that causes severe pulmonary injury. Currently, there are no effective means to counteract vesicant-induced lung injury....
Nitrogen mustard (NM) is an alkylating vesicant that causes severe pulmonary injury. Currently, there are no effective means to counteract vesicant-induced lung injury. MG53 is a vital component of cell membrane repair and lung protection. Here, we show that mice with ablation of MG53 are more susceptible to NM-induced lung injury than the wild-type mice. Treatment of wild-type mice with exogenous recombinant human MG53 (rhMG53) protein ameliorates NM-induced lung injury by restoring arterial blood oxygen level, by improving dynamic lung compliance and by reducing airway resistance. Exposure of lung epithelial and endothelial cells to NM leads to intracellular oxidative stress that compromises the intrinsic cell membrane repair function of MG53. Exogenous rhMG53 protein applied to the culture medium protects lung epithelial and endothelial cells from NM-induced membrane injury and oxidative stress, and enhances survival of the cells. Additionally, we show that loss of MG53 leads to increased vulnerability of macrophages to vesicant-induced cell death. Overall, these findings support the therapeutic potential of rhMG53 to counteract vesicant-induced lung injury.
Topics: Acute Lung Injury; Animals; Endothelial Cells; Lung; Mechlorethamine; Membrane Proteins; Mice; Recombinant Proteins
PubMed: 35199443
DOI: 10.1111/jcmm.16917 -
Journal of the European Academy of... Sep 2023Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, is characterized by proliferation of malignant skin-tropic T cells. Progression from... (Review)
Review
Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, is characterized by proliferation of malignant skin-tropic T cells. Progression from early-stage disease (skin patches and/or plaques) to more advanced stages (cutaneous tumours, erythroderma or extracutaneous involvement) occurs slowly and can be discontinuous. Prognosis is poor for the ~25% of patients who progress to advanced disease. Patients at any stage of MF may experience reduced health-related quality of life (QoL) via a spectrum of physically and psychologically debilitating symptoms that can impact many aspects of daily life. Allogeneic stem-cell transplantation is a curative treatment option for some patients with advanced disease, but otherwise there is currently no cure for MF; patients are often refractory to several treatments and require lifelong management. The goals of therapy are symptom control, prevention of disease progression, avoidance of treatment-related toxicity and maintenance/improvement of QoL. Although treatment regimens exist it can be difficult to know how to prioritize them, hence therapies are tailored according to patient needs and drug availabilities, following clinical recommendations. International consensus guidelines recommend skin-directed therapies (SDTs) as first-line treatment for early-stage disease, and SDTs combined with systemic therapy for advanced stages. Chlormethine (CL), also known as mechlorethamine, chlorethazine, mustine, HN2, caryolysine and embichin, is a synthetic deoxyribonucleic acid-alkylating agent that was used as a chemical weapon (mustard gas) during the First World War. Subsequent investigation revealed that survivors of mustard gas exposure had lymphocytopenia, and that CL could inhibit rapidly proliferating malignant T cells. CL has since been developed as a topical treatment for MF and prescribed as such for over 70 years. This review aims to summarize the current knowledge regarding the mechanism of action of CL in the cutaneous micro-environment, in the specific context of MF treatment.
Topics: Humans; Mechlorethamine; Quality of Life; Mustard Gas; Mycosis Fungoides; Skin Neoplasms; Tumor Microenvironment
PubMed: 37262305
DOI: 10.1111/jdv.19237 -
American Journal of Clinical Dermatology May 2021Chlormethine/mechlorethamine gel is a skin-directed therapy for patients with mycosis fungoides cutaneous T-cell lymphoma. Currently, real-world data on chlormethine gel... (Observational Study)
Observational Study
The PROVe Study: US Real-World Experience with Chlormethine/Mechlorethamine Gel in Combination with Other Therapies for Patients with Mycosis Fungoides Cutaneous T-Cell Lymphoma.
BACKGROUND
Chlormethine/mechlorethamine gel is a skin-directed therapy for patients with mycosis fungoides cutaneous T-cell lymphoma. Currently, real-world data on chlormethine gel are lacking.
OBJECTIVE
Our objective was to analyze the effect of chlormethine gel in combination with other therapies on efficacy, safety, and health-related quality of life in a real-world setting.
METHODS
This prospective, observational study enrolled adult patients actively using chlormethine gel. Patients were monitored for up to 2 years during standard-of-care clinic visits. No specific visit schedules or clinical assessments, with the exception of patient-completed questionnaires, were mandated because of the expected variability in practice patterns. The primary efficacy endpoint was the proportion of patients with stage IA-IB disease receiving chlormethine + topical corticosteroids + other with ≥ 50% decrease in body surface area from baseline to 12 months. Response was assessed at each visit using by-time analysis, which investigates the trend to treatment response and allows assessment of response over time. Health-related quality of life was assessed with the Skindex-29 questionnaire.
RESULTS
In total, 298 patients were monitored. At 12 months post-treatment initiation, 44.4% (chlormethine + topical corticosteroids + other) and 45.1% (patients receiving chlormethine + other treatment) of efficacy-evaluable patients were responders. By-time analysis demonstrated that peak response occurred (chlormethine + other; 66.7%) at 18 months. There was a significant correlation between responder status and lower post-baseline Skindex-29 scores.
