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Pharmaceuticals (Basel, Switzerland) Sep 2022The efficacy of pure and aluminum (Al)-doped boron nitride nanocarriers (BN and AlBN) in adsorbing Chlormethine (CM), an anti-cancer drug, was comparatively dissected by...
The efficacy of pure and aluminum (Al)-doped boron nitride nanocarriers (BN and AlBN) in adsorbing Chlormethine (CM), an anti-cancer drug, was comparatively dissected by means of the density functional theory method. The CM∙∙∙BN and ∙∙∙AlBN complexes were studied within two configurations, A and B, in which the adsorption process occurred via N∙∙∙ and Cl∙∙∙B/Al interactions, respectively. The electrostatic potential affirmations confirmed the opulent ability of the studied nanocarriers to engage in delivering CM via two prominent electrophilic sites (B and Al). Furthermore, the adsorption process within the CM∙∙∙AlBN complexes was noticed to be more favorable compared to that within the CM∙∙∙BN analog and showed interaction and adsorption energy values up to -59.68 and -52.40 kcal/mol, respectively, for configuration A. Symmetry-adapted perturbation theory results indicated that electrostatic forces were dominant in the adsorption process. Notably, the adsorption of CM over BN and AlBN nanocarriers exhibited predominant changes in their electronic properties. An elemental alteration was also revealed for the softness and hardness of BN and AlBN nanocarriers before and following the CM adsorption. Spontaneity and exothermic nature were obviously observed for the studied complexes and confirmed by the negative values of thermodynamic parameters. In line with energetic manifestation, Gibbs free energy and enthalpy change were drastically increased by the Al doping process, with values raised to -37.15 and -50.14 kcal/mol, respectively, for configuration A of the CM∙∙∙AlBN complex. Conspicuous enhancement was noticed for the adsorption process in the water phase more than that in the gas phase and confirmed by the negative values of the solvation energy up to -53.50 kcal/mol for configuration A of the CM∙∙∙AlBN complex. The obtained outcomes would be the linchpin for the future utilization of boron nitride as a nanocarrier.
PubMed: 36297293
DOI: 10.3390/ph15101181 -
Signal Transduction and Targeted Therapy Jan 2021Nitrogen mustard (NM) causes severe vesicating skin injury, which lacks effective targeted therapies. The major limitation is that the specific mechanism of NM-induced...
Nitrogen mustard (NM) causes severe vesicating skin injury, which lacks effective targeted therapies. The major limitation is that the specific mechanism of NM-induced skin injury is not well understood. Recently, autophagy has been found to play important roles in physical and chemical exposure-caused cutaneous injuries. However, whether autophagy contributes to NM-induced dermal toxicity is unclear. Herein, we initially confirmed that NM dose-dependently caused cell death and induced autophagy in keratinocytes. Suppression of autophagy by 3-methyladenine, chloroquine, and bafilomycin A1 or ATG5 siRNA attenuated NM-induced keratinocyte cell death. Furthermore, NM increased transient receptor potential vanilloid 1 (TRPV1) expression, intracellular Ca content, and the activities of Ca/calmodulin-dependent kinase kinase β (CaMKKβ), AMP-activated protein kinase (AMPK), unc-51-like kinase 1 (ULK1), and mammalian target of rapamycin (mTOR). NM-induced autophagy in keratinocytes was abolished by treatment with inhibitors of TRPV1 (capsazepine), CaMKKβ (STO-609), AMPK (compound C), and ULK1 (SBI-0206965) as well as TRPV1, CaMKKβ, and AMPK siRNA transfection. In addition, an mTOR inhibitor (rapamycin) had no significant effect on NM-stimulated autophagy or cell death of keratinocytes. Finally, the results of the in vivo experiment in NM-treated skin tissues were consistent with the findings of the in vitro experiment. In conclusion, NM-caused dermal toxicity by overactivating autophagy partially through the activation of TRPV1-Ca-CaMKKβ-AMPK-ULK1 signaling pathway. These results suggest that blocking TRPV1-dependent autophagy could be a potential treatment strategy for NM-caused cutaneous injury.
Topics: AMP-Activated Protein Kinase Kinases; Adenine; Animals; Autophagy; Autophagy-Related Protein 5; Autophagy-Related Protein-1 Homolog; Blister; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Cell Death; Chloroquine; Humans; Keratinocytes; Macrolides; Mechlorethamine; Mice; RNA, Small Interfering; Sirolimus; Skin; Skin Diseases; TOR Serine-Threonine Kinases; TRPV Cation Channels
PubMed: 33487631
DOI: 10.1038/s41392-020-00389-z -
Cutaneous and Ocular Toxicology Jun 2018Mass exposure to alkylating agents such as nitrogen mustard (NM), whether accidental or intentional as during warfare, are known to cause systemic toxicity and severe...
