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Skin Therapy Letter Mar 2023Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL), representing almost 50% of all lymphomas arising in the skin. There is an unmet need...
Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL), representing almost 50% of all lymphomas arising in the skin. There is an unmet need in the treatment of MF in Canada, as current available therapies for early-stage MF are limited, without topical agents previously indicated. Chlormethine gel is a topical antineoplastic agent with phase II clinical trial and real-world data demonstrating safety and efficacy as a treatment option for adults with MF. Skin-related side effects such as dermatitis can be managed through appropriate strategies. The use of chlormethine gel can be considered for patients with stage IA and IB MF-CTCL as it provides an easily administered, skin-directed treatment option that fills an unmet need in Canada.
Topics: Adult; Humans; Mechlorethamine; Skin Neoplasms; Mycosis Fungoides; Lymphoma, T-Cell, Cutaneous; Skin
PubMed: 37054720
DOI: No ID Found -
Evidence-based Complementary and... 2019The aim of the study is to explore the protective effect of new gelatin (NG, Xin'ejiao in China) on hematopoietic injury caused by chemotherapy. Zebrafish, at 48 hours...
The aim of the study is to explore the protective effect of new gelatin (NG, Xin'ejiao in China) on hematopoietic injury caused by chemotherapy. Zebrafish, at 48 hours post fertilization (hpf), was treated with different chemotherapeutic drugs to establish the zebrafish hematopoietic damage model with reduced thrombocytes and erythrocytes. The protecting effects of NG on the thrombocytes and erythrocytes were observed, respectively, on zebrafish models. Then, the RT-PCR method was used to detect the change of mRNA level of the hematopoiesis-related cytokines , , , , and genes. The results showed that 50 g·mL and 100 g·mL NG rescued and increased the thrombocytes numbers induced by vinorelbine (NVB) and chloramphenicol (CHL) and the erythrocytes numbers induced by methotrexate (MTX), doxorubicin (ADM), and mechlorethamine hydrochloride (MH) in zebrafish models. Meanwhile, the mRNA expression of , , and genes in the NG treatment group was raised compared with the MTX treatment group. Also, the mRNA expression of and in the NG treatment group was reduced compared with the MTX treatment group. In consequence, traditional Chinese medicine NG showed a certain degree protective effect on hematopoiesis injury induced by chemotherapy in this study, which may depend on the promotion of erythrocytes proliferation and the regulation of the hematopoietic genes level.
PubMed: 31531120
DOI: 10.1155/2019/8918943 -
JID Innovations : Skin Science From... Jan 2022Mycosis fungoides (MF) is a type of cutaneous T-cell lymphoma. Chlormethine (CL) is recommended as first-line therapy for MF, with a major purpose to kill tumor cells...
Mycosis fungoides (MF) is a type of cutaneous T-cell lymphoma. Chlormethine (CL) is recommended as first-line therapy for MF, with a major purpose to kill tumor cells through DNA alkylation. To study the extent of treatment susceptibility and tumor specificity, we investigated the gene expression of different DNA repair pathways, DNA double-stranded breaks, and tumor cell proliferation of clonal TCR Vβ+ tumor cell populations in cutaneous T-cell lymphoma skin cells on direct exposure to CL. Healthy human T cells were less susceptible to CL exposure than two T-lymphoma cell lines, resulting in higher proportions of viable cells. Interestingly, in T cells from MF lesions, we observed a downregulation of several important DNA repair pathways, even complete silencing of , , and involved in homologous recombination repair. In the presence of CL, the double-stranded DNA breaks in malignant MF skin T cells increased significantly as well as the expression of the apoptotic gene . These data point toward an important effect of targeting CL on MF skin tumor T cells, which support CL use as an early cutaneous lymphoma treatment and can be of synergistic use, especially beneficial in the setting of combination skin-directed therapies for cutaneous T-cell lymphoma.
PubMed: 34977846
DOI: 10.1016/j.xjidi.2021.100069 -
Frontiers in Oncology 2023Topical chlormethine (CL) is recommended as a first-line treatment for early-stage mycosis fungoides (MF) and in 2017, the European Medicines Agency approved the CL gel...
BACKGROUND
Topical chlormethine (CL) is recommended as a first-line treatment for early-stage mycosis fungoides (MF) and in 2017, the European Medicines Agency approved the CL gel formulation to treat adult patients. More recently, to increase patient compliance and adherence, clinicians have developed flexible protocols that allow the concomitant use of CL gel with topical corticosteroids in daily practice regimens. Therefore, sharing real-life data on CL gel use and side effects management may help improve the use of this agent.
