-
Canadian Medical Association Journal Aug 1985Most patients with early-stage Hodgkin's disease can now be cured by one of several therapeutic approaches. This review highlights the developments in the diagnosis and... (Review)
Review
Most patients with early-stage Hodgkin's disease can now be cured by one of several therapeutic approaches. This review highlights the developments in the diagnosis and treatment of the disease that have led to long-term survival rates greater than 90%. Past and present radio-therapy (RT) planning and treatment practices are discussed in the context of both clinical and pathological staging. The role of initial bimodal therapy (RT and chemotherapy [CT]) and the use of CT in patients who suffer relapse after initial treatment with RT alone are reviewed. On the basis of prognostic factors, subgroups of patients for whom bimodal therapy is recommended, including those with a bulky mediastinal mass, have now been identified. Although treatment is highly successful, debilitating consequences of RT and CT, such as infertility, infection and second malignant diseases, remain. Newer treatment regimens may reduce morbidity and have similar or better long-term results with respect to survival and quality of life.
Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Hodgkin Disease; Humans; Infertility; Leukemia; Lymphoma; Male; Mechlorethamine; Menstruation Disturbances; Neoplasm Staging; Prednisone; Procarbazine; Prognosis; Vincristine
PubMed: 3893668
DOI: No ID Found -
Toxicology Letters Jun 2020Mustard vesicants, including sulfur mustard (2,2'-dichlorodiethyl sulfide, SM) and nitrogen mustard (bis(2-chloroethyl)methylamine, HN2) are cytotoxic blistering agents...
Mustard vesicants, including sulfur mustard (2,2'-dichlorodiethyl sulfide, SM) and nitrogen mustard (bis(2-chloroethyl)methylamine, HN2) are cytotoxic blistering agents synthesized for chemical warfare. Because they contain highly reactive electrophilic chloroethyl side chains, they readily react with cellular macromolecules like DNA forming monofunctional and bifunctional adducts. By targeting DNA, mustards can compromise genomic integrity, disrupt the cell cycle, and cause mutations and cytotoxicity. To protect against genotoxicity following exposure to mustards, cells initiate a DNA damage response (DDR). This involves activation of signaling cascades including ATM (ataxia telangiectasia mutated), ATR (ataxia telangiectasia and Rad3-related) and DNA-PKcs (DNA-dependent protein kinase, catalytic unit). Signaling induced by the DDR leads to the recruitment and activation of repair related proteins such as phospho H2AX and phospho p53 to sites of DNA lesions. Excessive DNA modifications by mustards can overwhelm DNA repair leading to single and double strand DNA breaks, cytotoxicity and tissue damage, sometimes leading to cancer. Herein we summarize DDR signaling pathways induced by SM, HN2 and the half mustard, 2-chloroethyl ethyl sulfide (CEES). At the present time, little is known about how mustard-induced DNA damage leads to the activation of DDR signaling. A better understanding of mechanisms by which mustard vesicants induce the DDR may lead to the development of countermeasures effective in mitigating tissue injury.
Topics: Cell Survival; DNA Damage; Humans; Mechlorethamine; Mustard Gas; Mustard Plant; Signal Transduction
PubMed: 32173488
DOI: 10.1016/j.toxlet.2020.03.008 -
Cells Jun 2023Sulfur mustard gas (SM) is a vesicating and alkylating agent used as a chemical weapon in many mass-casualty incidents since World War I. Ocular injuries were reported...
