Reddy Bandaru S, Rao Chinthalapally V
Nutritional Carcinogenesis and Chemoprevention Program, American Health Foundation, Valhalla, NY 10595, USA.
J Environ Pathol Toxicol Oncol. 2002;21(2):155-64.
During recent years, multidisciplinary studies in epidemiology and molecular biology, as well as preclinical studies, have contributed much to our understanding of the etiology of colorectal cancer; more importantly they have enabled us to approach its prevention. An impressive body of epidemiological data suggests an inverse relationship between colorectal cancer risk and regular use of nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin. Clinical trials with NSAIDs have demonstrated that NSAID treatment caused regression of preexisting colon adenomas in patients with familial adenomatous polyposis. Preclinical efficacy studies have provided compelling evidence that several phytochemicals with antiinflammatory properties and NSAIDs act to retard, block, or reverse colon carcinogenesis. Equally exciting are opportunities for effective chemoprevention with selective cyclooxygenase-2 (COX-2) inhibitors including celecoxib and rofecoxib in a variety of preclinical models of colon cancer. Naturally occurring COX-2 inhibitors such as curcumin and certain phytosterols have been proven to be effective as chemopreventive agents against colon carcinogenesis with minimal gastrointestinal toxicity. Multistep process of carcinogenesis has provided substantial insights into the mechanisms by which naturally occurring and synthetic antiinflammatory agents modulate these events leading to suppression of tumorigenesis. Growing knowledge in this area has brought about innovative approaches using a combination of agents with different modes of action as a means of increasing efficacy and minimizing toxicity. The natural history of colorectal cancer, from dysplastic aberrant crypts to adenomas and adenocarcinomas, offers multiple opportunities for assessment and intervention. Of further importance would be to identify molecular targets that are critical in the growth and survival of the malignant colorectal cell and are modulated by NSAIDs and COX-2 inhibitors.
近年来，流行病学和分子生物学的多学科研究以及临床前研究，极大地增进了我们对结直肠癌病因的理解；更重要的是，它们使我们能够着手进行结直肠癌的预防。大量令人瞩目的流行病学数据表明，结直肠癌风险与定期使用包括阿司匹林在内的非甾体抗炎药（NSAIDs）之间呈负相关。NSAIDs的临床试验表明，NSAID治疗可使家族性腺瘤性息肉病患者已有的结肠腺瘤消退。临床前疗效研究提供了有力证据，表明几种具有抗炎特性的植物化学物质和NSAIDs可延缓、阻断或逆转结肠癌的发生。同样令人兴奋的是，在多种结肠癌临床前模型中，使用包括塞来昔布和罗非昔布在内的选择性环氧化酶-2（COX-2）抑制剂进行有效化学预防的机会。天然存在的COX-2抑制剂，如姜黄素和某些植物甾醇，已被证明作为化学预防剂对结肠癌发生有效，且胃肠道毒性最小。癌症发生的多步骤过程为天然和合成抗炎剂调节这些导致肿瘤发生抑制的事件的机制提供了大量见解。该领域不断增长的知识带来了创新方法，即联合使用具有不同作用方式的药物以提高疗效并使毒性最小化。结直肠癌从发育异常的隐窝到腺瘤和腺癌的自然病程提供了多个评估和干预机会。更重要的是，确定在恶性结肠癌细胞的生长和存活中起关键作用且受NSAIDs和COX-2抑制剂调节的分子靶点。