OBJECTIVES
To expand knowledge about the actual use of CL gel in patients with MF, the present study assessed the improvement of MF skin lesions after CL gel treatment and provided information on the management of cutaneous adverse events (AEs) in a real-life setting.
METHODS
This was an Italian retrospective study conducted among six dermatology referral centers. Patients ≥18 years affected by MF and in treatment with CL gel (160 µ/g), alone or in combination according to routine clinical practice, between December 2019 and December 2021 were considered. The study's primary aim was to evaluate the effectiveness of CL gel in terms of overall response rate (ORR) after 3 months of treatment.
RESULTS
A total of 79 patients (61% male) with different stages of MF (84% early stage) were included. CL gel was prescribed mainly in association with topical corticosteroids (66% of patients). ORR after 3 months of treatment was 42%, with no differences between early- and advanced-stage MF. Response rates improved over time up to 97% after 18 months of treatment. Overall, 66 AEs were reported in 67% of patients; most were hyperpigmentation (45%) and irritant contact dermatitis (37%). Six AEs led to treatment discontinuation, and five out of six (83%) patients who reported these events resumed treatment after interruption. No AEs were classified as severe.
CONCLUSIONS
Our observations support the use of CL gel in patients with early- and advanced-stage MF, making it a valuable treatment option.
PubMed: 38239642
DOI: 10.3389/fonc.2023.1298296 -
International Journal of Molecular... Jan 2024Vesicating chemicals like sulfur mustard (SM) or nitrogen mustard (NM) can cause devastating damage to the eyes, skin, and lungs. Eyes, being the most sensitive, have...
Vesicating chemicals like sulfur mustard (SM) or nitrogen mustard (NM) can cause devastating damage to the eyes, skin, and lungs. Eyes, being the most sensitive, have complicated pathologies that can manifest immediately after exposure (acute) and last for years (chronic). No FDA-approved drug is available to be used as medical counter measures (MCMs) against such injuries. Understanding the pathological mechanisms in acute and chronic response of the eye is essential for developing effective MCMs. Here, we report the clinical and histopathological characterization of a mouse model of NM-induced ocular surface injury (entire surface) developed by treating the eye with 2% (/) NM solution for 5 min. Unlike the existing models of specific injury, our model showed severe ocular inflammation, including the eyelids, structural deformity of the corneal epithelium and stroma, and diminished visual and retinal functions. We also observed alterations of the inflammatory markers and their expression at different phases of the injury, along with an activation of acidic sphingomyelinase (aSMase), causing an increase in bioactive sphingolipid ceramide and a reduction in sphingomyelin levels. This novel ocular surface mouse model recapitulated the injuries reported in human, rabbit, and murine SM or NM injury models. NM exposure of the entire ocular surface in mice, which is similar to accidental or deliberate exposure in humans, showed severe ocular inflammation and caused irreversible alterations to the corneal structure and significant vision loss. It also showed an intricate interplay between inflammatory markers over the injury period and alteration in sphingolipid homeostasis in the early acute phase.
Topics: Humans; Animals; Mice; Rabbits; Mechlorethamine; Eye Injuries; Eyelids; Disease Models, Animal; Mustard Gas; Sphingolipids; Inflammation
PubMed: 38255815
DOI: 10.3390/ijms25020742 -
The Journal of Pharmacology and... Jan 2024Nitrogen mustard (NM) is a known surrogate of sulfur mustard, a chemical-warfare agent that causes a wide range of ocular symptoms, from a permanent reduction in visual...
Nitrogen mustard (NM) is a known surrogate of sulfur mustard, a chemical-warfare agent that causes a wide range of ocular symptoms, from a permanent reduction in visual acuity to blindness upon exposure. Although it has been proposed that the two blistering agents have a similar mechanism of toxicity, the mode of NM-induced cell death in ocular tissue has not been fully explored. Therefore, we hypothesized that direct ocular exposure to NM in mice leads to retinal tissue injury through chronic activation of the unfolded protein response (UPR) PERK arm in corneal cells and VEGF secretion, eventually causing cell death. We topically applied NM directly to mice to analyze ocular and retinal tissues at 2 weeks postexposure. A dramatic decline in retinal function, measured by scotopic and photopic electroretinogram responses, was detected in the mice. This decline was associated with enhanced TUNEL staining in both corneal and retinal tissues. In addition, exposure of corneal cells to NM revealed 228 differentially and exclusively expressed proteins primarily associated with the UPR, ferroptosis, and necroptosis. Moreover, these cells exhibited activation of the UPR PERK arm and an increase in VEGF secretion. Enhancement of VEGF staining was later observed in the corneas of the exposed mice. Therefore, our data indicated that the mechanism of NM-induced ocular toxicity should be carefully examined and that future research should identify a signaling molecule transmitted via a prodeath pathway from the cornea to the retina. SIGNIFICANCE STATEMENT: This study demonstrated that NM topical exposure in mice results in dramatic decline in retinal function associated with enhanced TUNEL staining in both corneal and retinal tissues. We also found that the NM treatment of corneal cells resulted in 228 differentially and exclusively expressed proteins primarily associated with ferroptosis. Moreover, these cells manifest the UPR PERK activation and an increase in VEGF secretion. The latter was also found in the corneas of the cexposed mice.
