EXPERIMENTAL CHEMOTHERAPY OF PROLIFERATIVE SKIN DISEASES

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Psoriasis is a common and potentially debilitating disease, characterized by increased proliferation of skin. Several anti-proliferative agents, including methotrexate and hydroxyurea, are effective for the clinical control of this disease when given systemically. During the past 5 years, we have studied the anti-proliferative proper ties of o-dihydroxybenzene derivatives and have shown this effect to be mediated, in part, through inhibition of the enzymes ribonucleotide reductase and DNA polymerase. Since ribonucleotide reductase is central to the control of DNA synthesis in mammalian cells, we propose to study systemically the role of this enzyme and deoxyribonucleotide pool sizes in the control of the growth of human epidermal and related cells. We will also synthesize lipophilic analogs of known inhibitors of this enzyme as potential topical anti-psoriatic agents. Specifically, we will determine enzyme activity in normal and psoriatic skin, compare the levels of deoxyribonucleotides in normal and abnormal skin, and determine the relationship of ribonucleotide reductase and DNA polymerase in the control of DNA synthesis. We will also prepare 4 classes of derivatives, which include lipid-soluble analogs of hydroxyurea, thymidine, catechol, and guanazole. A series of long chain alkyl N-substituted derivatives of hydroxyurea, alkylphosphate esters of thymidine, alkylamino derivatives of catechol, and alkylacetyl derivatives of guanazole will be prepared. Bioassay will be conducted using highly differentiated squamous cell carcinoma cells in vitro, cultures of human epidermal cells, and nude mouse xenographs with human epidermis. These assays will confirm that the anti-proliferative activity is retained and that proper biophysical partition, indicating increased lipophilicity, has been achieved. Hopefully, the results of this proposal will permit us to understand the role of the important controlling enzyme ribonucleotide reductase in the growth and differentiation of human skin, as well as to evaluate its potential as a pharmacologic target for the topical chemotherapy of proliferative skin disease in man.