Armstrong William B, Wan X Steven, Kennedy Ann R, Taylor Thomas H, Meyskens Frank L
Department of Otolaryngology-Head and Neck Surgery, Chao Family Comprehensive Cancer Center, University of California-Irvine, 101 The City DriveSouth, Bldg. 25, Suite 191, Orange, CA 92868, USA.
Laryngoscope. 2003 Oct;113(10):1687-702. doi: 10.1097/00005537-200310000-00007.
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.
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.
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.
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).
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. This finding 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 Inhibitor concentrate and further evaluate these candidate biomarkers is under way.
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，人们对开发有效的头颈部癌症化学预防剂有着浓厚兴趣。类视黄醇是口腔癌前病变的典型化学预防剂。它们具有显著的临床效果，但广泛应用受到明显临床毒性的限制。鲍曼-伯克抑制剂是几种既具有强大抗癌活性又具有最小毒性的无毒化合物之一。本研究的目的是总结鲍曼-伯克抑制剂和一种鲍曼-伯克抑制剂浓缩物针对口腔癌前病变的临床前和临床开发情况，并评估在IIa期鲍曼-伯克抑制剂浓缩物口腔白斑化学预防试验中病变及同时获取的外观正常黏膜活检标本的神经（Neu）免疫组化染色强度。
第一部分是选定文献综述。第二部分是对从鲍曼-伯克抑制剂浓缩物IIa期临床试验前瞻性获取的病理标本进行回顾性分析。
使用3B - 5单克隆抗体，以盲法检查32组活检标本，这些标本来自用200至1066胰凝乳蛋白酶抑制单位剂量的鲍曼-伯克抑制剂浓缩物治疗前后的病变及未受累口腔黏膜，以评估Neu免疫组化染色强度。分析并比较鲍曼-伯克抑制剂浓缩物治疗前后病变和对照活检标本的染色强度评分，并与先前获得的血清Neu、口腔黏膜细胞Neu、蛋白酶活性及治疗临床反应的值进行比较。
与未受累黏膜相比，病变中的平均Neu染色评分显著更高（P <.001）。病变活检标本和外观正常组织的对照活检标本的预处理染色评分相关（斯皮尔曼相关系数[r] = 0.375，P =.045），但治疗后病变和对照活检标本评分之间无明显相关性。鲍曼-伯克抑制剂浓缩物治疗后对照部位活检标本中Neu染色评分的变化与病变面积的变化呈负相关（斯皮尔曼r = -0.493，P <.007）。
基于广泛的临床前研究以及I期和IIa期临床试验结果，鲍曼-伯克抑制剂浓缩物有望成为一种有效的无毒化学预防剂。鲍曼-伯克抑制剂浓缩物对口腔白斑具有剂量相关的临床活性，并可调节Neu水平和蛋白酶活性。当前研究发现，与鲍曼-伯克抑制剂浓缩物治疗前后同时获取的外观正常黏膜活检标本相比，增生性病变中的Neu染色强度增加。这一发现支持了先前的观察结果，即在一部分口腔癌前病变和头颈部癌症中存在Neu表达增加的情况。鲍曼-伯克抑制剂浓缩物治疗后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，引发了关于鲍曼-伯克抑制剂浓缩物作用机制的疑问。一种可能的解释是，鲍曼-伯克抑制剂使Neu的细胞外结构域稳定，从而防止受体截断和内化。对鲍曼-伯克抑制剂浓缩物治疗调节Neu和蛋白酶活性的进一步研究，可能会深入了解蛋白酶和蛋白酶抑制剂在口腔癌前病变中的作用以及鲍曼-伯克抑制剂浓缩物作用的潜在机制。一项确定鲍曼-伯克抑制剂浓缩物临床有效性并进一步评估这些候选生物标志物的IIb期随机、安慰剂对照临床试验正在进行中。