OBJECTIVE
Mass exposure to alkylating agents such as nitrogen mustard (NM), whether accidental or intentional as during warfare, are known to cause systemic toxicity and severe blistering from cutaneous exposure. Thus, establishing the timing and appropriate dose of any potential drug designed to reverse or impede these toxicities is critical for wound repair and survival. Our previous data demonstrates that a single intraperitoneal injection of low-dose 25-hydroxyvitamin D3 (25(OH)D) given as early as 1 h following NM exposure is sufficient to rescue mice from pancytopenia and death. However, the duration of time following exposure where intervention is still effective as a countermeasure is unknown. In this study, we sought to assess the maximal time permissible following NM exposure where 25(OH)D still affords protection against NM-induced cutaneous injury. Additionally, we determined if a higher dose of 25(OH)D would be more efficacious at time interval where low dose 25(OH)D is no longer effective.
METHODS
Low (5 ng) and high (50 ng) doses of 25(OH)D were administered intraperitoneally to mice following exposure to topical NM to assess wound resolution and survival. Mice were imaged and weighed daily to measure wound healing and to monitor systemic toxicity.
RESULTS
We demonstrated that 5 ng 25(OH)D administered as early as 1 h and as late as 24 h post-NM exposure is able to achieve 100% recovery in mice. In contrast, intervention at and beyond 48 h of NM exposure failed to achieve full recovery and resulted in ≥60% death between days 6 and 12, demonstrating the critical nature of timely intervention with 25(OH)D at each respective dose. In order to circumvent the observed failure at >48 h exposure, we provided two consecutive doses of 5 ng or 50 ng of 25(OH)D at 48 h and 72 h post-NM exposure. Repeat dosing with 25(OH)D at 48 h and beyond led to marked improvement of lesion size with 75% recovery from mortality.
CONCLUSIONS
The opportunity to use 25(OH)D as a medical countermeasure for NM-induced toxicity has a finite of window for intervention. However, modifications such as repeat dosing can be an effective strategy to extend the intervention potential of 25(OH)D.
Topics: Administration, Cutaneous; Animals; Calcifediol; Chemical Warfare Agents; Drug Administration Schedule; Female; Injections, Intraperitoneal; Mechlorethamine; Mice, Inbred C57BL; Wound Healing
PubMed: 28737434
DOI: 10.1080/15569527.2017.1355315 -
Dermatology and Therapy Mar 2022Treatment of early-stage mycosis fungoides (MF) requires safe, skin-directed therapies. Medication side effects can lead to underutilization of effective therapies. The...
Randomized Mechlorethamine/Chlormethine Induced Dermatitis Assessment Study (MIDAS) Establishes Benefit of Topical Triamcinolone 0.1% Ointment Cotreatment in Mycosis Fungoides.
INTRODUCTION
Treatment of early-stage mycosis fungoides (MF) requires safe, skin-directed therapies. Medication side effects can lead to underutilization of effective therapies. The objective of this study was to assess the use of topical triamcinolone 0.1% ointment as a means of reducing contact dermatitis associated with topical mechlorethamine/chlormethine gel for the treatment of MF.
METHODS
This prospective, randomized, open-label study evaluated 28 adults with mycosis fungoides who were eligible for treatment with topical mechlorethamine/chlormethine gel from December 17, 2017 to December 23, 2020. Patients were treated for 4 months with clinical follow-up through 12 months. Patients had half of their lesions also treated with topical triamcinolone 0.1% ointment (while the other half were treated with mechlorethamine/chlormethine alone). The study was self-controlled with separate lesions in the same patient receiving each treatment arm. Treatment arms were determined by the flip of a coin.
RESULTS
Twenty-eight patients enrolled (17 men (61%) and 11 women (39%)). Demographics included 25 White, 2 African Americans, and 1 Asian patient. Twenty-five completed the 12-month follow-up. Triamcinolone 0.1% ointment led to increased tolerability of mechlorethamine/chlormethine gel but did not change the efficacy of mechlorethamine/chlormethine. There was a statistically significant 50% decrease in dermatitis (SCORD score) at month 2 in the triamcinolone-treated arm.
