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

S-Adenosylmethionine-dependent transmethylation reactions are required for many critical pathways in human cells. The enzyme S-adenosylhomoc ysteine hydrolase converts S-adenosylhomocysteine, a potent endogenous inhibitor of S-adenosylmethionine-mediated methyltransferase reaction s, to adenosine and L-homocysteine. The effects of the inhibitor of S- adenosylhomocysteine hydrolase, Z-4',5'-didehydro-5'-deoxy-5'-fluoro-a denosine (MDL 28,842), on the growth -of cultured keratinocytes and cu taneous squamous cell carcinoma lines were investigated. MDL 28,842 su ppressed the proliferation of all cells in a dose-dependent manner, an d significantly increased keratinocyte differentiation at a concentrat ion of 1 muM. Following incubation with MDL 28,842, the methylation in dices (ratio of S-adenosylmethionine/S-adenosylhomocysteine) of undiff erentiated keratinocytes and squamous cell carcinoma lines were signif icantly decreased. These data demonstrate that the inhibitory effect o f MDL 28,842 on squamous carcinoma cells and keratinocyte proliferatio n may result directly from inhibition of S-adenosylhomocysteine hydrol ase activity. The antiproliferative activity of MDL 28,842 against squ amous carcinoma cells and keratinocytes suggests a potential role for MDL 28,842 as a novel therapeutic agent for neoplastic and hyperprolif erative disorders of the skin.