CONCLUSIONS
This real-world study confirmed that chlormethine gel is an important therapeutic option for patients with mycosis fungoides and contributes to reducing the severity of skin lesions and improving health-related quality of life.
Topics: Administration, Cutaneous; Administration, Oral; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Follow-Up Studies; Gels; Humans; Male; Mechlorethamine; Middle Aged; Mycosis Fungoides; Neoplasm Staging; Prospective Studies; Quality of Life; Severity of Illness Index; Skin Neoplasms; Treatment Outcome; United States
PubMed: 33656660
DOI: 10.1007/s40257-021-00591-x -
Current Medicinal Chemistry 2012DNA interstrand cross-linking (ICL) agents are an important group of cytotoxic drugs with the capability of binding covalently between two strands of DNA, thereby... (Review)
Review
DNA interstrand cross-linking (ICL) agents are an important group of cytotoxic drugs with the capability of binding covalently between two strands of DNA, thereby preventing vital processes such as replication or transcription in dividing cells. In anticancer therapy however, their potential is limited due to the resistance by various mechanisms. In order to develop highly effective antitumor drugs it is necessary to study both effective ICL formations and their subsequent repair mechanisms. This review presents an overview of development over the past decade and the use of both well-known and new DNA interstrand cross-linking agents. Their potential in applications especially as anticancer chemotherapeutics in the framework of current knowledge of repair mechanisms and development of combined chemotherapy is discussed.
Topics: Alkaloids; Anthraquinones; Antineoplastic Agents; Azepines; Aziridines; Coordination Complexes; Cross-Linking Reagents; DNA; DNA Repair; Humans; Mechlorethamine; Neoplasms
PubMed: 22335513
DOI: 10.2174/092986712803414295 -
Radiation Research Mar 1998Nitroarylmethyl quaternary ammonium nitrogen mustards are bioreductive drugs designed to release mechlorethamine, when reduced metabolically, via fragmentation of the...
Nitroarylmethyl quaternary ammonium nitrogen mustards are bioreductive drugs designed to release mechlorethamine, when reduced metabolically, via fragmentation of the initial nitro radical anion to a benzylic-type radical. This proposed mechanism (termed Type I) is analogous to the well-known reductive fragmentation of 2-nitrobenzyl halides. The lead nitroarylmethyl quaternary mustard SN 25246 (NSC 656581), which contains a 2-nitrobenzyl electron acceptor, was shown previously to release mechlorethamine in hypoxic cell cultures and to be a highly selective hypoxic cytotoxin. In the present work the mechanism of reductive release of mechlorethamine from nitroarylmethyl quaternary prodrugs was investigated by steady-state radiolysis with product analysis by high-performance liquid chromatography. SN 25246 releases mechlorethamine in high yield upon reduction, but several reducing equivalents are required (Type II mechanisms). Investigation of other nitroarylmethyl units identified two heterocyclic analogues, the 1-methyl-4-nitro-5-imidazolyl derivative SN 25341 and the 1-methyl-5-nitro-2-pyrrolyl derivative SN 26581, which have a reduction stoichiometry of about one reducing equivalent and which release mechlorethamine efficiently. The other products from reduction of SN 25341 are also consistent with Type I fragmentation, via intramolecular electron transfer, to give the 1-methyl-4-nitroimidazole-5-CH2. radical. The sensitivity of the 4-nitroimidazole and 5-nitropyrrole nitroarylmethyl quaternary mustards to Type I reductive fragmentation suggests that these electron acceptor units may be well suited to development of prodrugs which release tertiary amine effectors after metabolic or radiolytic reduction in hypoxic regions of tumors.
Topics: Antineoplastic Agents; Hypoxia; Mechlorethamine; Nitrogen Mustard Compounds; Oxidation-Reduction; Prodrugs; Radiochemistry; Structure-Activity Relationship
PubMed: 9496886
DOI: No ID Found -
Archives of Dermatology Apr 1982The use of topical mechlorethamine hydrochloride in the treatment of skin disease has been restricted because of the frequent development of contact dermatitis. A series...
The use of topical mechlorethamine hydrochloride in the treatment of skin disease has been restricted because of the frequent development of contact dermatitis. A series of 24 patients with mycosis fungoides in stages 1A (eight patients), 1B (15 patients), and 2 (one patient) were treated with ointment-based mechlorethamine, prepared by an anhydrous method. This preparation was therapeutically effective. Complete clearing occurred in 15 of 18 patients with active disease over evaluation periods of up to 27 months, and one patient had partial clearing. Two patients showed a partial relapse during their evaluation periods. The incidence of contact dermatitis was very low: 8% in individuals with a history of hypersensitivity to mechlorethamine and 0% in patients being exposed to the medication for the first time. This new preparation has been shown to be effective therapy for mycosis fungoides. Patient use is associated with minimal side effects.
Topics: Administration, Topical; Dermatitis, Contact; Humans; Mechlorethamine; Mycosis Fungoides; Ointment Bases; Recurrence
PubMed: 7065680
DOI: No ID Found