CONCLUSIONS
Topical triamcinolone ointment is a helpful adjuvant therapy when treating patients with topical mechlorethamine/chlormethine gel. It diminishes inflammation and does not reduce efficacy. The peak incidence of dermatitis in the study occurred in the second and third months.
TRIAL REGISTRATION
ClinicalTrials.gov identifier, NCT03380026.
PubMed: 35122614
DOI: 10.1007/s13555-022-00681-6 -
International Journal of Molecular... May 2021We developed two models of chemically induced chronic lung injury and pulmonary fibrosis in mice (intratracheally administered hydrochloric acid (HCl) and...
We developed two models of chemically induced chronic lung injury and pulmonary fibrosis in mice (intratracheally administered hydrochloric acid (HCl) and intratracheally administered nitrogen mustard (NM)) and investigated male-female differences. Female mice exhibited higher 30-day survival and less weight loss than male mice. Thirty days after the instillation of either HCl or NM, bronchoalveolar lavage fluid displayed a persistent, mild inflammatory response, but with higher white blood cell numbers and total protein content in males vs. females. Furthermore, females exhibited less collagen deposition, milder pulmonary fibrosis, and lower Ashcroft scores. After instillation of either HCl or NM, all animals displayed increased values of phosphorylated (activated) Heat Shock Protein 90, which plays a crucial role in the alveolar wound-healing processes; however, females presented lower activation of both transforming growth factor-β (TGF-β) signaling pathways: ERK and SMAD. We propose that female mice are protected from chronic complications of a single exposure to either HCl or NM through a lesser activation of TGF-β and downstream signaling. The understanding of the molecular mechanisms that confer a protective effect in females could help develop new, gender-specific therapeutics for IPF.
Topics: Animals; Collagen; Female; Gene Expression Regulation; HSP90 Heat-Shock Proteins; Humans; Hydrochloric Acid; Idiopathic Pulmonary Fibrosis; Lung; MAP Kinase Signaling System; Male; Mechlorethamine; Mice; Smad Proteins; Transforming Growth Factor beta
PubMed: 34072833
DOI: 10.3390/ijms22115909 -
Chemical Research in Toxicology Nov 2020The reversible generation and capture of certain electrophilic quinone methide intermediates support dynamic reactions with DNA that allow for migration and transfer of...
The reversible generation and capture of certain electrophilic quinone methide intermediates support dynamic reactions with DNA that allow for migration and transfer of alkylation and cross-linking. This reversibility also expands the possible consequences that can be envisioned when confronted by DNA repair processes and biological machines. To begin testing the response to such an encounter, quinone methide-based modification of DNA has now been challenged with a helicase (T7 bacteriophage gene protein four, T7gp4) that promotes 5' to 3' translocation and unwinding. This model protein was selected based on its widespread application, well characterized mechanism and detailed structural information. Little over one-half of the cross-linking generated by a bisfunctional quinone methide remained stable to T7gp4 and did not suppress its activity. The helicase likely avoids the topological block generated by this fraction of cross-linking by its ability to shift from single- to double-stranded translocation. The remaining fraction of cross-linking was destroyed during T7gp4 catalysis. Thus, this helicase is chemically competent to promote release of the quinone methide from DNA. The ability of T7gp4 to act as a Brownian ratchet for unwinding DNA may block recapture of the QM intermediate by DNA during its transient release from a donor strand. Most surprisingly, T7gp4 releases the quinone methide from both the translocating strand that passes through its central channel and the excluded strand that was typically unaffected by other lesions. The ability of T7gp4 to reverse the cross-link formed by the quinone methide does not extend to that formed irreversibly by the nitrogen mustard mechlorethamine.
Topics: Alkylation; Cross-Linking Reagents; DNA; Indolequinones; Molecular Structure
PubMed: 33147957
DOI: 10.1021/acs.chemrestox.0c00413 -
Acta Dermato-venereologica Jun 2022Chlormethine is a bifunctional cytotoxic alkylating agent that binds to DNA, resulting in cell death (apoptosis). Chlormethine (also known as mechlorethamine) gel (CL...
