The 1985 Walter Hubert lecture. Malignant cell differentiation as a potential therapeutic approach

Abstract

it was possible to demonstrate that physiological levels of retinoic acid and epidermal growth factor were capable of preventing the differentiation of these malignant keratinocytes into a mature tissue-like structure. The terminal differentiation caused by certain antineoplastic agents was investigated in HL-60 promyelocytic leukaemia cells to provide information on the mechanism by which chemotherapeutic agents induce cells to by-pass a maturation block. The anthracyclines aclacinomycin A and marcellomycin were potent inhibitors of N-glycosidically linked glycoprotein biosynthesis and transferrin receptor activity, and active inducers of maturation; temporal studies suggested that the biochemical effects were associated with the differentiation process. 6-Thioguanine produced cytotoxicity in parental cells by forming analog nucleotide. In hypoxanthine-guanine phosphoribosyltransferase negative HL-60 cells the 6-thiopurine initiated maturation; this action was due to the free base (and possibly the deoxyribonucleoside), a finding which separated termination of proliferation due to cytotoxicity from that caused by maturation.

Modulation of placental alkaline phosphatase activity and cytokeratins in human HN-1 cells by butyrate, retinoic acid, catecholamines and histamine

“…Indirect labeling of keratins with a polyclonal antibody showed that cytokeratin content was enhanced by butyrate but not by retinoic acid. Further analysis of cytokeratin content using four monoclonal antibodies showed that labeling of cytokeratins (5+8) As is shown in numerous reports, butyrate, retinoic acid, interferon, glucocorticoids, polar solvents, and certain chemotherapeutic agents can modulate terminal differentiation (Augeron & Laboisse, 1984;Burke, 1986;Jetten, 1984;Reiss et al, 1985;Sartorelli, 1985), accompanied by inhibition of proliferation (Pierce & Wallace, 1971;Prasad & Sinha, 1976), morphological changes (Abe & Kufe, 1984;Kamech et al, 1986), and an increase in the production of specific antigens and enzymes (Reese & Politano, 1981;Morita et al, 1982;Abe & Kufe, 1984;Reese et al, 1985), such as CEA and alkaline phosphatase. These effects were in most cases reversible, although some authors claimed a more permanently affected cell progeny after treatment (Augeron & Laboisse, 1984;Reiss et al, 1985).…”

Heterogeneous response to differentiation induction with different polar compounds in a clonal rat rhabdomyosarcoma cell line (BA-HAN-1C)

“…Thus, in many cancers at least some of the tumour cells spontaneously exhibit abortive attempts at normal differentiation (Pierce, 1974). Furthermore, induction of differentiation has been successfully achieved in several in vitro systems (for review see Freshney, 1985) indicating that the malignant phenotype does not necessarily represent an irreversible state and that the conversion of malignant cells to a more benign phenotype through differentiation induction may become an alternative therapeutic approach (Metcalf, 1983;Spremulli & Dexter, 1984;Freshney, 1985;Sartorelli, 1985;Sachs, 1987). We recently described the effects of retinoic acid on the differentiation and proliferation of the clonal rat rhabdomyosarcoma cell line BA-HAN-IC (Gabbert et al, 1988a).…”

Relationship between the induction of leukemia cell differentiation and the enhancement of reporter gene expression in 3T3 Swiss cells

“…The demonstration that certain chemical agents exhibit the ability to induce the terminal differentiation of a variety of transformed cell lines indicates that the differentiation block imposed in tumor cells by the carcinogenic process is not necessarily irreversible [1]. Thus, cancer therapy based upon the premise that the conversion of malignant cells to more mature end-stage forms lessens their proliferative and invasive capacity provides an attractive alternative to conventional cytotoxic cancer treatment (see, for example [2]). This approach termed "differentiation therapy" has culminated in the successful use of the vitamin A derivative all-trans retinoic acid (ATRA) as a primary treatment for patients with acute promyelocytic leukemia (APL) [3,4].…”