Sulfur mustard gas (SM) is a vesicating and alkylating agent used as a chemical weapon in many mass-casualty incidents since World War I. Ocular injuries were reported in >90% of exposed victims. The mechanisms underlying SM-induced blindness remain elusive. This study tested the hypothesis that SM-induced corneal fibrosis occurs due to the generation of myofibroblasts from resident fibroblasts via the SMAD2/3 signaling pathway in rabbit eyes in vivo and primary human corneal fibroblasts (hCSFs) isolated from donor corneas in vitro. Fifty-four New Zealand White Rabbits were divided into three groups (Naïve, Vehicle, SM-Vapor treated). The SM-Vapor group was exposed to SM at 200 mg-min/m3 for 8 min at the MRI Global facility. Rabbit corneas were collected on day 3, day 7, and day 14 for immunohistochemistry, RNA, and protein lysates. SM caused a significant increase in SMAD2/3, pSMAD, and ɑSMA expression on day 3, day 7, and day 14 in rabbit corneas. For mechanistic studies, hCSFs were treated with nitrogen mustard (NM) or NM + SIS3 (SMAD3-specific inhibitor) and collected at 30 m, 8 h, 24 h, 48 h, and 72 h. NM significantly increased TGFβ, pSMAD3, and SMAD2/3 levels. On the contrary, inhibition of SMAD2/3 signaling by SIS3 treatment significantly reduced SMAD2/3, pSMAD3, and ɑSMA expression in hCSFs. We conclude that SMAD2/3 signaling appears to play a vital role in myofibroblast formation in the cornea following mustard gas exposure.
Topics: Humans; Animals; Rabbits; Mustard Gas; Myofibroblasts; Chemical Warfare Agents; Cornea; Mechlorethamine; Signal Transduction; Smad2 Protein
PubMed: 37296653
DOI: 10.3390/cells12111533 -
The Ocular Surface Jan 2018Nitrogen mustard (NM), which simulates the effects of sulfur mustard (SM), is a potent vesicant known to cause irreversible corneal damage. This study investigates the...
PURPOSE
Nitrogen mustard (NM), which simulates the effects of sulfur mustard (SM), is a potent vesicant known to cause irreversible corneal damage. This study investigates the mechanisms by which NM induces corneal damage by examining the impact of NM exposure on the morphology and lipidome of the cornea.
METHODS
Intact ex vivo rabbit eyes were placed in serum-free DMEM organ culture. NM (0, 1, 2.5, 5 or 10 mg/ml) was applied to the central cornea for 5, 10 or 15 min using a 5 mm filter disk and subsequently rinsed with DMEM. Corneas were then cultured for 3, 24, or 48 h before being fixed for morphological analysis or for 24 h before being snap frozen for lipidomic analysis.
RESULTS
No morphological changes were detected 3 h after NM exposure. Twenty-four h after exposure, 1 mg/ml NM caused erosion of the corneal epithelium, but no damage to the underlying stroma. Damage caused by 2.5 mg/ml NM extended almost two thirds through the corneal stroma, while 5 mg/ml completely penetrated the corneal stroma. An altered lipid profile occurred 24 h after corneas were exposed to NM. Specific sphingomyelins, ceramides, and diacylglycerols were increased up to 9-, 60- and 10-fold, respectively.
CONCLUSIONS
NM induces concentration- and exposure time-dependent damage to the cornea that increases in severity over time. Alterations in the sphingomyelin-ceramide pathway may contribute to the damaging effects of NM exposure.
Topics: Animals; Ceramides; Chemical Warfare Agents; Chromatography, Liquid; Cornea; Corneal Injuries; Diglycerides; Dose-Response Relationship, Drug; Mechlorethamine; Microscopy, Fluorescence; Organ Culture Techniques; Rabbits; Sphingomyelins; Time Factors
PubMed: 29129753
DOI: 10.1016/j.jtos.2017.11.004 -
Toxicology Jun 2014The pathologic mechanisms of skin injuries, following the acute inflammatory response induced by vesicating agents sulfur mustard (SM) and nitrogen mustard (NM)...
