Orthotopic Metastatic Mouse Models for Anticancer Drug Discovery and Evaluation: a Bridge to the Clinic
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- Hoffman, R.M. Invest New Drugs (1999) 17: 343. doi:10.1023/A:1006326203858
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Currently used rodent tumor models, including transgenictumor models, or subcutaneously-growing human tumors inimmunodeficient mice, do not sufficiently represent clinicalcancer, especially with regard to metastasis and drugsensitivity. In order to obtain clinically accurate models, wehave developed the technique of surgical orthotopic implantation(SOI) to transplant histologically-intact fragments of humancancer, including tumors taken directly from the patient, to thecorresponding organ of immunodeficient rodents. It has beendemonstrated in 70 publications describing 10 tumor types thatSOI allows the growth and metastatic potential of thetransplanted tumors to be expressed and reflects clinical cancer.Unique clinically-accurate and relevant SOI models of humancancer for antitumor and antimetastatic drug discovery include:spontaneous SOI bone metastatic models of prostate cancer, breastcancer and lung cancer; spontaneous SOI liver and lymph nodeultra-metastatic model of colon cancer, metastatic models ofpancreatic, stomach, ovarian, bladder and kidney cancer.Comparison of the SOI models with transgenic mouse models ofcancer indicate that the SOI models have more features ofclinical metastatic cancer. Cancer cell lines have been stablytransfected with the jellyfish Aequorea victoriagreenfluorescent protein (GFP) in order to track metastases in freshtissue at ultra-high resolution and externally image metastasesin the SOI models. Effective drugs can be discovered andevaluated in the SOI models utilizing human tumor cell lines andpatient tumors. These unique SOI models have been used forinnovative drug discovery and mechanism studies and serve as abridge linking pre-clinical and clinical research and drugdevelopment.