DIET, CELL PROLIFERATION, AND COLON NEOPLASIA STUDY

严格测试饮食模式和营养的功效 结肠癌的预防成分在人类中已经非常 受到实际限制的限制。 使用结肠肿瘤作为终点 在临床试验中需要非常大的样本量， 后续，或两者。 此外，维持长期的复杂饮食 临床试验中的干预是困难的。 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， 结肠隐窝上皮细胞的过度增殖是 或结肠肿瘤的前驱病变， 过度增殖可以通过营养干预逆转， 从而降低结肠癌的风险。 有限的错误信息是 关于结肠上皮细胞增殖的关系 （CECP）与人类结肠肿瘤的关系，并仅限于CECP 使用S期细胞的氚化胸苷标记进行测量。 这 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，不适用于全规模的人类 干预试验。 我们现在已经采用了更可靠和可行的 增殖细胞核抗原（PCNA）和整个隐窝有丝分裂计数 （WCMC）测量CECP的技术。 由于早期的验证研究 使用了不适合大规模临床试验的技术， 正如我们现在所知道的，没有足够的研究来证明大规模 临床试验中，我们建议更恰当地评估 的CECP的风险结肠肿瘤在人类和这样做使用较新的 技术（PCNA和WCMC）。 我们建议通过财政和 技术上有效的权宜之计，扩大和修改我们目前的 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完成结肠癌调查问卷 风险因素，如饮食，营养补充剂的摄入，家族史， 等 患者还需要抽血检测血脂和DNA， 乙酰转移酶和APC基因型。 腺瘤患者的发病率 例，以及结肠镜检查正常且无 结肠肿瘤为对照。 我们建议从直肠，乙状结肠， 和近端结肠粘膜活检， 由此通过PCNA和WCMC技术确定CECP。 从 这些信息，我们将建立结肠之间的相互关系， 肿瘤风险因素（尤其是饮食）、CECP和结肠肿瘤; 直肠活检测量的CECP水平是否反映了 整个结肠;无论是通过PCNA或WCMC测量的CECP 技术或两者的组合提供了更大的区别 区分肿瘤形成风险增加的水平和原因的能力; 以及PCNA或WCMC技术是否更可靠和/或 适用于全面的饮食/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.