ABSTRACT
ALDARA (imiquimod cream 5%) recently became available for the treatment of genital and perianal warts; however, the topical mechanism of action of imiquimod is not fully understood. Imiquimod, and its analogs R-842, S-27609, and S-28463, are potent anti-viral and anti-tumor agents in animal models. Much of the biologic activity of these compounds can be attributed to the induction of cytokines, including interferon-alpha, tumor necrosis factor-alpha, interleukins-1, -6, -8, and others. This study was performed to characterize the response of mice and rats to topical application of imiquimod and S-28463 and also to evaluate these agents in cultures of murine and human skin cells. Topical administration of imiquimod or S-28463 to the flanks of hairless mice and rats leads to increases in local concentrations of interferon and tumor necrosis factor in the skin. The concentrations of interferon and tumor necrosis factor were higher at the site of drug application than in skin from the contralateral flank or skin from untreated animals. Interferon-alpha mRNA levels were also elevated in the skin of mice after topical application of either imiquimod or S-28463. In vitro, both imiquimod and S-28463 induced increases in interferon and tumor necrosis factor in cultures of cells isolated from hairless mouse skin. Imiquimod also increased interleukin-8 concentrations in human keratinocyte and fibroblast cultures, whereas S-28463 induced increases in tumor necrosis factor in fibroblast cultures. These results demonstrate that imiquimod and S-28463 stimulate production of cytokines in the skin after topical application, which may play a major role in its activity in genital wart patients.
Subject(s)
Adjuvants, Immunologic/pharmacology , Aminoquinolines/pharmacology , Cytokines/metabolism , Skin/metabolism , Administration, Topical , Animals , Antibody Formation/drug effects , Cells, Cultured , Female , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Imiquimod , Interferon-alpha/genetics , Keratinocytes/drug effects , Keratinocytes/metabolism , Male , Melanocytes/drug effects , Melanocytes/metabolism , Mice , Mice, Hairless , RNA, Messenger/metabolism , Rats , Rats, Nude , Skin/cytology , Skin/drug effectsABSTRACT
Recently, a new class of immunomodulating agents, represented by the molecules imiquimod and R-842, has demonstrated potent antiviral and antitumor activities in animal models. In this study, another representative of this class, S-28463 (4-amino-2-ethoxymethyl-alpha,alpha-dimethyl-1H-imidazo[4,5-c]quinoline- 1- ethanol) was evaluated for its immunomodulating and antiviral activities. S-28463 induced IFN and other cytokines in vivo in mice, rats, monkeys and in vitro in human peripheral blood mononuclear cell cultures. S-28463 showed potent antiviral activity against herpes simplex virus-challenged guinea pigs when given subcutaneously, dermally, or intravaginally 24 h before infection. Antiviral activity in guinea pigs correlated with the induction of serum 2',5'-oligoadenylate synthetase activity. Thus, S-28463, like the other imidazoquinolines, demonstrates potent antiviral and immunomodulating effects in a number of models.
