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.

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.

• Authors: Brian Crain, Shiyin Yao, Vina Keophilaone, Victor Promessi, McNancy Kang, Alcide Barberis, Roberto Maj, Emanuela Mura, Nadia Passini, Johanna Holldack, Ricardo Ochoa, Howard B Cottam, Dennis A Carson, Tomoko Hayashi
• Journal: European journal of dermatology : EJD (Eur J Dermatol) 2013 Sep-Oct Vol. 23 Issue 5 Pg. 618-28 ISSN: 1952-4013 [Electronic] France
• PMID: 24225049 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminoquinolines
• Antineoplastic Agents
• Chemotactic Factors
• Gels
• Glycerophospholipids
• Interleukin-1
• Interleukin-6
• Membrane Glycoproteins
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• Proto-Oncogene Proteins c-myc
• TMX-202
• Tlr7 protein, mouse
• Toll-Like Receptor 7
• Tumor Necrosis Factor-alpha
• Interferon-gamma
• Adenine
• Imiquimod

Topics

• Adenine (analogs & derivatives, blood, pharmacology, therapeutic use)
• Aminoquinolines (blood, pharmacology)
• Animals
• Antineoplastic Agents (blood, pharmacology, therapeutic use)
• Cell Line
• Cell Proliferation (drug effects)
• Chemotactic Factors (blood)
• Dendritic Cells (physiology)
• Gels (pharmacology, therapeutic use)
• Glycerophospholipids (blood, pharmacology, therapeutic use)
• Humans
• Imiquimod
• Interferon-gamma (metabolism)
• Interleukin-1 (metabolism)
• Interleukin-6 (metabolism)
• Keratinocytes (physiology)
• Keratosis, Actinic (drug therapy, genetics)
• Leukocytes, Mononuclear (drug effects)
• Macrophages (physiology)
• Maximum Tolerated Dose
• Membrane Glycoproteins (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Myeloid Differentiation Factor 88 (genetics)
• Proto-Oncogene Proteins c-myc (genetics)
• Toll-Like Receptor 7 (genetics)
• Tumor Necrosis Factor-alpha (blood, metabolism)