1. Inhibition of keratinocyte proliferation by phospholipid-conjugates of a TLR7 ligand in a Myc-induced hyperplastic actinic keratosis model in the absence of systemic side effects
- Author
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Victor J. Promessi, Brian Crain, McNancy Kang, Shiyin Yao, Tomoko Hayashi, Dennis A. Carson, Johanna Holldack, Roberto Maj, Vina Keophilaone, Nadia Passini, Alcide Barberis, Howard B. Cottam, Emanuela Mura, and Ricardo Ochoa
- Subjects
Keratinocytes ,Maximum Tolerated Dose ,Antineoplastic Agents ,Mice, Transgenic ,Imiquimod ,Glycerophospholipids ,Dermatology ,Pharmacology ,Article ,Cell Line ,Proto-Oncogene Proteins c-myc ,Interferon-gamma ,Mice ,In vivo ,medicine ,Animals ,Humans ,Potency ,Cell Proliferation ,Mice, Knockout ,Membrane Glycoproteins ,Chemotactic Factors ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,business.industry ,Adenine ,Macrophages ,Actinic keratosis ,Dendritic Cells ,TLR7 ,medicine.disease ,In vitro ,Keratosis, Actinic ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Toll-Like Receptor 7 ,Myeloid Differentiation Factor 88 ,Toxicity ,Aminoquinolines ,Leukocytes, Mononuclear ,Keratinocyte ,business ,Gels ,Interleukin-1 ,medicine.drug - Abstract
Background. The Toll-like receptor 7 (TLR7) activator imiquimod (IMQ) is safe and effective in treating actinic keratosis; however, an intermittent treatment regimen is necessary because of excessive local reactions. Objectives. To evaluate in vitro potency, pharmacodynamics/pharmacokinetics, toxicity and efficacy in vivo of the newly developed TLR7 ligand-phospholipid conjugate, TMX-202, in a gel formulation. Material and Methods. The effects of TMX-202 were assessed both in vitro on a murine macrophage cell line and in primary bone marrow-derived dendritic cells and in vivo on mice (C57BL/6-wild type, Myd88 -/- and Tlr7 -/- ). Results. TMX-202 was more potent than IMQ in vitro using murine and human cells. In contrast, in vivo it showed less systemic pro-inflammatory activity and better safety than IMQ. Moreover, the TMX-202 gel formulation exhibited at least comparable efficacy to Aldara in a mouse model for skin proliferative diseases. Conclusion. TMX-202 is safe and efficacious without causing excessive adverse effects, suggesting that it may be an alternative to Aldara for the treatment of proliferative skin conditions.
- Published
- 2013
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