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.