Retinoids and Demethylating Agents— Looking for Partners

Extract

The concept that carcinogenesis may be the result of a deficiency or a failure of the action of substances that are negative regulators of control of proliferation and growth of cells is hardly new (1) and certainly antedates current interest in the mutation of tumor suppressor genes in the causation of cancer. Thus, in their classic article on the role of retinoid deficiency in control of epithelial proliferation and differentiation, Wolbach and Howe (2) noted that retinoid-deficient epithelial tissues had a premalignant phenotype that was characterized by enhanced mitotic activity and loss of differentiation. Retinoids may indeed be considered prototypes of such negative regulators of epithelial cell growth, and there is an immense literature on their mechanism of action and potential use for cancer prevention [reviewed in (3)].

However, although there have been a few major advances in the clinical use of retinoids to prevent or to treat several types of cancer (4–6), the widespread practical use of these agents in the field of oncology, either preventively or therapeutically, has yet to be achieved. Thus, while the proven efficacy of selective estrogen receptor modulators (SERMs) as agents to prevent breast cancer (7,8) justifies the present large clinical Study of Tamoxifen and Raloxifene (STAR) to compare the relative benefits of two SERMs (tamoxifen and raloxifene) without a placebo control, the practical use of retinoids to prevent breast cancer in postmenopausal women remains to be demonstrated, in spite of an impressive amount of data from animal experiments that strongly suggest that prevention should be possible. Retinoids are still a hope, rather than a practical reality, in most of clinical oncology. The report by Widschwendter et al. (9) in this issue of the Journal suggests one possible mechanism for this lack of clinical efficacy of retinoids and indicates a practical strategy to make retinoids more effective, both as preventive and as therapeutic agents.