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Rapid in Vivo Assay for Oral Cancer Chemoprevention

口腔癌化学预防的快速体内检测

基本信息

批准号：
6514890
负责人：
Dennis B. Solt
金额：
$ 6.91万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-01 至 2003-12-31
项目状态：
已结题

项目摘要

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快速的口腔癌化学预防剂（OCCAs）的体内检测方法，该方法基于以下假设：有效的药物（或药物组合）将通过抑制或阻断参与致癌过程中每个步骤的关键细胞和细胞群的诱导、扩增和持久性来阻止或预防口腔癌的形成。在仓鼠颊囊上皮（HBPE）模型的口腔癌，局灶性群体的基底细胞表现出γ-谷氨酰转肽酶组织化学活性（GGT灶），和补丁的基底细胞表现出核p53免疫组化染色（p53灶）似乎是两个这样的相关人群。具体目标1是量化一组已知抗癌药抑制早期（即，4或10天）GGT病灶，如在HBPE全标本中检测到的，当在强效化学致癌物7，12-二甲基苯并蒽（DMBA）和N-甲基-N-苄基亚硝胺（MBN）之前和同时将试剂应用于粘膜表面时。具体目标2是量化在暴露于DMBA或MBN的21天方案期间，从显示抑制SA 1中GGT病灶诱导的那些中选择的三种推定的OCCA也抑制GGT病灶扩展的程度。还将使用SA 2方案评价在仓鼠囊标准切片中鉴定早期p53病灶的可行性，从而定量这些病变形成中抗癌剂介导的抑制作用。具体目标3将采用完整的致癌方案来量化在SA 2中检查的三种化学预防剂也抑制的程度：（1）GGT灶和p53灶的诱导（7周时观察），（2）诱导异型增生病变，p53阳性和p53阴性（7周时观察），（3）持续性p53灶的诱导和扩增（在12周和21周观察），（4）诱导持续性发育异常病变，p53阳性和p53阴性（在12和21周观察到），（5）在12周时细胞学涂片中可检测到的发育异常细胞（包括持续性发育异常细胞，以及p53阳性和p53阴性细胞）的发展，和（6）HBPE癌形成。(7)在SA 3方案中，还将在7周处死的仓鼠中评估抗癌剂介导的前胃乳头状瘤抑制。概述的研究还表明了一种合理的策略，用于鉴定可能在临床试验中表现出累加或协同效应的有效OCCA组合-特别是单独表现出对与关键参与细胞群的诱导、扩增和持久性相关的各种癌症替代终点的最大抑制的药物组合。