Topics: Animals; Mice; Mechlorethamine; Vascular Endothelial Growth Factor A; Toxic Optic Neuropathy; Cornea; Chemical Warfare Agents; Mustard Gas; Unfolded Protein Response
PubMed: 37914413
DOI: 10.1124/jpet.123.001814 -
Experimental Eye Research Jan 2020The purpose of the current work was to utilize a three dimensional (3D) corneal epithelial tissue model to study dry eye disease and oxidative stress-related corneal...
The purpose of the current work was to utilize a three dimensional (3D) corneal epithelial tissue model to study dry eye disease and oxidative stress-related corneal epithelial injuries for the advancement of ocular therapeutics. Air-liquid interface cultures of normal human corneal epithelial cells were used to produce 3D corneal epithelial tissues appropriate for physiologically relevant exposure to environmental factors. Oxidative stress was generated by exposing the tissues to non-toxic doses of ultraviolet radiation (UV), hydrogen peroxide, vesicating agent nitrogen mustard, or desiccating conditions that stimulated morphological, cellular, and molecular changes relevant to dry eye disease. Corneal specific responses, including barrier function, tissue viability, reactive oxygen species (ROS) accumulation, lipid peroxidation, cytokine release, histology, and gene expression were evaluated. 3D corneal epithelial tissue model structurally and functionally reproduced key features of molecular responses of various types of oxidative stress-induced ocular damage. The most pronounced effects for different treatments were: UV irradiation - intracellular ROS accumulation; hydrogen peroxide exposure - barrier impairment and IL-8 release; nitrogen mustard exposure - lipid peroxidation and IL-8 release; desiccating conditions - tissue thinning, a decline in mucin expression, increased lipid peroxidation and IL-8 release. Utilizing a PCR gene array, we compared the effects of corneal epithelial damage on the expression of 84 oxidative stress-responsive genes and found specific molecular responses for each type of damage. The topical application of lubricant eye drops improved tissue morphology while decreasing lipid peroxidation and IL-8 release from tissues incubated at desiccating conditions. This model is anticipated to be a valuable tool to study molecular mechanisms of corneal epithelial damage and aid in the development of therapies against dry eye disease, oxidative stress- and vesicant-induced ocular injuries.
Topics: Alkylating Agents; Cell Survival; Corneal Injuries; Cytokines; Dry Eye Syndromes; Electric Impedance; Epithelium, Corneal; Fluorescent Antibody Technique, Indirect; Humans; Hydrogen Peroxide; Imaging, Three-Dimensional; Lipid Peroxidation; Mechlorethamine; Models, Biological; Oxidants; Oxidative Stress; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Ultraviolet Rays
PubMed: 31705899
DOI: 10.1016/j.exer.2019.107867 -
Dermatology (Basel, Switzerland) 2022Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma. Patients can be treated using chlormethine gel, a skin-directed therapy developed and... (Randomized Controlled Trial)
Randomized Controlled Trial
Post hoc Analysis of a Randomized, Controlled, Phase 2 Study to Assess Response Rates with Chlormethine/Mechlorethamine Gel in Patients with Stage IA-IIA Mycosis Fungoides.
BACKGROUND
Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma. Patients can be treated using chlormethine gel, a skin-directed therapy developed and approved for MF. In the randomized, controlled 201 trial, chlormethine gel was found to be noninferior to equal-strength chlormethine ointment. However, there remains a need to gain more insight into outcome measures after treatment.
OBJECTIVE
The aim of this study was to further investigate the potential of chlormethine gel treatment through a novel post hoc analysis of the 201 trial data (NCT00168064).
METHODS
Patients were randomized to chlormethine gel or ointment; response assessments included Composite Assessment of Index Lesion Severity (CAILS) and total body surface area (BSA). In this post hoc analysis, additional subgroup response analyses were performed for stage IA/IB-IIA MF. Very good partial response (75 to <100% improvement) was included as an additional response category. Time to response and overall response trends were determined. Finally, multivariate time-to-event analyses were performed to determine whether associations were observed between treatment frequency, response, and adverse events.