The pathologic mechanisms of skin injuries, following the acute inflammatory response induced by vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) exposure, are poorly understood. Neutrophils which accumulate at the site of injury, abundantly express myeloperoxidase (MPO), a heme protein that is implicated in oxidant-related antimicrobial and cytotoxic responses. Our previous studies have shown that exposure to SM analog 2-chloroethyl ethyl sulfide (CEES) or NM results in an inflammatory response including increased neutrophilic infiltration and MPO activity. To further define the role of neutrophil-derived MPO in NM-induced skin injury, here we used a genetic approach and examined the effect of NM exposure (12h and 24h) on previously established injury endpoints in C57BL/6J wild type (WT) and B6.129X1-MPOtm1Lus/J mice (MPO KO), homozygous null for MPO gene. NM exposure caused a significant increase in skin bi-fold thickness, epidermal thickness, microvesication, DNA damage and apoptosis in WT mice compared to MPO KO mice. MPO KO mice showed relatively insignificant effect. Similarly, NM induced increases in the expression of inflammatory and proteolytic mediators, including COX-2, iNOS and MMP-9 in WT mice, while having a significantly lower effect in MPO KO mice. Collectively, these results show that MPO, which generates microbicidal oxidants, plays an important role in NM-induced skin injuries. This suggests the development of mechanism-based treatments against NM- and SM-induced skin injuries that inhibit MPO activity and attenuate MPO-derived oxidants.
Topics: Animals; Apoptosis; Blister; Chemical Warfare Agents; Cyclooxygenase 2; DNA Damage; Male; Matrix Metalloproteinase 9; Mechlorethamine; Metabolism, Inborn Errors; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type II; Peroxidase; Skin; Time Factors
PubMed: 24631667
DOI: 10.1016/j.tox.2014.02.013 -
Toxicology and Applied Pharmacology Feb 2022Nitrogen mustard (NM) is an analogue of the potent vesicating agent sulfur mustard, with well-established ocular injury models in rabbit eyes to study vesicant-induced...
Nitrogen mustard (NM) is an analogue of the potent vesicating agent sulfur mustard, with well-established ocular injury models in rabbit eyes to study vesicant-induced ocular toxicity. The effects of NM-exposure to eyes may include irritation, redness, inflammation, fibrosis, epithelial degradation, blurred vision, partial/complete blindness, which may be temporary or permanent, depending on the route, duration, and dosage of exposure. Effective countermeasures against vesicant exposure are presently not available and are warranted in case of any terrorist activity or accidental leakage from stockpiles. Herein, our focus was to evaluate whether dexamethasone (DEX), an FDA approved potent corticosteroid with documented anti-inflammatory activities, could be an effective treatment modality. Accordingly, utilizing NM-induced corneal injuries in rabbit ocular in vivo model, we examined and compared the efficacy of DEX treatments when administration was started at early (2 h), intermediate (4 h), and late (6 h) therapeutic windows of intervention after NM-exposure and administered every 8 h thereafter. The effects of NM-exposure and DEX treatments were evaluated on clinical (corneal opacity, ulceration, and neovascularization), biological (epithelial thickness, epithelial-stromal separation, blood vessels density, and inflammatory cell and keratocyte counts) and molecular (COX-2 and VEGF expression) parameters, at day 1, 3, 7 and 14. Results indicated that DEX treatment markedly and effectively reversed the NM-induced injury markers in rabbit corneas. Early administration of DEX at 2 h was found to be most effective in reversing NM-induced corneal injuries, followed by DEX 4 h and DEX 6 h administration initiation, indicating that DEX has best efficacy at the early therapeutic window in our study model.
Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Corneal Injuries; Dexamethasone; Irritants; Male; Mechlorethamine; Rabbits
PubMed: 35108561
DOI: 10.1016/j.taap.2022.115904 -
JAMA Dermatology Jan 2013To evaluate the efficacy and safety of a novel mechlorethamine hydrochloride, 0.02%, gel in mycosis fungoides. DESIGN Randomized, controlled, observer-blinded,... (Comparative Study)
Comparative Study Randomized Controlled Trial
Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides.
OBJECTIVE
To evaluate the efficacy and safety of a novel mechlorethamine hydrochloride, 0.02%, gel in mycosis fungoides. DESIGN Randomized, controlled, observer-blinded, multicenter trial comparing mechlorethamine, 0.02%, gel with mechlorethamine, 0.02%, compounded ointment. Mechlorethamine was applied once daily for up to 12 months. Tumor response and adverse events were assessed every month between months 1 and 6 and every 2 months between months 7 and 12. Serum drug levels were evaluated in a subset of patients.
SETTING
Academic medical or cancer centers.
