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Fertility and Sterility Sep 2014To determine consequences of lymphoma treatments on sperm characteristics and sperm DNA, and to evaluate predictors of sperm recovery.
OBJECTIVE
To determine consequences of lymphoma treatments on sperm characteristics and sperm DNA, and to evaluate predictors of sperm recovery.
DESIGN
Multicenter prospective longitudinal study of patients analyzed before treatment and after 3, 6, 12, and 24 months.
SETTING
University hospitals.
PATIENT(S)
Seventy-five Hodgkin lymphoma and non-Hodgkin lymphoma patients and a control group of 257 fertile men.
INTERVENTION(S)
Semen analyses, and sperm DNA and chromatin assessments.
MAIN OUTCOME MEASURE(S)
Comparisons of sperm characteristics before and after treatment.
RESULT(S)
Patients already had altered sperm characteristics before lymphoma treatment, with no identified risk factor. Sperm count, total sperm count, motility, and vitality decreased after treatment, with lowest values at 3 and 6 months. Twelve months after treatment, mean sperm count recovered to pretreatment values after doxorubicin, bleomycin, vinblastine, darcarbacine (ABVD) or ABVD+radiotherapy, but not after doxorubicin, cyclophosphamide, vincristine, prednisone (CHOP) or mechlorethamine, oncovin, procarbazine, prednisone (MOPP) chemotherapies. It was noteworthy that 7% of patients remained azoospermic at 24 months. After 24 months, Kaplan-Meier estimates showed that more than 90% of patients will recover normal sperm count after ABVD or ABVD+radiotherapy vs. 61% for CHOP chemotherapies. In multivariate analyses including diagnosis and treatment protocol, only pretreatment total sperm count was related to recovery. Compared with a control group, lymphoma patients had higher sperm chromatin alterations and DNA fragmentation before any treatment. After treatment, DNA fragmentation assessed by TUNEL assay and sperm chromatin structure assay decreased from 3 and 6 months, respectively, while remaining higher than in the control group during follow-up.
CONCLUSION(S)
Lymphoma patients had altered sperm DNA and chromatin before treatment. Lymphoma treatment had damaging effects on spermatogenesis. These data on both the recovery period according to treatment modalities and the pre- and post-treatment chromatin status of sperm are useful tools for counseling patients wishing to conceive.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Case-Control Studies; Combined Modality Therapy; Cyclophosphamide; DNA; DNA Damage; Dacarbazine; Doxorubicin; Hodgkin Disease; Humans; Longitudinal Studies; Lymphoma, Non-Hodgkin; Male; Mechlorethamine; Prednisone; Procarbazine; Semen Analysis; Sperm Count; Spermatogenesis; Spermatozoa; Vinblastine; Vincristine; Young Adult
PubMed: 25044088
DOI: 10.1016/j.fertnstert.2014.06.008 -
American Journal of Clinical Dermatology Jul 2022Chlormethine gel was approved for treatment of mycosis fungoides, the most common cutaneous T-cell lymphoma, on the basis of results from study 201 and study 202. A...
BACKGROUND
Chlormethine gel was approved for treatment of mycosis fungoides, the most common cutaneous T-cell lymphoma, on the basis of results from study 201 and study 202. A post-hoc analysis of study 201 found interesting trends regarding improved efficacy of chlormethine gel vs ointment and noted a potential association between dermatitis and clinical response.
OBJECTIVE
To expand these results by performing a post-hoc analysis of study 202.
PATIENTS AND METHODS
Patients received chlormethine gel or ointment during study 201 (12 months) and higher-concentration chlormethine gel during study 202 (7-month extension). Response was assessed using Composite Assessment of Index Lesion Severity (CAILS). Associations between treatment frequency, response, and skin-related adverse events (AEs) were assessed using multivariate time-to-event analyses. Time-to-response and repeated measures analyses were compared between patients who only used chlormethine gel and those who switched from ointment to gel.
RESULTS
No associations were seen between treatment frequency and improved skin response (CAILS) or AE occurrence within the 201/202 study populations. However, an association was observed specifically between contact dermatitis and improved CAILS response at the next visit (p < 0.0001). Patients who used chlormethine gel during both studies had a significantly (p < 0.05) shorter time to response and higher overall response rates than patients who initiated treatment with ointment.
