Induction of leukemia cell differentiation by chemotherapeutic agents

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.