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首页> 外文期刊>The Laryngoscope: A Medical Journal for Clinical and Research Contributions in Otolaryngology, Head and Neck Medicine and Surgery, Facial Plastic and Reconstructive Surgery .. >Development of the Bowman-Birk inhibitor for oral cancer chemoprevention and analysis of Neu immunohistochemical staining intensity with Bowman-Birk inhibitor concentrate treatment.
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Development of the Bowman-Birk inhibitor for oral cancer chemoprevention and analysis of Neu immunohistochemical staining intensity with Bowman-Birk inhibitor concentrate treatment.

机译：Bowman-Birk抑制剂用于口腔癌化学预防的开发以及使用Bowman-Birk抑制剂浓缩液治疗后Neu免疫组织化学染色强度的分析。

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OBJECTIVES/HYPOTHESIS: Cancer chemoprevention is a rapidly evolving approach to reverse or inhibit carcinogenesis, and there is active interest in development of effective chemopreventive agents against head and neck cancers. The retinoids are archetypal chemopreventive agents for oral premalignant lesions. They have significant clinical effect, but widespread use is limited by significant clinical toxicity. The Bowman-Birk Inhibitor is one of several nontoxic compounds exhibiting both potent anticarcinogenic activity and minimal toxicity. The purposes of the study were to summarize the preclinical and clinical development of Bowman-Birk Inhibitor and a Bowman-Birk Inhibitor concentrate against oral premalignant lesions and to evaluate Neu immunohistochemical staining intensity for lesions and simultaneously obtained biopsy specimens of normal-appearing mucosa from the Phase IIa Bowman-Birk Inhibitor concentrate oral leukoplakia chemoprevention trial. STUDY DESIGN: Part I is a selected literature review. Part II is a retrospective analysis of pathological specimens prospectively obtained from the Phase IIa clinical trial of Bowman-Birk Inhibitor concentrate. METHODS: Thirty-two sets of biopsy specimens from lesions and uninvolved oral mucosa before and after treatment with Bowman-Birk Inhibitor concentrate in doses ranging from 200 to 1066 chymotrypsin inhibitory units were examined in blinded fashion for Neu immunohistochemical staining intensity using the 3B-5 monoclonal antibody. Staining intensity scores among the lesion and control biopsy specimens before and after Bowman-Birk Inhibitor concentrate treatment were analyzed and compared with previously obtained values for serum Neu, oral mucosal cell Neu, protease activity, and clinical response to treatment. RESULTS: Mean Neu staining score was significantly higher in lesions compared with uninvolved mucosa (P <.001). Pretreatment staining scores for biopsy specimens of lesions and control biopsy specimens of normal-appearing tissues were correlated (Spearman correlation coefficient [r] = 0.375, P =.045), but no correlation between lesion and control biopsy specimen scores was evident after treatment. The change in Neu staining score with Bowman-Birk Inhibitor