Many human skin diseases display a hyperproliferative or proliferative epidermis, or cutaneous inflammation, or combinations of these two pathological characteristics (e. g., psoriasis). As an example, the keratinocytes of psoriatic epidermis are both hyperproliferative and produce elevated levels of Amphiregulin, IL-8, IL-1alpha and TNFalpha cytokines that may both attract and activate inflammatory cells, and promote psoriatic epidermal keratinocyte hyperproliferation. Additionally, the aberrant activity of the immune system may direct the mitogenic activation of these cells by activating an endogenous epidermal growth factor (EGF) pathway in the psoriatic epidermal keratinocytes. In addition to treating this pathology with immunosuppressive therapies, it is also thought that an effective blockade of EGF signaling could also be of therapeutic benefit. Endogenous purine-related compounds have been shown to dampen the inflammatory state by inhibiting the activity of immune cells. We have demonstrated that these naturally occurring purine-related compounds can reversibly inhibit the EGF receptor-dependent proliferation of both normal and psoriatic keratinocytes in vitro. We have also shown that these compounds also suppress the expression of cytokines such as IL-8, IL-1alpha and TNFalpha which are expressed in keratinocyte cell cultures treated with phorbol ester. We have recently demonstrated that a previously synthesized, non-naturally occurring purine-related analog inhibits both the proliferation of cultured human keratinocytes and phorbol-ester-induced keratinocyte inflammatory cytokine expression. Our proposed investigation will examine activity of this analog, and related purine analogs, on both human keratinocyte cultures, and intact human skin organ culture models. The results of the proposed study will determine whether these compounds might represent candidate non-steroidal drugs for further preclinical testing as therapeutics for inflammatory-proliferative skin disease states (e. g., psoriasis).
