Tallman M S, Wiernik P H
Division of Hematology-Oncology, Northwestern University Medical School, Chicago, IL 60611.
J Clin Pharmacol. 1992 Oct;32(10):868-88. doi: 10.1002/j.1552-4604.1992.tb04633.x.
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.
自从最初的研究确定维生素A及其衍生物（类视黄醇）在维持上皮组织完整性方面的重要作用以来，这些化合物一直是探索癌变药理学修饰的实验研究范例。类视黄醇已被明确证明可抑制实验动物中化学诱导的乳腺癌和尿路上皮癌。母体化合物维生素A的毒性过高，促使人们系统地寻找治疗指数更高的合成衍生物。现已合成了1500多种此类化合物，其中许多仍具有化学预防潜力，但毒性较小。尽管在20世纪70年代末和80年代初出现了几篇轶事报道，证实顺式维甲酸对急性早幼粒细胞白血病和骨髓增生异常综合征患者有治疗益处，但1988年中国的黄及其同事进行的卓越研究报告称，维甲酸的反式异构体（全反式维甲酸）可使这种罕见类型的急性髓性白血病患者完全缓解，这引发了人们对类视黄醇作为癌症预防和治疗分化剂的兴趣再度高涨。此外，分子研究表明，急性早幼粒细胞白血病患者位于17号染色体上的视黄酸α核受体存在DNA重排，这种疾病总是与15号和17号染色体之间的易位相关，这直接将核受体改变与人类恶性肿瘤的发生联系起来。类视黄醇在原发性肿瘤得到治疗后预防复发性恶性肿瘤方面也可能具有重要的有益作用，例如对头颈部鳞状细胞癌。由于类视黄醇在诱导非早幼粒细胞白血病细胞分化方面似乎效果较差，研究人员进行了多项研究，以探索类视黄醇与其他分化剂或生物效应器之间的潜在协同作用。分化疗法和化学预防是强化细胞毒性化疗的有吸引力的替代方法。现在很清楚，类视黄醇是一类有可能逆转恶性疾病进展并预防癌变的化合物。
