Dragnev K H, Rigas J R, Dmitrovsky E
The Norris Cotton Cancer Center and Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA.
Oncologist. 2000;5(5):361-8. doi: 10.1634/theoncologist.5-5-361.
Carcinogenesis is a multistep process that converts normal cells into malignant cells. Once transformed, malignant cells acquire the ability to invade and metastasize, leading to clinically evident disease. During this continuum from normal to metastatic cells, carcinogenic steps can be arrested or reversed through pharmacological treatments, known as cancer chemoprevention. Chemoprevention strategies represent therapeutic interventions at early stages of carcinogenesis, before the onset of invasive cancer. Effective chemoprevention should reduce or avoid the clinical consequences of overt malignancies by treating early neoplastic lesions before development of clinically apparent signs or symptoms. Preclinical, clinical, and epidemiological data provide considerable support for cancer chemoprevention as an attractive therapeutic strategy. This clinical approach was validated in the recent tamoxifen randomized trial, demonstrating that a selective estrogen receptor modulator reduces the risk of breast cancer in women at high risk for this malignancy. Derivatives of vitamin A, the retinoids, have reported activity in treating specific premalignant lesions and reducing incidence of second primary tumors in patients with prior head and neck, lung or liver cancers. Whether the retinoids will prevent primary cancers at these sites is not yet known. Notably, a carotenoid (beta-carotene) was shown as inactive in primary prevention of lung cancers in high-risk individuals. This underscores the need for relevant in vitro models to identify pathways signaling chemopreventive effects. These models should assess the activity of candidate chemoprevention agents before the conduct of large and costly prevention trials. An improved understanding of cancer prevention mechanisms should aid in the discovery of new therapeutic targets and chemoprevention agents. Ideally, these agents should have tolerable clinical toxicities suitable for chronic administration to individuals at high risk for developing primary or second cancers. This article reviews what is now known from clinical and preclinical studies about the retinoids as cancer prevention agents.
癌症发生是一个将正常细胞转化为恶性细胞的多步骤过程。一旦发生转化，恶性细胞就获得了侵袭和转移的能力，从而导致临床上明显的疾病。在从正常细胞到转移细胞的这一连续过程中，致癌步骤可以通过药物治疗被阻断或逆转，这被称为癌症化学预防。化学预防策略代表了在侵袭性癌症发生之前的癌症发生早期阶段的治疗干预。有效的化学预防应通过在临床明显体征或症状出现之前治疗早期肿瘤病变来减少或避免明显恶性肿瘤的临床后果。临床前、临床和流行病学数据为癌症化学预防作为一种有吸引力的治疗策略提供了相当多的支持。这种临床方法在最近的他莫昔芬随机试验中得到了验证，表明一种选择性雌激素受体调节剂可降低患这种恶性肿瘤风险较高的女性患乳腺癌的风险。维生素A的衍生物类视黄醇，已报道在治疗特定的癌前病变以及降低先前患有头颈癌、肺癌或肝癌的患者发生第二原发性肿瘤的发生率方面具有活性。类视黄醇是否能预防这些部位的原发性癌症尚不清楚。值得注意的是，一种类胡萝卜素（β-胡萝卜素）在高危个体肺癌的一级预防中被证明没有活性。这突出了需要相关的体外模型来确定化学预防作用的信号传导途径。这些模型应在进行大型且昂贵的预防试验之前评估候选化学预防剂的活性。对癌症预防机制的更好理解应有助于发现新的治疗靶点和化学预防剂。理想情况下，这些药剂应具有可耐受的临床毒性，适合长期给予有发生原发性或继发性癌症高风险的个体。本文综述了目前从临床和临床前研究中已知的关于类视黄醇作为癌症预防剂的情况。
