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Role of transgenic mice in pharmaceutical companies
The role that preclinical models play in the evaluation of drug efficacy and optimization of lead compounds is an essential one in pharmaceutical companies.Without a robust, dependable animal model of human disease development of structural-activity relationships in the design of better molecules becomes a daunting task. In the cancer arena, while not all chemotherapeutic agents which test positively in mouse models are efficacious in humans, those agents which are efficacious in humans are also effective in mice. The clinical failure of novel chemotherapeutics is often not established until phase II or phase III clinical studies, after costly investments of time and money have been made. Therefore it is highly desirable to have models of human cancers that will more accurately represent human disease and predict clinical outcomes. For this objective, transgenic and knockout mouse and rat models have held great promise, but yet have been underutilized by the pharmaceutical industry, the NCI, and the FDA. The limited use of such models is likely due in part to the failure of many current transgenic and knockout models to exhibit essential qualities of preclinical screening models; validity, reliability, and utility.
The in vivo models typically employed by the pharmaceutical industry for preclinical testing of anticancer therapeutics are transplantable mouse (allo-) or human (xeno-) tumor grafts, such as the murine B16BL6 melanoma line or human HT-29 tumor line. Implantation of these tumor lines can be performed subcutaneously, intravenously, or orthotopically, providing a source of versatility. Although widely used by pharmaceutical companies for drug efficacy screening, tumor xenograft models also possess intrinsic disadvantages, making it surprising that genetically engineered models of cancer have seen little use either in conjunction or in lieu of the transplantable tumors. In this review, we will briefly cover the drawbacks of most transgenic models and discuss the features that such models of cancer should ideally possess for preclinical testing of anti-cancer therapies. Despite the shortcomings of transgenic and knockout models of cancer for drug efficacy evaluations, they represent a more natural in vivo history of tumor development. Thus outcomes of compound efficacy in transgenic and knockout mice will likely be more predictive of the clinical outcome. Their use may increase the confidence going into the clinic and...