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.
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.


OBJECTIVE
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.


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.


CONCLUSIONS
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.
Moores Cancer Center, University California San Diego, La Jolla CA, USA. 92093-0695.
Brian
B
Crain
Shiyin
S
Yao
Vina
V
Keophilaone
Victor
V
Promessi
McNancy
M
Kang
Alcide
A
Barberis
Roberto
R
Maj
Emanuela
E
Mura
Nadia
N
Passini
Johanna
J
Holldack
Ricardo
R
Ochoa
Howard B
HB
Cottam
Dennis A
DA
Carson
Tomoko
T
Hayashi
D000225:Adenine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D000634:Aminoquinolines / Q000097:blood / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002630:Chemotactic Factors / Q000097:blood; D003713:Dendritic Cells / Q000502:physiology; D005782:Gels / Q000494:pharmacology / Q000627:therapeutic use; D020404:Glycerophospholipids / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D000077271:Imiquimod; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D015603:Keratinocytes / Q000502:physiology; D055623:Keratosis, Actinic / Q000188:drug therapy* / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008264:Macrophages / Q000502:physiology; D020714:Maximum Tolerated Dose; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D051199:Toll-Like Receptor 7 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism
D000634:Aminoquinolines; D000970:Antineoplastic Agents; D002630:Chemotactic Factors; D005782:Gels; D020404:Glycerophospholipids; D007375:Interleukin-1; D015850:Interleukin-6; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016271:Proto-Oncogene Proteins c-myc; C000590331:TMX-202; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000225:Adenine; D000077271:Imiquimod
Myc; Toll like receptor-7; skin proliferative disease