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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 -
Toxicological Sciences : An Official... Jan 2016Sulfur mustard and nitrogen mustard (mechlorethamine, HN2) are potent vesicants developed as chemical warfare agents. These electrophilic, bifunctional alkylating agents...
Sulfur mustard and nitrogen mustard (mechlorethamine, HN2) are potent vesicants developed as chemical warfare agents. These electrophilic, bifunctional alkylating agents cause skin injury, including inflammation, edema, and blistering. HN2 covalently modifies macromolecules such as DNA, RNA, and proteins or is scavenged by glutathione, forming adducts that can contribute to toxicity. Multidrug resistance-associated protein 1 (Mrp1/MRP1) is a transmembrane ATPase known to efflux glutathione-conjugated electrophiles. In the present studies, we examined the effects of modulating Mrp1-mediated transport activity on the sensitivity of primary and PAM212 mouse keratinocytes to HN2. Primary keratinocytes, and to a lesser extent, PAM212 cells, express Mrp1 mRNA and protein and possess Mrp1 functional activity, as measured by calcein efflux. Sulforaphane, an activator of Nrf2, increased Mrp1 mRNA, protein, and functional activity in primary keratinocytes and PAM212 cells and decreased their sensitivity to HN2-induced growth inhibition (IC(50) = 1.4 and 4.8 µM in primary keratinocytes and 1 and 13 µM in PAM212 cells, in the absence and presence of sulforaphane, respectively). The Mrp1 inhibitor, MK-571, reversed the effects of sulforaphane on HN2-induced growth inhibition in both primary keratinocytes and PAM212 cells. In primary keratinocytes from Nrf2(-/-) mice, sulforaphane had no impact on Mrp1 expression or activity, or on sensitivity to HN2, demonstrating that its effects depend on Nrf2. These data suggest that Mrp1-mediated efflux is important in regulating HN2-induced keratinocyte growth inhibition. Enhancing HN2 efflux from keratinocytes may represent a novel strategy for mitigating vesicant-induced cytotoxicity.
Topics: Animals; Heme Oxygenase-1; Isothiocyanates; Keratinocytes; Mechlorethamine; Membrane Proteins; Mice; Mice, Inbred C57BL; Multidrug Resistance-Associated Proteins; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Propionates; Quinolines; Sulfoxides
PubMed: 26454883
DOI: 10.1093/toxsci/kfv226 -
Experimental and Molecular Pathology Jun 2020Nitrogen mustard (NM) is a highly reactive bifunctional alkylating agent that induces inflammation, edema and blistering in skin. An important mechanism mediating the...
Nitrogen mustard (NM) is a highly reactive bifunctional alkylating agent that induces inflammation, edema and blistering in skin. An important mechanism mediating the action of NM and related mustards is oxidative stress. In these studies a modified murine patch-test model was used to analyze DNA damage and the antioxidant/stress response following NM exposure in isolated epidermis. NM (20 μmol) was applied to glass microfiber filters affixed to a shaved dorsal region of skin of CD-1 mice. NM caused structural damage to the stratum corneum as reflected by increases in transepidermal water loss and skin hydration. This was coordinate with edema, mast cell degranulation and epidermal hyperplasia. Within 3 h of NM exposure, a 4-fold increase in phosphorylated histone H2AX, a marker of DNA double-stranded breaks, and a 25-fold increase in phosphorylated p53, a DNA damage marker, were observed in the epidermis. This was associated with a 40% increase in 8-oxo-2'-deoxyguanosine modified DNA in the epidermis and a 4-fold increase in 4-hydroxynonenal modified epidermal proteins. At 12 h post NM, there was a 3-75 fold increase in epidermal expression of antioxidant/stress proteins including heme oxygenase-1, thioredoxin reductase, superoxide dismutase, glutathione reductase, heat shock protein 27 and cyclooxygenase 2. These data indicate that NM induces early oxidative epidermal injury in mouse skin leading to an antioxidant/stress response. Agents that enhance this response may be useful in mitigating mustard-induced skin injury.
