The use of animal models for cancer chemoprevention drug development.
The use of animal models for cancer chemoprevention drug development.
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DOI：
10.1053/j.seminoncol.2010.05.010
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发表时间：
2010-08
影响因子：
4
通讯作者：
Lubet RA
中科院分区：
文献类型：
--
作者：
Steele VE;Lubet RA
动物模型目前用于评估潜在化学预防剂的功效，包括合成化学品、从天然产物和天然产物混合物中获得的化学剂。在这些模型中进行的观察以及其他数据，然后用于优先考虑代理，以确定哪些有资格进行临床化学预防试验。采用器官特异性动物模型来确定哪种药剂或哪类药剂在无毒剂量下可能最有效地预防器官特异性形式的癌症。然后，这些结果被用于在临床试验中靶向高危人群的特定器官。使用的动物模型是用特定器官部位的致癌物诱导的，或者它们是在已知增强特定器官中的癌症的靶基因位点处具有插入、缺失或突变的转基因/突变动物。具有有利于化学预防研究特征的动物肿瘤模型可用于肺、结肠、皮肤、膀胱、乳腺、前列腺、头颈部、食管、卵巢和胰腺。除了单一药剂剂量反应测试之外，此类模型还经常用于测试药剂组合、测试不同的给药途径、评估替代终点生物标志物以及生成初始药代动力学和毒理学数据。对于一些更标准的动物模型，与人类化学预防试验结果有显着相关性。有越来越多的积极的人类化学预防试验，其中使用的药物或组合在动物试验中呈阳性。阴性人体临床试验的数量较少，但同样与阴性动物结果相关。显然，验证动物模型，以预测药物在人体临床试验中的疗效，将等待进一步的人类数据的积极和消极的结果与化学预防剂。无论是否经过验证，动物疗效数据仍然是临床试验决策过程的核心。
Animal models currently are used to assess the efficacy of potential chemopreventive agents, including synthetic chemicals, chemical agents obtained from natural products and natural product mixtures. The observations made in these models as well as other data are then used to prioritize agents to determine which are qualified to progress to clinical chemoprevention trials. Organ specific animal models are employed to determine which agents or classes of agents are likely to be the most effective at nontoxic doses to prevent organ-specific forms of cancer. These results are then used to target specific organs in high risk populations in clinical trials. The animal models used are either carcinogen-induced with carcinogens specific for particular organ sites or they are transgenic/mutant animals with insertions, deletions, or mutations at targeted gene sites known to enhance cancers in a specific organ. Animal tumor models with characteristics favorable to chemoprevention studies are available for lung, colon, skin, bladder, mammary, prostate, head and neck, esophagus, ovary and pancreas. In addition to single agent dose-response testing, such models are frequently used for testing combinations of agents, testing different routes of administration, evaluating surrogate endpoint biomarkers, and generating initial pharmacokinetics and toxicology data. For some of the more standard animal models there is significant correlation with human chemopreventive trial results. There are a growing number of positive human chemoprevention trials which used agents or combinations which were positive in animal testing. The number of negative human clinical trials have been fewer, but again correlating with negative animal results. Clearly the validation of animal models to predict the efficacy of agents in human clinical trials will await further human data on positive and negative outcomes with chemopreventive agents. Whether validated or not, animal efficacy data remain central to the clinical trial decision-making process.
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影响因子：
158.5
作者：
Bertagnolli, Monica M.;Eagle, Craig J.;Hawk, Ernest T.
通讯作者：
Hawk, Ernest T.
影响因子：
6.4
作者：
Balansky, Roumen;Ganchev, Gancho;De Flora, Silvio
通讯作者：
De Flora, Silvio
影响因子：
6.8
作者：
Burkardt, HJ
通讯作者：
Burkardt, HJ
影响因子：
120.7
作者：
Cook, NR;Lee, IM;Buring, JE
通讯作者：
Buring, JE
影响因子：
3.3
作者：
Hakim, Amy A.;Barry, Catherine P.;Rodriguez, Gustavo C.
通讯作者：
Rodriguez, Gustavo C.