PATIENTS
In total, 260 patients with stage IA to IIA mycosis fungoides who had not used topical mechlorethamine within 2 years and were naive to prior use of topical carmustine therapy.
MAIN OUTCOME MEASURES
Response rates of all the patients based on a primary clinical end point (Composite Assessment of Index Lesion Severity) and secondary clinical end points (Modified Severity-Weighted Assessment Tool and time-to-response analyses).
RESULTS
Response rates for mechlorethamine gel vs ointment were 58.5% vs 47.7% by the Composite Assessment of Index Lesion Severity and 46.9% vs 46.2% by the Modified Severity-Weighted Assessment Tool. By the Composite Assessment of Index Lesion Severity, the ratio of gel response rate to ointment response rate was 1.23 (95% CI, 0.97-1.55), which met the prespecified criterion for noninferiority. Time-to-response analyses demonstrated superiority of mechlorethamine gel to ointment (P< .01). No drug-related serious adverse events were seen. Approximately 20.3% of enrolled patients in the gel treatment arm and 17.3% of enrolled patients in the ointment treatment arm withdrew because of drug-related skin irritation. No systemic absorption of the study medication was detected.
CONCLUSION
The use of a novel mechlorethamine, 0.02%, gel in the treatment of patients with mycosis fungoides is effective and safe.
TRIAL REGISTRATION
clinicaltrials.gov Identifier:NCT00168064.
Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Female; Gels; Humans; Male; Mechlorethamine; Middle Aged; Mycosis Fungoides; Neoplasm Staging; Ointments; Severity of Illness Index; Single-Blind Method; Skin Neoplasms; Time Factors; Treatment Outcome; Young Adult
PubMed: 23069814
DOI: 10.1001/2013.jamadermatol.541 -
Nitrogen mustard exposure perturbs oocyte mitochondrial physiology and alters reproductive outcomes.Reproductive Toxicology (Elmsford, N.Y.) Dec 2018Nitrogen mustard (NM) is an alkylating chemical warfare agent, and its derivatives are used in chemotherapy. Alkylating agents can cause mitochondrial damage, so exposed...
Nitrogen mustard (NM) is an alkylating chemical warfare agent, and its derivatives are used in chemotherapy. Alkylating agents can cause mitochondrial damage, so exposed females may transmit damaged genomes to their children, since mitochondria are maternally inherited and oocytes are not thought to undergo mitophagy (Boudoures et al. [1]). The objective of this study is to investigate NM's effects on oocyte mitochondria to understand risks facing female soldiers, cancer patients, and their children. Mice were injected intraperitoneally with NM, monitored for reproductive outcomes, and ovaries and oocytes were isolated for analysis. Escalating doses of NM increased oxidative stress in parental and F1 generation oocytes, suggesting that mitochondrial damage by NM is enhanced by mitochondrial superoxide. NM-treated ovaries in vitro exhibited smaller mitochondrial volume, more electron-dense and multivesicular structures, and lower birth weight litters. These results demonstrate that females must be protected from alkylating agents for their health, and the health of their offspring.
Topics: Animals; Chemical Warfare Agents; Female; Mechlorethamine; Mice; Microscopy, Electron; Mitochondria; Oocytes; Reproduction
PubMed: 30308227
DOI: 10.1016/j.reprotox.2018.10.002 -
Toxicology and Applied Pharmacology Jul 2016Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is...
Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation. Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARα and FAAH were all constitutively expressed in mouse epidermis and dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARα, a response that persisted throughout the wound healing process. Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical countermeasures against vesicants.
Topics: Alkylating Agents; Amidohydrolases; Animals; Chemical Warfare Agents; Female; Irritants; Male; Mechlorethamine; Mice; Mice, Hairless; Mustard Gas; PPAR alpha; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Skin
PubMed: 27125198
DOI: 10.1016/j.taap.2016.04.014 -
British Medical Journal Jan 1963
Topics: Chlorambucil; Humans; Mechlorethamine; Waldenstrom Macroglobulinemia
PubMed: 14034304
DOI: 10.1136/bmj.1.5323.120-a