concentrate treatment in control site biopsy specimens demonstrated an inverse relationship of change in lesion area with Bowman-Birk Inhibitor concentrate treatment (Spearman r = -0.493, P <.007). CONCLUSION: Bowman-Birk Inhibitor concentrate shows promise to become an effective nontoxic chemopreventive agent based on results of extensive preclinical studies, and Phase I and Phase IIa clinical trials. Bowman-Birk Inhibitor concentrate has dose-related clinical activity against oral leukoplakia and modulates levels of Neu and protease activity. The current investigation identified increased Neu staining intensity in hyperplastic lesions compared with simultaneously obtained biopsy specimens of normal-appearing mucosa both before and after Bowman-Birk Inhibitor concentrate treatment. Thisfinding supports prior observations that increased Neu expression is present in a subset of oral premalignant lesions and head and neck cancers. The trend of increased Neu staining score in control biopsy tissues of subjects exhibiting decreased lesion area following Bowman-Birk Inhibitor concentrate treatment raises questions about the mechanisms of Bowman-Birk Inhibitor concentrate action. One possible explanation is that Bowman-Birk Inhibitor stabilizes the extracellular domain of Neu, thereby preventing receptor truncation and internalization. Further study of modulation of Neu and protease activity by Bowman-Birk Inhibitor concentrate treatment may provide insights into the role of proteases and protease inhibitors in oral premalignant lesions and the mechanisms underlying Bowman-Birk Inhibitor concentrate effects. A Phase IIb randomized, placebo-controlled clinical trial to determine the clinical effectiveness of Bowman-Birk Inh
机译：目的/假设：癌症化学预防是一种迅速发展的逆转或抑制致癌作用的方法，并且人们对开发有效的化学预防剂来治疗头颈癌抱有浓厚的兴趣。类维生素A是口腔癌变前病变的原型化学预防剂。它们具有显着的临床效果，但是广泛的使用受到显着的临床毒性的限制。 Bowman-Birk抑制剂是几种无毒的化合物之一，具有强大的抗癌活性和最小的毒性。该研究的目的是概述针对口腔癌前病变的Bowman-Birk抑制剂和Bowman-Birk抑制剂浓缩物的临床前和临床开发，并评估病变的Neu免疫组化染色强度，并同时从正常人的黏膜中获得正常出现的粘膜活检标本。 IIa期Bowman-Birk抑制剂浓缩口服白斑化学预防试验。研究设计：第一部分是部分文献综述。第二部分是对从Bowman-Birk抑制剂浓缩物的IIa期临床试验中预期获得的病理学标本的回顾性分析。方法：用3B-5盲法检查了鲍曼-伯克抑制剂浓度为200至1066的胰凝乳蛋白酶抑制单位治疗前后病灶和未受累口腔粘膜的三十二份活检标本，以Neu免疫组化染色强度进行了检查。单克隆抗体。分析鲍曼-伯克抑制剂浓缩物治疗前后病变和对照活检标本中的染色强度得分，并将其与先前获得的血清Neu，口腔粘膜细胞Neu，蛋白酶活性和对治疗的临床反应值进行比较。结果：与未受累的粘膜相比，病变中的平均Neu染色评分显着更高（P <.001）。病变组织活检标本与正常组织的对照活检标本的治疗前染色评分相关（Spearman相关系数[r] = 0.375，P = .045），但治疗后病灶与对照活检标本评分之间无明显相关性。对照部位活检标本中Bowman-Birk抑制剂浓缩液处理后Neu染色评分的变化表明，Bowman-Birk抑制剂浓缩液处理后病变区域的变化呈反比关系（Spearman r = -0.493，P <.007）。结论：基于广泛的临床前研究以及I期和IIa期临床试验的结果，Bowman-Birk抑制剂浓缩物有望成为一种有效的无毒化学预防剂。 Bowman-Birk抑制剂浓缩物对口腔白斑具有剂量相关的临床活性，并调节Neu和蛋白酶活性的水平。当前的研究表明，与同时获得的鲍曼-伯克抑制剂浓缩物治疗前后正常出现的粘膜活检标本相比，增生性病变中Neu染色强度增加。该发现支持先前的观察结果，即在口腔癌前病变和头颈癌的子集中存在Neu表达增加。在鲍曼-伯克抑制剂浓缩物治疗后表现出病变面积减小的受试者的对照活检组织中，Neu染色评分增加的趋势提出了关于鲍曼-伯克抑制剂浓缩物作用机理的问题。一种可能的解释是Bowman-Birk抑制剂可稳定Neu的胞外域，从而防止受体截断和内在化。 Bowman-Birk抑制剂浓缩物处理对Neu和蛋白酶活性的调节作用的进一步研究可能提供洞察蛋白酶和蛋白酶抑制剂在口腔癌变前病变中的作用以及Bowman-Birk抑制剂浓缩物作用的潜在机制。 IIb期随机，安慰剂对照临床试验，以确定Bowman-Birk Inh的临床有效性

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