Differentiation of Malignant Cells as a Therapeutic Approach

Abstract

The hematological malignancies may be considered to be diseases of altered maturation in which the rate of proliferation is increased relative to that of terminal differentiation. Many neoplastic cells, however, retain the capacity to mature to end-stage cells with a finite life-span. Differentiation to a nonmalignant state can be produced in many different malignant cell types by exposure to a variety of structurally diverse biological and chemical agents, including cytokines, solvents, hormones, vitamins, tumor promoters and cancer chemotherapeutic agents. The induced transformation to a terminally differentiated phenotype demonstrates the reversibility of the malignant state.

A number of structurally diverse cancer chemotherapeutic agents, such as the anthracyclines, epipodophyllotoxins, alkylating agents, vinca alkaloids, antifolates, purine antimetabolites, and pyrimidine nucleoside analogs, are capable of inducing differentiation, making it conceivable that the antineoplastic effects of these agents are the result of a combination of both cytodestruction and terminal differentiation. The alterations responsible for the termination of proliferation by these two mechanisms in some cases are the result of different metabolic events. We have shown that for the antileukemic agent 6-thioguanine, the free base is the form that initiates the maturation process by interacting with benzodiazepine receptors present on the surface of the leukemic cells, while conversion to the nucleotide forms of the 6-thiopurine is responsible for cytotoxicity. In an analogous manner the trisaccharide-containing anthracyclines, aclacinomycin and marcellomycin, are capable of inducing differentiation, whereas the monosaccharide-containing anthracyclines, adriamycin and pyromycin, cause cytodestruction. The granulocyte colony-stimulating factor (G-CSF) and its receptor constitute an example of the importance of a physiological cytokine to the differentiation process.

Termination of proliferation through the induction of differentiation is a programmed event and the production of a differentiated phenotype results in a partial normalization of cellular events. This has been shown by the demonstration that leukemia cells primarily express a facilitated diffusion transport system for the pyrimidine nucleoside uridine, which tends to equilibrate internal and external concentrations of this ribonucleoside in a manner characteristic of most neoplastic tissues. The induction of differentiation by dimethylsulfoxide or by 12-O-tetradecanoylphorbol 13-acetate causes a down-regulation of the facilitated transport mechanism and the predominance of a Na⁺-dependent active transporter characteristic of normal tissue. This results in an accumulation of free uridine in the mature cells. Studies conducted with the HL-60 human promyelocytic leukemia and the WEHI-3B monomyelocytic leukemia have been used to provide the examples of these phenomena.