Retinoids in Cancer Treatment

Abstract

Since initial studies identifying the important role of vitamin A and its derivatives (retinoids) in maintaining the integrity of epithelial tissues, these compounds have served as paradigms for experimental studies exploring the pharmacologic modification of carcinogenesis. Retinoids have clearly been shown to inhibit chemically induced mammary and urothelial carcinogenesis in experimental animals. Prohibitive toxicity of the parent compound, vitamin A, led to a systematic search for synthetic derivatives with an improved therapeutic index. More than 1500 such compounds have been synthesized, many retaining chemopreventive potential, but with less toxicity. Although several anecdotal reports confirming therapeutic benefits of cis-retinoic acid in patients with acute promyelocytic leukemia and myelodysplastic syndromes appeared in the late 1970s and early 1980s, the remarkable studies of Huang and his colleagues in China in 1988 reporting complete remissions in patients with this uncommon variety of acute myelogenous leukemia with the transisomer of retinoic acid (all-trans-retinoic acid) led to a resurgence of interest in the retinoids as differentiating agents for the prevention and therapy of cancer. Furthermore, molecular studies showing DNA rearrangements of the alpha nuclear receptor for retinoic acid located on chromosome 17 in patients with acute promyelocytic leukemia, a disease invariably associated with a translocation between chromosomes 15 and 17, provided a direct connection between an altered nuclear receptor and the development of a human malignancy. The retinoids also may have important beneficial effects in prevention of recurrent malignancies once the primary tumor has been treated, such as in squamous cell carcinoma of the head and neck. Because retinoids appear to be less effective in inducing differentiation in nonpromyelocytic leukemia cells, investigators have conducted a number of studies to exploit potential synergism between retinoids and other differentiating agents or biologic effectors. Differentiation therapy and chemoprevention are attractive alternative approaches to intensive cytotoxic chemotherapy. It is now clear that retinoids represent one class of compounds with which it may be possible to reverse the progression of malignant disease and prevent carcinogenesis.

A Phase II pilot trial of 13-cis retinoic acid and interferon-? in patients with advanced pancreatic carcinoma

“…Retinoids, which are referred to as natural and synthetic derivatives of vitamin A, have been shown to inhibit proliferation and/or induce differentiation in a variety of preclinical models. [7][8][9][10] In addition, several clinical trials demonstrated beneficial effects of retinoids in the prevention and treatment of various malignancies (reviewed in references [11][12][13]. We previously demonstrated that retinoids inhibit growth and induce differentiation in a broad panel of human pancreatic carcinoma cells in vitro and in vivo.…”

Modifying Effects of 1'-Acetoxychavicol Acetate (ACA) and the Novel Synthetic Retinoids Re-80, Am-580 and Am-55P in a Two-Stage Carcinogenesis Model in Female Rats

“…Retinoids have been shown to suppress the induction of mammary tumors by a variety of carcinogens in rat models (Moon, 1989;Tallman and Wiernik, 1992), and Re-80 and Am-580 also have anti-proliferative effects on normal mammary epithelium or human breast carcinoma cells (Lee et al, 1995b;Cho et al, 1997). Nevertheless, there were no differences in incidences, multiplicities and volumes of mammary tumors with the novel retinoids-treated groups in the present study.…”

Antioxidant Properties of Novel Benzimidazole Retinoids

“…The use of retinoic acid in many animal models of carcinogenesis has also suggested that its action may depend on its antioxidant activity [1]. Retinoids have recently received considerable attention as agents that may be useful for both cancer prevention and treatment due to their cell differentiation, proliferation and antioxidant effects [2]. In addition, retinoids have been shown to function as effective antioxidants by inhibiting microsomal lipid peroxidation [3,4].…”