Z-4',5'-Didehydro-5'-deoxy-5'-fluoroadenosine (MDL 28,842), an Irreversible Inhibitor of S-Adenosylhomocysteine Hydrolase, Suppresses Proliferation of Cultured Keratinocytes and Squamous Carcinoma Cell Lines

5-Adenosylmethionine-dependent transmethylation reactions are required for many critical pathways in human cells. The enzyme 5-adenosylhomocysteine hydrolase converts 5-adenosylhomocysteine, a potent endogenous inhibitor of 5-adenosylmethionine-mediated methyltransferase reactions, to adenosine and L-homocysteine. The effects of the inhibitor of 5-adenosylhomocysteine hydrolase, Z-4',5'-didehydro-5'-deoxy-5'-fluoroadenosine (MDL 28,842), on the growth of cultured keratinocytes and cutaneous squamous cell carcinoma lines were investigated. MDL 28,842 suppressed the proliferation of all cells in a dose-dependent manner, and significantly increased keratinocyte differentiation at a concentration of 1 M. Following incubation with MDL 28,842, the methylation indices (ratio of S-adenosylmethionine/5-adenosylhomocysteine) of undifferentiated keratinocytes and squamous cell carcinoma lines were significantly decreased. These data demonstrate that the inhibitory effect of MDL 28,842 on squamous carcinoma cells and keratinocyte proliferation may result directly from inhibition of 5-adenosylhomocysteine hydrolase activity. The antiproliferative activity of MDL 28,842 against squamous carcinoma cells and keratinocytes suggests a potential role for MDL 28,842 as a novel therapeutic agent for neoplastic and hyperproliferative disorders of the skin.