CONCLUSIONS
This post-hoc analysis shows that patients who initiated treatment using chlormethine gel had faster and higher responses compared with patients who initially used chlormethine ointment for 12 months. The development of contact dermatitis may be a potential prognostic factor for response.
TRIAL REGISTRATION NUMBERS AND DATES OF REGISTRATION
Study 201: NCT00168064, September 14, 2002; Study 202: NCT00535470, September 26, 2007.
Topics: Clinical Trials as Topic; Dermatitis, Contact; Gels; Humans; Mechlorethamine; Mycosis Fungoides; Ointments; Skin Neoplasms; Treatment Outcome
PubMed: 35536441
DOI: 10.1007/s40257-022-00687-y -
Clinical and Translational Medicine Feb 2021Nitrogen mustard (NM) causes severe skin injury with an obvious inflammatory response, which is lack of effective and targeted therapies. Vitamin D3 (VD3) has excellent...
Nitrogen mustard (NM) causes severe skin injury with an obvious inflammatory response, which is lack of effective and targeted therapies. Vitamin D3 (VD3) has excellent anti-inflammatory properties and is considered as a potential candidate for the treatment of NM-induced dermal toxicity; however, the underlying mechanisms are currently unclear. Cyclooxygenase-2 (COX2; a widely used marker of skin inflammation) plays a key role in NM-induced cutaneous inflammation. Herein, we initially confirmed that NM markedly promoted COX2 expression in vitro and in vivo. NM also increased NOD-like receptor family pyrin domain containing 3 (NLRP3) expression, caspase-1 activity, and interleukin-1β (IL-1β) release. Notably, treatment with a caspase-1 inhibitor (zYVAD-fmk), NLRP3 inhibitor (MCC950), and NLRP3 or caspase-1 siRNA attenuated NM-induced NLRP3 inflammasome activation, with subsequent suppression of COX2 expression and IL-1β release in keratinocytes. Meanwhile, NM increased mitochondrial reactive oxygen species (mtROS) and decreased manganese superoxide dismutase 2 (SOD2) and sirtuin 3 (SIRT3) activities. Mito-TEMPO (a mtROS scavenger) ameliorated NM-caused NLRP3 inflammasome activation in keratinocytes. Moreover, VD3 improved SIRT3 and SOD2 activities, decreased mtROS contents, inactivated the NLRP3 inflammasome, and attenuated cutaneous inflammation induced by NM in vitro and in vivo. The beneficial activity of VD3 against NM-triggered cutaneous inflammation was enhanced by the inhibitors of IL-1, mtROS, NLRP3, caspase-1, and NLRP3 or caspase-1 siRNAs, which was abolished in SIRT3 inhibitor or SIRT3 siRNA-treated keratinocytes and skins from SIRT3 mice. In conclusion, VD3 ameliorated NM-induced cutaneous inflammation by inactivating the NLRP3 inflammasome, which was partially mediated through the SIRT3-SOD2-mtROS signaling pathway.
Topics: Animals; Dermatitis, Contact; Female; HaCaT Cells; Humans; Inflammasomes; Keratinocytes; Mechlorethamine; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Reactive Oxygen Species; Signal Transduction; Sirtuin 3; Superoxide Dismutase; Vitamin D
PubMed: 33634989
DOI: 10.1002/ctm2.312 -
Clinical Cancer Research : An Official... Jan 2006MOPPEBVCAD (mechlorethamine, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine) chemotherapy with... (Comparative Study)
Comparative Study Randomized Controlled Trial
PURPOSE
MOPPEBVCAD (mechlorethamine, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine) chemotherapy with limited radiotherapy was devised in 1987 to reduce late toxicity and second tumor incidence while trying to improve effectiveness through increases of dose intensity and dose density. Late results, toxicity, and second tumor incidence were reviewed in all the patients treated.
