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Abstract

One of the most serious obstacles facing investigators involved in the development and assessment of new anti-cancer drugs is the failure of preclinical rodent tumor models to predict in a reliable way whether a given drug will have anti-tumor activity and acceptable toxicity in humans. Most previous investigations for assessing drug activity in vivo have utilized rapidly growing non-metastatic transplantable mouse or human tumors injected ectopically in syngeneic or nude mice, respectively. Some of the reasons for the inadequacy of such models are well known and, as a result, there has been a gradual movement toward the use of transgenic oncomouse models for anti-cancer drug testing. It is too early to conclude, one way or the other, whether these will be superior to transplantable tumor models. Moreover, such transgenic models have a number of limitations which are not widely appreciated. It is argued that transplantable tumor models, with various modifications, might be made significantly more predictive than current models, and would thus constitute a more economic alternative to the use of large numbers of transgenic oncomice. These modifications include the use of slower growing and genetically tagged (e.g. LacZ or GFP) tumors which are transplanted initially into orthotopic organ sites. These methods would facilitate the growth and detection of distant microscopic and macroscopic metastases, the response of which to anti-cancer drugs, using 'clinically equivalent doses,' could be evaluated.

An Orthotopic Model of Pancreatic Somatostatin Receptor (SSTR)-Positive Tumors Allows Bimodal Imaging Studies Using 3T MRI and Animal PET-Based Molecular Imaging of SSTR Expression

“…Accordingly, the tissue-specific interactions between tumor cells and the stromal and vascular compartments, respectively, were maintained. These interactions are increasingly recognized as major determinants of the tumor phenotype, including drug responsiveness [23]. Furthermore, vascularization and perfusion affect the kinetics of drug delivery and accumulation, which is predicted to be of particular relevance in imaging studies.…”

Mouse models of advanced spontaneous metastasis for experimental therapeutics

“…It is also unclear whether ectopic (out of the normal place) subcutaneously implanted tumours — still a standard methodology — will respond to a therapy in the same way if grown in an orthotopic site 1 (in their organ or tissue of origin, such as breast cancers in mammary fat pads). In addition, tumour-bearing mice are often treated with drugs at levels, or with pharmacokinetics, that are not relevant to humans 2–4 . Furthermore, almost all the preclinical models that have been studied have not involved tumours that were pre-exposed to another therapy, whereas many Phase I and Phase II clinical trials involve patients who have already undergone and progressed under first, second, or even more therapies and to which their tumours have become refractory.…”

Mouse Models of Colorectal Cancer and Liver Metastases

“…A disadvantage is that metastases form infrequently (if at all) and unpredictably. However, if they form, they do so spontaneously thereby resembling the process in cancer patients [32]. …”