Topics: Alkylating Agents; Animals; Antioxidants; Apoptosis; Cyclooxygenase 2; DNA Damage; Epidermis; Glutathione Reductase; HSP27 Heat-Shock Proteins; Heme Oxygenase-1; Humans; Inflammation; Mechlorethamine; Mice; Oxidative Stress; Phosphorylation; Skin; Stress, Physiological; Superoxide Dismutase; Thioredoxin-Disulfide Reductase
PubMed: 32113906
DOI: 10.1016/j.yexmp.2020.104410 -
Advances in Therapy Sep 2022Mycosis fungoides (MF) is a rare disease and is the most common form of cutaneous T cell lymphoma. Topical chlormethine (CL) gel is the first cytotoxic chemotherapy gel... (Review)
Review
Mycosis fungoides (MF) is a rare disease and is the most common form of cutaneous T cell lymphoma. Topical chlormethine (CL) gel is the first cytotoxic chemotherapy gel that was specifically developed for treatment of MF. In this review, we provide an overview of all available data on the use of CL gel for treatment of patients with MF. On the basis of the current data collected, CL gel is highly effective, with good response rates observed both in clinical trial and real-world settings. While the gel is approved for monotherapy, it is also used in combination with concomitant skin-directed or systemic therapies in clinical practice. Responses to CL gel treatment can be rapid, but they also frequently occur with a delayed onset of up to 6 months. This indicates that continued treatment with CL gel is important. CL gel has a manageable safety profile, with most adverse events being mild and skin related. Contact dermatitis is one of the more common skin-related adverse events to occur with CL gel treatment that can potentially lead to treatment discontinuation. The data from the literature indicate that patients being treated with CL gel should be monitored carefully, and that dermatitis must be managed effectively to allow patients to continue treatment and achieve the best possible response to treatment.
Topics: Clinical Trials as Topic; Gels; Humans; Lymphoma, T-Cell, Cutaneous; Mechlorethamine; Mycosis Fungoides; Skin Neoplasms
PubMed: 35852707
DOI: 10.1007/s12325-022-02219-w -
BMJ (Clinical Research Ed.) Feb 1994
Topics: Administration, Topical; Humans; Lymphoma, T-Cell, Cutaneous; Mechlorethamine; Methoxsalen; Randomized Controlled Trials as Topic; Skin Neoplasms; Ultraviolet Therapy
PubMed: 8031362
DOI: 10.1136/bmj.308.6928.551 -
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 -
Annals of the New York Academy of... Nov 2020Nitrogen mustard (NM) and sulfur mustard are cytotoxic alkylating agents that cause severe and progressive damage to the respiratory tract. Evidence indicates that...
Nitrogen mustard (NM) and sulfur mustard are cytotoxic alkylating agents that cause severe and progressive damage to the respiratory tract. Evidence indicates that macrophages play a key role in the acute inflammatory phase and the later resolution/profibrotic phase of the pathogenic response. These diverse roles are mediated by inflammatory macrophages broadly classified as M1 proinflammatory and M2 anti-inflammatory that sequentially accumulate in the lung in response to injury. The goal of the present study was to identify signaling mechanisms contributing to macrophage activation in response to mustards. To accomplish this, we used RNA sequencing to analyze the gene expression profiles of lung macrophages isolated 1 and 28 days after intratracheal exposure of rats to NM (0.125 mg/kg) or phosphate-buffered saline control. We identified 641 and 792 differentially expressed genes 1 and 28 days post-NM exposure, respectively. These genes are primarily involved in processes related to cell movement and are regulated by cytokines, including tumor necrosis factor-α, interferon-γ, and interleukin-1β. Some of the most significantly enriched canonical pathways included STAT3 and NF-κB signaling. These cytokines and pathways may represent potential targets for therapeutic intervention to mitigate mustard-induced lung toxicity.
Topics: Animals; Chemical Warfare Agents; Gene Expression Regulation; Inflammation; Lung Injury; Macrophages, Alveolar; Male; Mechlorethamine; RNA-Seq; Rats; Rats, Wistar
PubMed: 32767459
DOI: 10.1111/nyas.14444 -
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 -
Toxicological Sciences : An Official... May 2017Nitrogen mustard (NM)-induced lung injury is associated with an accumulation of proinflammatory/cytotoxic M1 and antiinflammatory/wound repair M2 macrophages, which have...