Chlormethine is a bifunctional cytotoxic alkylating agent that binds to DNA, resulting in cell death (apoptosis). Chlormethine (also known as mechlorethamine) gel (CL gel) was approved in the European Union in 2017 and was first used in 2019. The aim of the study is to examine evidence regarding the efficacy and safety of chlormethine gel in everyday clinical experience from a cutaneous lymphoma centre. Twenty-three patients with stage IA-IIB mycosis fungoides received chlormethine gel between September 2020 and May 2021. All patients started by applying the gel daily and were monitored every month. At 1, 3, 6 and 9 months, 0%, 43.47%, 56.52% and 65.22% of patients, respectively, achieved an overall response. Five out of 23 patients (21.73%) achieved near complete response at a mean time of 6 months. Chlormethine gel was given as monotherapy in 12 patients (52.17%), and in addition to systemic treatments (methotrexate and peginterferon alpha-2a) in 11 patients (47.82%). Adverse events (AE) were recorded in 43.47% of patients, but only 3 discontinued treatment, due to dermatitis. Scale down of the treatment to application 3-times per week led to better patient compliance. This study shows that chlormethine gel is effective and safe in patients with mycosis fungoides with different types of skin lesions.
Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Humans; Mechlorethamine; Mycosis Fungoides; Skin Diseases; Skin Neoplasms
PubMed: 35199177
DOI: 10.2340/actadv.v102.1095 -
Anatomical Record (Hoboken, N.J. : 2007) Sep 2021Amino-Plex (SM1997) is a spray or liquid cosmeceutical that has been used for skin dryness, aging, or sun exposure. Its formulation includes electrolytes, trace...
Amino-Plex (SM1997) is a spray or liquid cosmeceutical that has been used for skin dryness, aging, or sun exposure. Its formulation includes electrolytes, trace minerals, amino acids, peptides, nucleosides and nucleotides, all substances that are <10 kDa. It is designed to increase oxygen levels in cells, improve glucose transport, stimulate ATP synthesis, and stimulate collagen formation, actions that can help facilitate repair of damaged cells. It also supports collagen synthesis and formation of healthy granulation tissue, accelerating reepithelization of damaged skin. Here, SM1997 has been tested as an agent to improve the healing of mustard injury to the cornea. The results indicate that SM1997 facilitates the retention of corneal epithelial attachment when applied to corneal organ cultures after nitrogen mustard exposure. In addition, it reduces the activation of enzymes that lead to epithelial-stromal separation, namely, ADAM17 and MMP-9. Therefore, SM1997 should be further investigated as a potential therapy sulfur mustard and nitrogen mustard exposure.
Topics: Collagen; Cornea; Epithelial Attachment; Mechlorethamine; Mustard Plant
PubMed: 33554453
DOI: 10.1002/ar.24597 -
Clinical Lymphoma, Myeloma & Leukemia Feb 2021The pivotal 201 Study investigated chlormethine/mechlorethamine gel treatment for patients with early stage disease mycosis fungoides and demonstrated the treatment was...
Evaluating the Treatment Patterns of Chlormethine/Mechlorethamine Gel in Patients With Stage I-IIA Mycosis Fungoides: By-time Reanalysis of a Randomized Controlled Phase 2 Study.
BACKGROUND
The pivotal 201 Study investigated chlormethine/mechlorethamine gel treatment for patients with early stage disease mycosis fungoides and demonstrated the treatment was not inferior to chlormethine ointment. However, overall response rates do not provide information about response patterns. The study objective was to assess the value of by-time analysis of clinical response data in visualizing response over time.
METHODS
This post hoc analysis re-evaluated chlormethine efficacy using a by-time approach that investigated the trend to treatment response and permitted assessment of response, both monthly between 1 and 6 months, and once every 2 months between 7 and 12 months, over the course of 1 year. In addition, very good partial response was redefined as a ≥ 75% response.
RESULTS
By-time analyses of Composite Assessment of Index Lesion Severity (CAILS) and modified severity-weighted assessment tool (mSWAT) showed response rates at 1 month (respectively, 8.5% and 5.9%) that increased over time to peak at 10 months (78.9% and 54.4%). Early, intermittent, and late response patterns were observed. In total, 32.5% of patients experienced very good partial response over 2 consecutive visits, indicating that ∼ 33% of patients could expect to have very good to complete response within 1 year.
CONCLUSION
By-time analysis for clinical response provides complementary information to traditional overall response rate data regarding response peak time and changes over time.
Topics: Antineoplastic Agents, Alkylating; Clinical Trials, Phase II as Topic; Gels; Humans; Mechlorethamine; Mycosis Fungoides; Neoplasm Staging; Randomized Controlled Trials as Topic; Skin Neoplasms; Time Factors; Treatment Outcome
PubMed: 33358692
DOI: 10.1016/j.clml.2020.11.022