EXPERIMENTAL DESIGN
The drugs of three previous alternating regimens [CAD (lomustine, melphalan, and vindesine), MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), and ABV (doxorubicin, bleomycin, and vinblastine)] were intensified and hybridized, the cumulative dose of mechlorethamine was lowered, and irradiation was delivered to no more than two sites either bulky or partially responding to chemotherapy.
RESULTS
A total of 307 previously untreated advanced-stage patients underwent MOPPEBVCAD chemotherapy. Radiotherapy was delivered to 118 of 307 patients (38%). Remission was complete in 290 patients (94%). With a median follow-up of 114 months, 10-year overall, disease-free, and failure-free survival rates were 79%, 84%, and 71%, respectively. Forty-two patients relapsed and 60 died. The causes of death were Hodgkin's lymphoma in 36 patients, second neoplasms in 12, cardiorespiratory diseases in 4, pulmonary diseases in 2, and unknown in 6. Sixteen second tumors (of which nine were myelodysplasia and/or acute leukemia) were diagnosed in all. Outside this series of 307 patients, MOPPEBVCAD obtained complete responses in 12 of 15 relapsed and 9 of 9 refractory patients who had previously been treated with other regimens.
CONCLUSIONS
Clinical response and long-term results are very satisfactory, whereas the second tumor incidence was lower than would have been expected with MOPP analogues. Given its response/late toxicity balance, MOPPEBVCAD does not undermine the leading role of ABVD as first-line regimen but can be indicated as a very effective second-line conventional therapy.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Combined Modality Therapy; Disease-Free Survival; Doxorubicin; Drug-Related Side Effects and Adverse Reactions; Epirubicin; Female; Hodgkin Disease; Humans; Lomustine; Male; Mechlorethamine; Middle Aged; Neoplasms, Second Primary; Pilot Projects; Prednisone; Procarbazine; Survival Rate; Treatment Outcome; Vinblastine; Vincristine; Vindesine
PubMed: 16428496
DOI: 10.1158/1078-0432.CCR-05-1707 -
Journal of Proteome Research Jun 2011Antitumor nitrogen mustards, such as bis(2-chloroethyl)methylamine (mechlorethamine), are useful chemotherapeutic agents with a long history of clinical application. The...
Antitumor nitrogen mustards, such as bis(2-chloroethyl)methylamine (mechlorethamine), are useful chemotherapeutic agents with a long history of clinical application. The antitumor effects of nitrogen mustards are attributed to their ability to induce DNA-DNA and DNA-protein cross-links (DPCs) that block DNA replication. In the present work, a mass spectrometry-based methodology was employed to characterize in vivo DNA-protein cross-linking following treatment of human fibrosarcoma (HT1080) cells with cytotoxic concentrations of mechlorethamine. A combination of mass spectrometry-based proteomics and immunological detection was used to identify 38 nuclear proteins that were covalently cross-linked to chromosomal DNA following treatment with mechlorethamine. Isotope dilution HPLC-ESI(+)-MS/MS analysis of total proteolytic digests revealed a concentration-dependent formation of N-[2-(S-cysteinyl)ethyl]-N-[2-(guan-7-yl)ethyl]methylamine (Cys-N7G-EMA) conjugates, indicating that mechlorethamine cross-links cysteine thiols within proteins to N-7 positions of guanine in DNA.
Topics: Alkylating Agents; Cell Line, Tumor; Cell Survival; Chromatography, High Pressure Liquid; Cross-Linking Reagents; DNA, Neoplasm; DNA-Binding Proteins; Fibrosarcoma; Humans; Mechlorethamine; Peptide Fragments; Proteomics; Tandem Mass Spectrometry
PubMed: 21486066
DOI: 10.1021/pr200042u -
International Journal of Molecular... Sep 2022Ocular surface exposure to nitrogen mustard (NM) leads to severe ocular toxicity which includes the separation of epithelial and stromal layers, loss of endothelial...