Nitrogen mustard (NM)-induced lung injury is associated with an accumulation of proinflammatory/cytotoxic M1 and antiinflammatory/wound repair M2 macrophages, which have been implicated in tissue injury and repair. Herein, we analyzed the effects of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor with antiinflammatory and antioxidant activity, on lung macrophages responding to NM. Treatment of rats with NM (0.125 mg/kg, i.t.) resulted in structural alterations in the lung and a macrophage-rich inflammatory cell infiltrate, at 3 d and 7 d. This was accompanied by expression of PCNA, a marker of proliferation, and CYPb5, HO-1, and MnSOD, markers of oxidative stress. Administration of VPA (300 mg/kg/day; i.p.), beginning 30 min after NM, reduced increases in PCNA, CYPb5, HO-1, and MnSOD. This was associated with increases in immature CD11b+CD43+ M1 macrophages in the lung, and decreases in mature CD11b+CD43- M2 macrophages 3 d post NM, suggesting delayed maturation and phenotypic switching. VPA also attenuated NM-induced increases in lung iNOS+ and CCR2+ M1 macrophages, a response correlated with downregulation of NOS2, IL12B, PTGS2, MMP-9, and CCR2 expression. Conversely, numbers of CD68+, CD163+ , and ATR-1α+ M2 macrophages increased after VPA, along with the expression of IL10, ApoE, and ATR-1A. NM exposure resulted in increased HDAC activity and upregulation of HDAC2 and acetylated H3K9 in the lung. Whereas VPA blunted the effects of NM on HDAC2 expression, histone H3K9 acetylation increased. These data suggest that alterations in the balance between histone acetylases and deacetylases contribute to lung macrophage maturation and activation following NM exposure.
Topics: Animals; Bronchoalveolar Lavage Fluid; Cell Proliferation; Histone Deacetylase Inhibitors; Inflammation; Macrophage Activation; Male; Mechlorethamine; Oxidative Stress; Rats; Rats, Wistar; Valproic Acid
PubMed: 28184907
DOI: 10.1093/toxsci/kfx032 -
Toxicology and Applied Pharmacology Jul 2021Activated macrophages have been implicated in lung injury and fibrosis induced by the cytotoxic alkylating agent, nitrogen mustard (NM). Herein, we determined if...
Activated macrophages have been implicated in lung injury and fibrosis induced by the cytotoxic alkylating agent, nitrogen mustard (NM). Herein, we determined if macrophage activation is associated with histone modifications and altered miRNA expression. Treatment of rats with NM (0.125 mg/kg, i.t.) resulted in increases in phosphorylation of H2A.X in lung macrophages at 1 d and 3 d post-exposure. This DNA damage response was accompanied by methylation of histone (H) 3 lysine (K) 4 and acetylation of H3K9, marks of transcriptional activation, and methylation of H3K36 and H3K9, marks associated with transcriptional repression. Increases in histone acetyl transferase and histone deacetylase were also observed in macrophages 1 d and 28 d post-NM exposure. PCR array analysis of miRNAs (miR)s involved in inflammation and fibrosis revealed unique and overlapping expression profiles in macrophages isolated 1, 3, 7, and 28 d post-NM. An IPA Core Analysis of predicted mRNA targets of differentially expressed miRNAs identified significant enrichment of Diseases and Functions related to cell cycle arrest, apoptosis, cell movement, cell adhesion, lipid metabolism, and inflammation 1 d and 28 d post NM. miRNA-mRNA interaction network analysis revealed highly connected miRNAs representing key upstream regulators of mRNAs involved in significantly enriched pathways including miR-34c-5p and miR-27a-3p at 1 d post NM and miR-125b-5p, miR-16-5p, miR-30c-5p, miR-19b-3p and miR-148b-3p at 28 d post NM. Collectively, these data show that NM promotes histone remodeling and alterations in miRNA expression linked to lung macrophage responses during inflammatory injury and fibrosis.
Topics: Acute Lung Injury; Animals; Gene Expression; Histones; Lung; Macrophage Activation; Male; Mechlorethamine; Mice; MicroRNAs; Rats; Rats, Wistar
PubMed: 33971176
DOI: 10.1016/j.taap.2021.115569