RESULTS
Response rates were significantly higher for patients with stage IA MF for CAILS (intent-to-treat [p = 0.0014] and efficacy-evaluable [EE; p = 0.0036] populations) and BSA (EE population [p = 0.0488]) treated with gel versus ointment. Time to first CAILS response and response trends were better for all-stage gel-treated patients overall. No association was seen between treatment frequency and response or occurrence of adverse events at the following visit. An association was observed between the occurrence of contact dermatitis and improved clinical response at the next visit (p = 0.0001).
CONCLUSION
This post hoc analysis shows that treatment with chlormethine gel may result in higher and faster response rates compared with chlormethine ointment, which confirms and expands results reported in the original analysis. The incidence of contact dermatitis may potentially be a prognostic indicator for clinical response; this needs to be confirmed in a larger population.
Topics: Antineoplastic Agents, Alkylating; Humans; Lymphoma, T-Cell, Cutaneous; Mechlorethamine; Mycosis Fungoides; Neoplasm Staging; Skin Neoplasms
PubMed: 34091453
DOI: 10.1159/000516138 -
International Journal of Trichology 2020Lichen Planopilaris (LPP) is a lymphocyte-mediated scarring alopecia that frequently is treatment resistance to both topical and systemic therapies.
BACKGROUND
Lichen Planopilaris (LPP) is a lymphocyte-mediated scarring alopecia that frequently is treatment resistance to both topical and systemic therapies.
AIMS AND OBJECTIVES
The object of this pilot study was to assess the effectiveness of topical mechlorethamine 0.016% gel (Valchlor®) in decreasing disease activity in LPP and the related clinical variant frontal fibrosing alopecia (FAA).
METHODS
Twelve patients with biopsy-proven LPP/FAA who failed prior topical or systemic therapy with active disease were included. Participants applied mechlorethamine 0.016% gel to involved areas daily for 24 weeks. Outcome measures included LPP Activity Index (LPPAI) score, Physician Global Assessment (PGA) score, Dermatology Quality of Life Index (DQLI) score, and phototrichograms assessing follicular counts before and after six months of therapy.
RESULTS
LPP Activity Index (LPPAI) before and after treatment was significantly different (5.0 before treatment, 2.0 after treatment; p value=0.006). Mean follicular density and follicular units were unchanged during the treatment period.
CONCLUSION
Treatment with mechlorethamine 0.016% gel for 24 weeks resulted in statistically significant improvement of LLP/FFA with no change in phototrichogram parameters. Treatment duration was limited by high rate of contact dermatitis. Further investigation to optimize dosing frequency and to assess the role of combination topical therapy is needed.
PubMed: 33531744
DOI: 10.4103/ijt.ijt_16_20 -
Dermatology and Therapy Nov 2022The DNA-alkylating agent chlormethine (CL, or mechlorethamine) is approved in several countries worldwide as a 0.016% w/w topical CL gel formulation, to treat mycosis...
INTRODUCTION
The DNA-alkylating agent chlormethine (CL, or mechlorethamine) is approved in several countries worldwide as a 0.016% w/w topical CL gel formulation, to treat mycosis fungoides cutaneous T-cell lymphoma, with a positive benefit/risk ratio.
METHODS
Release profiles of CL from the gel and a compounded ointment-based 0.016% CL formulation were compared via in vitro release testing (IVRT), utilizing static diffusion cells, a pseudo-infinite dose, and polytetrafluoroethylene membranes, over 5 h. The percutaneous absorption profile of CL gel in ex vivo human skin was also examined, using in vitro permeation testing (IVPT) with flow-through diffusion cells, dermatomed skin (epidermis plus dermis) and epidermal membranes, a finite dose, over 24 h.
RESULTS
In IVRT experiments, the mean ± SD CL release rate was significantly higher for the gel versus the ointment (5.70 ± 0.73 versus 2.38 ± 1.03 μg/cm/√h); the formulations were inequivalent per the US Food and Drug Administration scale-up and postapproval changes for nonsterile semisolid dosage forms (FDA SUPAC-SS) criteria. Mean IVPT cumulative CL (gel) permeating through epidermal membrane was higher than for dermatomed skin (4.6% versus 2.5% of applied dose). Mean residual CL on the epidermal membrane surface was 1.3% of the applied dose.
CONCLUSIONS
CL gel (0.016%) and ointment were inequivalent, with an optimized release profile, suggesting minimal passage of CL gel through human epidermal tissue to the dermis.
PubMed: 36229764
DOI: 10.1007/s13555-022-00813-y