Ocular surface exposure to nitrogen mustard (NM) leads to severe ocular toxicity which includes the separation of epithelial and stromal layers, loss of endothelial cells, cell death, and severe loss of tissue function. No definitive treatment for mustard gas-induced ocular surface disorders is currently available. The research was conducted to investigate the therapeutic potential of mesenchymal stem cell-conditioned media (MSC-CM) in NM-induced corneal wounds. NM was added to different types of corneal cells, the ocular surface of porcine, and the ocular surface of mice, followed by MSC-CM treatment. NM significantly induced apoptotic cell death, cellular ROS (Reactive oxygen species), and reduced cell viability, metabolic gene expression, and mitochondrial function, and, in turn, delayed wound healing. The application of MSC-CM post NM exposure partially restored mitochondrial function and decreased intracellular ROS generation which promoted cell survival. MSC-CM therapy enhanced wound healing process. MSC-CM inhibited NM-induced apoptotic cell death in murine and porcine corneal tissue. The application of MSC-CM following a chemical insult led to significant improvements in the preservation of corneal structure and wound healing. In vitro, ex vivo, and in vivo results suggest that MSC-CM can potentially provide targeted therapy for the treatment of chemical eye injuries, including mustard gas keratopathy (MGK) which presents with significant loss of vision alongside numerous corneal pathologies.
Topics: Animals; Corneal Injuries; Culture Media, Conditioned; Endothelial Cells; Mechlorethamine; Mesenchymal Stem Cells; Mice; Mustard Gas; Reactive Oxygen Species; Stem Cell Factor; Swine; Wound Healing
PubMed: 36232805
DOI: 10.3390/ijms231911510 -
CMAJ : Canadian Medical Association... Sep 1986Combination chemotherapy (CT) has been the mainstay of treatment of advanced-stage Hodgkin's disease since the late 1960s. Although treatment with MOPP (nitrogen... (Review)
Review
Combination chemotherapy (CT) has been the mainstay of treatment of advanced-stage Hodgkin's disease since the late 1960s. Although treatment with MOPP (nitrogen mustard, vincristine sulfate [Oncovin], procarbazine and prednisone) has resulted in long-term disease-free survival rates exceeding 50%, newer approaches have been studied to improve on this success rate and to reduce the toxic effects associated with MOPP. Prognostic factors have now been defined that identify patients who may require more aggressive treatment; they include age greater than 40 years, presence of B symptoms and more advanced (especially extranodal) disease. A small number of patients with pathological stage III disease may still be successfully treated with extensive radiotherapy (RT) alone. Among patients with advanced-stage disease, significantly better therapeutic results are being obtained with newer treatment approaches than with MOPP, particularly in patients with factors that predict a poor outcome. These newer approaches include combination CT plus RT, alternating cycles of two non-cross-resistant CT regimens and hybrid regimens, which combine agents from two different CT regimens in one cycle. The prognosis of patients who suffer relapse after combination CT remains poor, even with newer drug regimens. The newer treatment approaches may well lead to better cure rates and fewer short-term and long-term toxic effects.
Topics: Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Combined Modality Therapy; Dacarbazine; Doxorubicin; Drug Administration Schedule; Hodgkin Disease; Humans; Mechlorethamine; Neoplasm Staging; Prednisone; Procarbazine; Prognosis; Recurrence; Vinblastine; Vincristine
PubMed: 2427176
DOI: No ID Found -
Annals of the New York Academy of... Nov 2020Nitrogen mustard (NM) causes acute lung injury, which progresses to fibrosis. This is associated with a macrophage-dominant inflammatory response and the production of...
Nitrogen mustard (NM) causes acute lung injury, which progresses to fibrosis. This is associated with a macrophage-dominant inflammatory response and the production of proinflammatory/profibrotic mediators, including tumor necrosis factor alpha (TNF-α). Herein, we refined magnetic resonance imaging (MRI) and computed tomography (CT) imaging methodologies to track the progression of NM-induced lung injury in rodents and assess the efficacy of anti-TNF-α antibody in mitigating toxicity. Anti-TNF-α antibody was administered to rats (15 mg/kg, every 8 days, intravenously) beginning 30 min after treatment with phosphate-buffered saline control or NM (0.125 mg/kg, intratracheally). Animals were imaged by MRI and CT prior to exposure and 1-28 days postexposure. Using MRI, we characterized acute lung injury and fibrosis by quantifying high-signal lung volume, which represents edema, inflammation, and tissue consolidation; these pathologies were found to persist for 28 days following NM exposure. CT scans were used to assess structural components of the lung and to register changes in tissue radiodensities. CT scans showed that in control animals, total lung volume increased with time. Treatment of rats with NM caused loss of lung volume; anti-TNF-α antibody mitigated this decrease. These studies demonstrate that MRI and CT can be used to monitor lung disease and the impact of therapeutic intervention.
