Kelloff G J, Boone C W, Crowell J A, Steele V E, Lubet R A, Doody L A, Malone W F, Hawk E T, Sigman C C
Chemoprevention Branch, National Cancer Institute (NCI), Bethesda, MD 20892, USA.
J Cell Biochem Suppl. 1996;26:1-28. doi: 10.1002/jcb.240630703.
Clinical chemoprevention trials of more than 30 agents and agent combinations are now in progress or being planned. The most advanced agents are well known and are in large Phase III chemoprevention intervention trials or epidemiological studies. These drugs include several retinoids [e.g., retinol, retinyl palmitate, all-trans-retinoic acid, and 13-cis-retinoic acid], calcium, Beta carotene, vitamin E, tamoxifen, and finasteride. Other newer agents are currently being evaluated in or being considered for Phase II and early Phase III chemoprevention trials. Prominent in this group are all-trans-N-(4-hydroxy phenyl)retinamide (4-HPR) (alone and in combination with tamoxifen), 2-difluoromethylornithine (DFMO), nonsteroidal antiinflammatory drugs (aspirin, piroxicam, sulindac), oltipraz, and dehydroepiandrostenedione (DHEA). A third group is new agents showing chemopreventive activity in animal models, epidemiological studies, or in pilot clinical intervention studies. They are now in preclinical toxicology testing or Phase I safety and pharmacokinetics trials preparatory to chemoprevention efficacy trials. These agents include S-allyl-l-cysteine, curcumin, DHEA analog 8354 (fluasterone), genistein, ibuprofen, indole-3-carbinol, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, sulindac sulfone, tea extracts, ursodiol, vitamin D analogs, and p-xylyl selenocyanate. A new generation of agents and agent combinations will soon enter clinical chemoprevention studies based primarily on promising chemopreventive activity in animal models and in mechanistic studies. Among these agents are more efficacious analogs of known chemopreventive drugs including novel carotenoids (e.g., alpha-carotene and lutein). Also included are safer analogs which retain the chemopreventive efficacy of the parent drug such as vitamin D3 analogs. Other agents of high interest are aromatase inhibitors (e.g., (+)-vorozole), and protease inhibitors (e.g., Bowman-Birk soybean trypsin inhibitor). Combinations are also being considered, such as vitamin E with l-selenomethionine. Analysis of signal transduction pathways is beginning to yield classes of potentially active and selective chemopreventive drugs. Examples are ras isoprenylation and epidermal growth factor receptor inhibitors.
目前，超过30种药物及药物组合的临床化学预防试验正在进行或正在计划之中。最先进的药物广为人知，正处于大规模的III期化学预防干预试验或流行病学研究阶段。这些药物包括几种维甲酸类药物（如视黄醇、棕榈酸视黄酯、全反式维甲酸和13 - 顺式维甲酸）、钙、β - 胡萝卜素、维生素E、他莫昔芬和非那雄胺。其他较新的药物目前正在II期和早期III期化学预防试验中进行评估或正在考虑用于此类试验。这组药物中比较突出的有全反式 - N -（4 - 羟基苯基）维甲酰胺（4 - HPR）（单独使用及与他莫昔芬联合使用）、2 - 二氟甲基鸟氨酸（DFMO）、非甾体抗炎药（阿司匹林、吡罗昔康、舒林酸）、奥替普拉和脱氢表雄酮（DHEA）。第三组是在动物模型、流行病学研究或初步临床干预研究中显示出化学预防活性的新药。它们目前正处于临床前毒理学测试或I期安全性和药代动力学试验阶段，为化学预防疗效试验做准备。这些药物包括S - 烯丙基 - L - 半胱氨酸、姜黄素、DHEA类似物8354（氟司睾酮）、染料木黄酮、布洛芬、吲哚 - 3 - 甲醇、紫苏醇、苯乙基异硫氰酸酯、9 - 顺式维甲酸、舒林酸砜、茶提取物、熊去氧胆酸、维生素D类似物和对二甲苯硒氰酸盐。新一代的药物及药物组合将很快进入临床化学预防研究，这主要基于它们在动物模型和机制研究中展现出的有前景的化学预防活性。这些药物中有已知化学预防药物的更有效类似物，包括新型类胡萝卜素（如α -胡萝卜素和叶黄素）。还包括保留母体药物化学预防功效的更安全类似物，如维生素D3类似物。其他备受关注的药物有芳香化酶抑制剂（如（+） - 伏洛唑）和蛋白酶抑制剂（如鲍曼 - 伯克大豆胰蛋白酶抑制剂）。也正在考虑药物组合，如维生素E与L - 硒代蛋氨酸的组合。对信号转导途径的分析开始产生潜在的活性和选择性化学预防药物类别。例如ras异戊烯化和表皮生长因子受体抑制剂。
