thioguanine-anhydrous and marcellomycin

The antineoplastic agents marcellomycin (and related anthracycline antibiotics) and 6-thioguanine are effective inducers of the differentiation of cultured leukemia cells. Studies designed to investigate the relationship between structure and activity conducted with the anthracyclines in HL-60 human acute promyelocytic leukemia cells indicated a dissociation between cytotoxicity and maturation-inducing properties of these agents. In an analogous manner, 6-thioguanine induced effective erythroid and granulocytic differentiation of Friend and HL-60 leukemias, respectively, only in hypoxanthine-guanine phosphoribosyltransferase deficient cells. These findings suggest that 6-thioguanine need not be metabolized to a nucleotide to be active as an inducer of differentiation, and that the concentration of the 6-thiopurine required to initiate the commitment to maturation is greater than that producing cytotoxicity. Erythrodifferentiation of HGPRT negative Friend murine leukemia cells by 6-thioguanine was antagonized by tetracaine, d, 1-propranolol and 12-O-tetradecanoylphorbol-13-acetate, providing evidence for a cell membrane mediated component in the action of the purine antimetabolite. This suggests that the biochemical events that produce differentiation after exposure to 6-thioguanine may differ from those responsible for the toxic actions of the drug. Studies such as these, designed to gain an understanding of the target sites of inducers of differentiation, may lead to the development of new agents of potential therapeutic benefit in the treatment of certain forms of cancer based on the conversion of malignant cells to their non-proliferating mature counterparts.

Topics: Acute Disease; Anthracyclines; Antibiotics, Antineoplastic; Cell Differentiation; Cell Line; Humans; Leukemia, Experimental; Naphthacenes; Structure-Activity Relationship; Thioguanine

Granulocytic maturation of HL-60 promyelocytic leukemia cells induced by dimethylsulfoxide has been shown to produce a decrease in cellular protein phosphotyrosine residues and increases in both tyrosine kinase and protein phosphotyrosine phosphatase activities (D. A. Frank and A. C. Sartorelli, Biochem. Biophys. Res. Commun., 140: 440-447, 1986). These changes have been shown to not be restricted to dimethylsulfoxide-induced differentiation, since similar changes occur in HL-60 cells initiated with retinoic acid and in HL-60 sublines resistant to dimethylsulfoxide-induced differentiation treated with the retinoid. These regulatory events are not directly coupled to growth arrest, which accompanies terminal maturation, since the anthracycline antibiotics aclacinomycin A and marcellomycin, which induce HL-60 differentiation, cause these changes in phosphotyrosine metabolism, while Adriamycin, at a level which produces an equivalent degree of growth inhibition but does not initiate the maturation of HL-60 cells, does not. Furthermore, an HL-60 subline deficient in hypoxanthine-guanine phosphoribosyltransferase, which differentiates in the presence of 6-thioguanine, produced a decrease in phosphotyrosine residues and increases in tyrosine kinase and phosphotyrosine phosphatase activities in response to the purine antimetabolite, while the parental HL-60 line, in which 6-thioguanine inhibits cellular proliferation but does not induce maturation, does not exhibit these changes. Finally, similar alterations in phosphotyrosine regulation were exhibited during anthracycline-induced differentiation of the murine myelomonocytic leukemia cell line WEHI-3B D+, supporting the concept that the phenomena measured represent a general response to inducers of the granulocytic differentiation of leukemia cells.

Topics: Aclarubicin; Anthracyclines; Antibiotics, Antineoplastic; Cell Differentiation; Dimethyl Sulfoxide; Humans; Leukemia, Myeloid, Acute; Naphthacenes; Phosphoprotein Phosphatases; Phosphorylation; Protein Tyrosine Phosphatases; Protein-Tyrosine Kinases; Thioguanine; Tumor Cells, Cultured; Tyrosine