Topics: Acute Lung Injury; Animals; Antibodies, Monoclonal, Murine-Derived; Irritants; Magnetic Resonance Imaging; Male; Mechlorethamine; Pulmonary Fibrosis; Rats; Time Factors; Tomography, X-Ray Computed; Tumor Necrosis Factor-alpha
PubMed: 33165947
DOI: 10.1111/nyas.14525 -
Annals of the New York Academy of... Nov 2020Nitrogen mustard (NM) is a highly toxic alkylating agent. Inhalation exposure can cause acute and chronic lung injury. This study's aims were to develop an in vitro...
Nitrogen mustard (NM) is a highly toxic alkylating agent. Inhalation exposure can cause acute and chronic lung injury. This study's aims were to develop an in vitro coculture model of mustard-induced airway injury and to identify growth factors contributing to airway pathology. Primary human bronchial epithelial cells cultured with pulmonary endothelial cells were exposed to NM (25, 50, 100, 250, or 500 μM) or PBS (control) for 1 hour. Lactate dehydrogenase (LDH) and transepithelial electrical resistance (TEER) were measured before and 24 h after NM exposure. Fixed cultures were stained for hematoxylin and eosin or live/dead staining. Culture media were analyzed for 11 growth factors. A 1-h vapor exposure to greater than or equal to 50 μM NM increased supernatant LDH, decreased TEER, and caused airway epithelial cell detachment. Endothelial cell death occurred at 500 μM NM. Vascular endothelial growth factor A (VEGF-A) and placental growth factor (PlGF) expression increased in 500 μM NM-exposed cultures compared with PBS-exposed control cultures. NM vapor exposure causes differential cytotoxicity to airway epithelial and endothelial injury in culture. Increased VEGF-A and PlGF expression occurred acutely in airway cocultures. Future studies are required to validate the role of VEGF signaling in mustard-induced airway pathology.
Topics: Cell Line; Cytotoxins; Endothelial Cells; Epithelial Cells; Gene Expression Regulation; Humans; Lung; Mechlorethamine; Membrane Proteins; Vascular Endothelial Growth Factor A
PubMed: 32408394
DOI: 10.1111/nyas.14367 -
Acta Dermato-venereologica Sep 2021Mycosis fungoides is a type of cutaneous T-cell lymphoma, which accounts for the majority of cases of cutaneous T-cell lymphoma. Mycosis fungoides can be classified as...
Mycosis fungoides is a type of cutaneous T-cell lymphoma, which accounts for the majority of cases of cutaneous T-cell lymphoma. Mycosis fungoides can be classified as early-stage (IA-IIA) or late-stage (IIB or greater) disease. In early-stage mycosis fungoides, skin-directed therapies are commonly used to manage the disease. Chlormethine, or mechlorethamine, is a topical chemotherapeutic, which has been in use for over 60 years. In 2013, the US Food and Drug Administration approved chlormethine/mechlorethamine gel (Valchlor®) for treatment of stage IA and IB mycosis fungoides. Chlormethine/mechlorethamine gel is an effective therapy; however, its use may be limited by the development of adverse cutaneous reactions. Off-label dosing modifications, as well as co-administration of topical steroids and an aggressive moisturization regimen, can be used to reduce these side-effects. We report here 4 cases of mycosis fungoides treated with chlormethine/mechlorethamine gel at the Comprehensive Skin Cancer Center at Columbia University Irving Medical Center, which provide insights into the use of this therapy in clinical practice.
Topics: Antineoplastic Agents, Alkylating; Humans; Mechlorethamine; Mycosis Fungoides; Skin Neoplasms; Universities
PubMed: 34436621
DOI: 10.2340/00015555-3911