DIET, CELL PROLIFERATION, AND COLON NEOPLASIA STUDY

严格测试饮食模式和营养的有效性 人类结肠癌预防中的成分一直以来都是 受到实际约束的限制。以结肠肿瘤为终点 在临床试验中需要极大的样本量，延长 后续行动，或者两者兼而有之。此外，维持长时间的复合饮食 临床试验的干预是困难的。动物实验 在人类身上的证据和令人兴奋的初步证据强烈表明 结肠隐窝上皮细胞过度增殖是一种生物标志物 或结肠肿瘤的前驱病变，而这 过度增殖可以通过营养干预来逆转， 从而降低了患结肠癌的风险。有缺陷的有限信息是 结肠上皮细胞增殖关系的研究进展 (CECP)至人类结肠肿瘤，仅限于CECP 用氚标记的胸腺嘧啶核苷标记S期细胞进行检测。这 该程序及其未经验证的继任者5-溴脱氧尿苷(BrdU) S期细胞的标记不适用于全尺寸人体 干预试验。我们现在已经调整了更可靠和更可行的 增殖细胞核抗原与全隐窝有丝分裂计数 (WCMC)测量CECP的技术。因为早先的验证研究 使用了一种不适合大规模临床试验的技术， 正如我们现在所知，没有足够的研究来证明大规模 临床试验，我们建议更恰当地评估两者之间的关系 CECP对人类结肠肿瘤风险的影响以及使用较新的 技术(增殖细胞核抗原和WCMC)。我们建议通过财政和 技术高效的权宜之计，扩大和修改我们现有的 结肠息肉的病例对照研究。在目前的病例对照研究中， 接受结肠镜检查的患者填写结肠癌调查问卷 危险因素，如饮食、营养补充剂摄入量、家族史、 等。患者还抽取血液进行血脂和DNA检测 乙酰转移酶和APC基因分型。发生腺瘤的患者有 例，以及结肠镜检查正常且无结肠镜检查病史的患者 结肠肿瘤为对照。我们建议取直肠、乙状结肠、 和近端结肠粘膜活检在这些日常护理的结肠镜检查和 根据这些结果，用增殖细胞核抗原和WCMC技术确定CECP。从… 这些信息，我们将建立冒号之间的相互关系 肿瘤危险因素(尤其是饮食)、CECP和结肠肿瘤； 在直肠活检中测量的CECP水平是否反映了 在整个结肠中；CECP是由增殖细胞核抗原还是WCMC测量 技术或两者的组合提供了更大的歧视性 在区分肿瘤风险增加的程度和原因方面的能力； 无论是增殖细胞核抗原技术还是WCMC技术更可靠和/或 可应用于全面的饮食/化学预防试验。

Rigorous testing of the efficacy of dietary patterns and nutritional components in colon cancer prevention in humans has been extremely limited by practical constraints. Using colonic neoplasms as endpoints in clinical trials requires extremely large sample sizes, prolonged follow-up, or both. In addition, maintaining prolonged complex dietary interventions in clinical trials is difficult. Animal experimental evidence and exciting preliminary evidence in humans strongly suggests that hyperproliferation of colonic crypt epithelial cells is a biomarker or precursor lesion for colonic neoplasia and that this hyperproliferation can be reversed by nutritional intervention and the risk of colonic cancer thereby reduced. Limited flawed information is available regarding the relation of colonic epithelial cell proliferation (CECP) to colonic neoplasia in humans and is restricted to CECP measurement using tritiated thymidine labeling of S-phase cells. This procedure and its unvalidated successor, 5-bromodeoxyuridine (BrdU) labeling of S-phase cells, are not feasible for use in full-scale human intervention trials. We have now adapted the more reliable and feasible proliferating cell nuclear antigen (PCNA) and whole crypt mitotic count (WCMC) techniques of measuring CECP. Since earlier validation studies used a technique not suitable for large scale clinical trials and were, as we now know, inadequate studies on which to justify large scale clinical trials, we propose to evaluate more properly the relationship of CECP to risk of colon neoplasia in humans and to do so using the newer techniques (PCNA and WCMC). We propose to do this by the financially and technically efficient expedient of extending and modifying our current case-control study of colonic polyps. In the current case-control study, patients going to colonoscopy complete questionnaires on colon cancer risk factors such as diet, nutritional supplement intake, family history, etc. Patients also have blood drawn for lipid profiles and DNA for acetyltransferase and APC genotypes. Incident adenoma patients are cases, and patients with normal colonoscopies and without a history of colonic neoplasms are controls. We propose to obtain rectal, sigmoid, and proximal colon mucosal biopsies at these usual-care colonoscopies and from these determine CECP by both the PCNA and WCMC techniques. From this information, we will establish interrelationships among colon neoplasia risk factors (especially dietary), CECP, and colon neoplasia; whether or not CECP levels measured on a rectal biopsy reflects levels throughout the colon; whether CECP measured by the PCNA or the WCMC techniques or a combination of the two provides greater discriminatory power in distinguishing levels and causes of increased risk of neoplasia; and whether the PCNA or the WCMC technique is more reliable and/or feasible for application to full-scale dietary/chemoprevention trials.