formycins and Leukemia--Erythroblastic--Acute

We have isolated an unusual nucleoside, aristeromycin, from the culture filtrate of Actinomycetes as a compound that induces normal morphology in v-ablts-NIH3T3 cells. Aristeromycin also induced erythroid differentiation in abl-expressing human chronic myelogenous leukaemia K562 cells. It did not affect the amount of Abl or the Abl-associated tyrosine kinase activity in either v-ablts-NIH3T3 or K562 cells. As a potent inhibitor of S-adenosylhomocysteine hydrolase, aristeromycin inhibited methylation of phosphatidylethanolamine to form phosphatidylcholine in K562 cells. Among aristeromycin analogues, the activity to inhibit S-adenosylhomocysteine hydrolase was paralleled with the induction of erythroid differentiation. Thus, aristeromycin inhibits abl functions indirectly, possibly by inhibiting biological methylations.

Topics: 3T3 Cells; Adenosine; Adenosylhomocysteinase; Animals; Cell Differentiation; Cell Division; Cell Line; Cell Line, Transformed; Cell Transformation, Neoplastic; Dose-Response Relationship, Drug; Formycins; Genes, abl; Humans; Hydrolases; Isomerism; Kinetics; Leukemia, Erythroblastic, Acute; Mice; Tubercidin; Tumor Cells, Cultured

5'-Methylthioformycin, a structural analog of 5'-methylthioadenosine in which the N-C glycosidic bond is substituted by a C-C bond, has been synthesized by a newly developed procedure. Membrane permeability of the molecule has been compared to that of methylthioadenosine in intact human erythrocytes and Friend erythroleukemia cells. The formycinyl compound is taken up with a rate significantly lower than that of 5'-methylthioadenosine and is not metabolized by the cells. 5'-Methylthioformycin inhibits Friend erythroleukemia cells' growth: the effect is dose-dependent, fully reversible and not caused by cytotoxicity. Several enzymes related to methylthioadenosine metabolism are inhibited by methylthioformycin. Rat liver methylthioadenosine phosphorylase is competitively inhibited with a Ki value of 2 microM. Among the propylamine transferases tested only rat brain spermine synthase is significantly inhibited, while rat brain spermidine synthase is less sensitive. Rat liver S-adenosylhomocysteine hydrolase is irreversibly inactivated with 50% inhibition at 400 microM methylthioformycin. 5'-Methylthioformycin does not exert any significant effect on protein carboxyl-O-methyltransferase. Inferences about the mechanism of the antiproliferative effect of the drug have been drawn from the above results.

Topics: Adenosine; Adenosylhomocysteinase; Animals; Antibiotics, Antineoplastic; Brain; Cell Division; Cell Membrane Permeability; Deoxyadenosines; Erythrocytes; Formycins; Friend murine leukemia virus; Humans; Hydrolases; Leukemia, Erythroblastic, Acute; Liver; Purine-Nucleoside Phosphorylase; Rats; Spermidine Synthase; Spermine Synthase; Thionucleosides