Lippman S M, Heyman R A, Kurie J M, Benner S E, Hong W K
University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
J Cell Biochem Suppl. 1995;22:1-10. doi: 10.1002/jcb.240590802.
Retinoids, which include natural vitamin A (retinol) and its esters and synthetic analogues, are the best-studied class of agents in chemoprevention. There are more than 4,000 different retinoids which have a wide spectrum of preclinical activities, structures, pharmacological profiles, tissue distributions, receptor specificities, and toxicities. A number of retinoids have significant activity in many in vivo experimental systems including skin, bladder, lung, breast and oral carcinogenesis. In clinical trials, several retinoids have achieved significant activity in the reversal of head and neck, skin, and cervical premalignancy, and in the prevention of second primary tumors associated with head and neck, skin, and non-small cell lung cancer. Since 1984, our group has conducted a series of clinical trials to explore the chemopreventive potential of 13-cis-retinoic acid (13cRA) in the aerodigestive tract. We have conducted two consecutive randomized studies in subjects with premalignant lesions of the oral cavity. These studies showed that high-dose 13cRA alone can achieve significant short-term reversal of oral premalignancy, and that high-dose followed by low-dose 13cRA can maintain suppression of oral carcinogenesis. Three other randomized trials have confirmed significant retinoid activity in this human carcinogenic system. We also developed a randomized, placebo-controlled trial of adjuvant high-dose 13cRA in patients with head and neck cancer. Second primary tumor development was significantly decreased in the 13cRA group, but 13cRA had no impact on primary disease recurrence or survival. This presentation will update the current status of clinical trials and correlative laboratory studies of potential intermediate endpoint biomarkers in retinoid chemoprevention of aerodigestive tract carcinogenesis.
维甲酸类物质，包括天然维生素A（视黄醇）及其酯类以及合成类似物，是化学预防领域研究最为深入的一类物质。有超过4000种不同的维甲酸类物质，它们具有广泛的临床前活性、结构、药理学特性、组织分布、受体特异性和毒性。许多维甲酸类物质在包括皮肤、膀胱、肺、乳腺和口腔致癌作用在内的多种体内实验系统中具有显著活性。在临床试验中，几种维甲酸类物质在逆转头颈部、皮肤和宫颈的癌前病变以及预防与头颈部、皮肤和非小细胞肺癌相关的第二原发性肿瘤方面取得了显著活性。自1984年以来，我们小组开展了一系列临床试验，以探索13 - 顺式维甲酸（13cRA）在气消化道的化学预防潜力。我们对患有口腔癌前病变的受试者进行了两项连续的随机研究。这些研究表明，单独使用高剂量13cRA可在短期内显著逆转口腔癌前病变，高剂量后接低剂量13cRA可维持对口腔致癌作用的抑制。另外三项随机试验证实了维甲酸类物质在这一人致癌系统中的显著活性。我们还开展了一项针对头颈癌患者的辅助高剂量13cRA的随机、安慰剂对照试验。13cRA组的第二原发性肿瘤发生显著减少，但13cRA对原发性疾病复发或生存没有影响。本报告将更新维甲酸类物质化学预防气消化道致癌作用的临床试验现状以及潜在中间终点生物标志物的相关实验室研究情况。
