Rapid in Vivo Assay for Oral Cancer Chemoprevention

口腔癌化学预防的快速体内检测

• 批准号: 6401093
• 负责人: Dennis B. Solt
• 金额: $ 6.97万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6401093
• 关键词: cancer prevention; carcinogenesis inhibitor; chemical carcinogen; chemical carcinogenesis; chemoprevention; cutaneous papilloma; difluoromethylornithine; drug interactions; enzyme induction /repression; epithelium; hamsters; immunocytochemistry; nonhuman therapy evaluation; nutrition aspect of cancer; nutrition related tag; oral pharyngeal neoplasm; p53 gene /protein; protein glutamine gamma glutamyltransferase; tocopherols

The long range objective of this research is to develop a rapid in vivo assay for oral cancer chemopreventive agents(OCCAs), based on the hypothesis that effective agents(or combinations of agents) will impede or prevent oral cancer formation by inhibiting or blocking the induction, expansion, and persistence of the key cells and cell populations participating in each step in the carcinogenic process. In the hamster buccal pouch epithelial (HBPE) model of oral carcinogenesis, focal populations of basal cells exhibiting gamma-glutamyl transpeptidase histochemical activity(GGT foci), and patches of basal cells exhibiting nuclear p53 immunohistochemical staining (p53 foci) appear to be two such relevant populations. Specific Aim 1 is to quantify the extent to which a group of known anticarcinogens inhibit the induction of early (i.e., 4 or 10 days) GGT foci, as detected in HBPE whole mounts, when the agents are applied to the mucosal surfaces prior to and concurrent with the potent chemical carcinogens 7,12- dimethylbenz(a)anthracene(DMBA) and N-methyl-N- benzylnitrosamine(MBN). Specific Aim 2 is to quantify the extent to which three presumptive OCCAs, selected from among those shown to inhibit GGT foci induction in SA1, also inhibit the expansion of GGT foci, during a 21-day regimen of exposure to the either DMBA or MBN,. The feasibility of identifying early p53 foci in standard sections of hamster pouch, and thus of quantifying anticarcinogen-mediated inhibition in the formation of these lesions will also be evaluated using the SA2 protocol. Specific Aim 3 will employ a complete carcinogenesis protocol to quantify the extent to which three chemopreventive agents examined in SA2, also inhibit: (1) induction of GGT foci and p53 foci(observed at 7 weeks), (2) induction of dysplastic lesions, both p53 positive and p53 negative(observed at 7 weeks), (3) induction and expansion of persistent p53 foci(observed at 12 and 21 weeks), (4) induction of persistent dysplastic lesions, both p53 positive and p53 negative(observed at 12 and 21 weeks), (5) development of dysplastic cells (including persistent dysplastic cells, and both p53 positive and p53 negative cells) detectable in cytologic smears at 12 weeks, and (6) HBPE cancer formation. (7) Anticarcinogen- mediated inhibition of forestomach papillomas will also be assessed in hamsters sacrificed at 7 weeks in the SA3 protocol. The research outlined also suggests a rational strategy for the identification of combinations of efficacious OCCAs which are likely to exhibit an additive or synergistic effect in clinical trials -specifically, combinations of agents which individually exhibit maximal inhibition of various surrogate end points of cancer relating to induction, expansion, and persistence of the key participating cell populations.

本研究的长期目标是开发一种口腔癌化学预防剂（OCCAs）的快速体内检测方法，基于有效药物（或药物组合）将通过抑制或阻断参与致癌过程每一步的关键细胞和细胞群的诱导、扩增和持续来阻止或预防口腔癌的形成的假设。在仓鼠口腔癌变的颊袋上皮（HBPE）模型中，显示γ -谷氨酰转肽酶组织化学活性的基底细胞群（GGT灶）和显示核p53免疫组织化学染色的基底细胞斑块（p53灶）似乎是两个相关的群体。具体目标1是量化一组已知的抗癌物在多大程度上抑制早期（即4或10天）GGT灶的诱导，如在HBPE整个小鼠中检测到的，当这些药物在强效化学致癌物7,12-二甲基苯(a)蒽（DMBA）和n -甲基- n -苄基亚硝胺（MBN）之前和同时应用于粘膜表面时。具体目标2是量化在暴露于DMBA或MBN的21天方案中，从SA1中显示抑制GGT灶诱导的三种假定OCCAs也抑制GGT灶扩展的程度。在仓鼠眼袋标准切片中识别早期p53病灶的可行性，以及量化这些病变形成过程中抗癌物质介导的抑制作用的可行性，也将使用SA2方案进行评估。特异性目标3将采用完整的致癌方案来量化SA2中检测的三种化学预防剂的抑制程度：(1)诱导GGT灶和p53灶（7周观察），(2)诱导p53阳性和p53阴性的发育不良病变（7周观察），(3)诱导持续性p53灶并扩大（12周和21周观察），(4)诱导持续性p53阳性和p53阴性的发育不良病变（12周和21周观察），(5)发育不良细胞（包括持续性发育不良细胞）的发育不良。以及12周细胞学涂片中检测到的p53阳性和p53阴性细胞，以及(6)HBPE癌形成。(7)在SA3方案中，还将在7周时牺牲的仓鼠中评估抗癌物质介导的前胃乳头瘤的抑制作用。该研究还提出了一种合理的策略，用于识别有效的OCCAs组合，这些OCCAs可能在临床试验中表现出附加或协同效应-具体而言，组合药物单独表现出与关键参与细胞群的诱导，扩增和持久性相关的各种替代癌症终点的最大抑制。