Increased Chlormethine-Induced DNA Double-Stranded Breaks in Malignant T Cells from Mycosis Fungoides Skin Lesions

Chang, Yun‐Tsan; Ignatova, Desislava; Hoetzenecker, Wolfram; Pascolo, Steve; Guenova, Emmanuella

doi:10.1016/j.xjidi.2021.100069

Cited by 11 publications

(33 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, further study is needed to confirm this hypothesis. Of interest, given that in MF atypical cells are located predominantly within the epidermis [ 1 ], a recent in vitro study confirmed that CL directly inhibits mainly rapidly proliferating malignant T-cells in MF [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…Chlormethine (CL; also known as mechlorethamine) is a bifunctional deoxyribonucleic acid (DNA)-alkylating agent that inhibits rapidly proliferating cells [ 1 , 9 , 10 ]. CL also induces DNA double-stranded breaks, increases caspase 3 gene expression, and suppresses DNA-repair genes in a subpopulation of malignant skin T-cells from patients with MF-CTCL [ 11 ]. CL is a well-established and effective topical therapy for MF-CTCL [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Chlormethine Gel for the Treatment of Mycosis Fungoides Cutaneous T-Cell Lymphoma: In Vitro Release and Permeation Testing

Giuliano

Frizzarin

Alonzi

et al. 2022

Dermatol Ther (Heidelb)

View full text Add to dashboard Cite

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 2 /√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. Supplementary Information The online version contains supplementary material available at 10.1007/s13555-022-00813-y.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chlormethine Gel for the Treatment of Mycosis Fungoides Cutaneous T-Cell Lymphoma: In Vitro Release and Permeation Testing

Giuliano

Frizzarin

Alonzi

et al. 2022

Dermatol Ther (Heidelb)

View full text Add to dashboard Cite

show abstract

“…CL gel is the first CL formulation that has been developed and approved for treatment of patients with MF, with no evidence of systemic absorption [ 26 ]. Recent data on the CL mode of action have shown that CL predominantly inhibits rapidly proliferating malignant skin T cells [ 62 ]. The gel is effective for treatment of MF, with high response rates seen both in clinical trial and real-world settings.…”

Section: Discussionmentioning

confidence: 99%

Chlormethine Gel for Patients with Mycosis Fungoides Cutaneous T Cell Lymphoma: A Review of Efficacy and Safety in Clinical Trial and Real-World Settings

et al. 2022

View full text Add to dashboard Cite

“…Chlormethine is a bifunctional alkylating agent that inhibits rapidly proliferating cells. Current evidence suggests that chlormethine renders malignant MF skin T cells more prone to apoptosis by inducing double-stranded DNA breaks, upregulating the pro-apoptotic gene CASP3, and suppressing the expression of genes involved in homologous recombination repair [10]. These data all indicate an important effect of targeting MF skin tumor cells and provide a rationale for chlormethine as an early and valuable skin-directed treatment option for cutaneous lymphoma.…”

Section: Introductionmentioning

confidence: 95%

Chlormethine Gel Versus Chlormethine Ointment for Treatment of Patients with Mycosis Fungoides: A Post-Hoc Analysis of Clinical Trial Data

Hodak

2022

Am J Clin Dermatol

View full text Add to dashboard Cite

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.

show abstract

Increased Chlormethine-Induced DNA Double-Stranded Breaks in Malignant T Cells from Mycosis Fungoides Skin Lesions

Cited by 11 publications

References 34 publications

Chlormethine Gel for the Treatment of Mycosis Fungoides Cutaneous T-Cell Lymphoma: In Vitro Release and Permeation Testing

Chlormethine Gel for the Treatment of Mycosis Fungoides Cutaneous T-Cell Lymphoma: In Vitro Release and Permeation Testing

Chlormethine Gel for Patients with Mycosis Fungoides Cutaneous T Cell Lymphoma: A Review of Efficacy and Safety in Clinical Trial and Real-World Settings

Chlormethine Gel Versus Chlormethine Ointment for Treatment of Patients with Mycosis Fungoides: A Post-Hoc Analysis of Clinical Trial Data

Contact Info

Product

Resources

About