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Tissue Culture Models
 The question of whether cell lines can be considered true models for normal cells is one that comes up often and is not yet settled.  This is especially evident in drug discovery platforms that heavily rely on cell lines to screen candidate molecules for toxicity and validation against the drug target.  It is estimated that 9 out of 10 drugs tested are too toxic to be further developed.  By anyone’s estimation, the drug development process is one that requires a lot of excess since most compounds fall out early during in vitro testing. 

While many reasons could be responsible for this, one main question is whether we are using the correct models to test compounds prior to animal studies.  Even our brief discussion concerning the derivation of immortalized cell lines is enough to raise questions on whether cell lines accurately represent normal cell function. 

Most scientists would agree that established cell lines are useful but do not represent normal physiology.  Cell lines usually represent mature clones that have a tendency to be genetically unstable, with hybrid phenotypes and possibly atypical signaling mechanisms.  The days of relying on one cell line from which to draw conclusion are well over.  This is becoming more evident from reports comparing primary cells to established cell lines, highlighting the deficiencies of established cell lines as models for normal physiology. 

This is particularly the case with liver cell lines that are used for toxicity studies or proof of principle evaluation of drug targets.  While these cell lines are homogenous, easy to propagate and manipulate in culture they have acquired documented genetic and phenotypic differences from their primary counterparts.  Experiments from such cell lines have to be interpreted with caution and verified that the same data can be derived from primary liver cells.  As we can imagine, the implications are extensive when high-throughput drug toxicity testing relies on such cell lines.  Not to mention, that since immortalized cell lines genetically deviate from their primary counterparts, the drug targets that they express and their toxicity thresholds might also differ from those of primary cells.  These considerations are persuading more and more companies to use primary cells for their screening process, or at the very least use primary cells before a decision is taken to advance the testing in animal models. 

The pioneers of this approach have taken an even higher standard and suggested the use of 3-D organotypic cultures for high-throughput screening of drug targets and/or drug candidates.  This is becoming a more viable option, the more we understand that cells in the body respond and are influenced by a microenvironment that is made of several different cell types and not the homogenous monolayer that is represented in culture.  As an example, the field of oncology has put all of its efforts into eradicating the tumor without much consideration to the “normal” cellular environment in which the tumor resides.  A very good example of this situation involves prostate cancer cells.  We have overwhelming evidence that the stromal compartment of the prostate influences and controls the growth and invasive behavior of the prostate cancer cells.  Therefore, the normal stromal cells are viable platforms for drug discovery, but are often overlooked since most experiments are done in established prostate cancer cell lines.  A good example of targeting the tumor microenvironment to limit tumor growth involves anti-angionenic drugs such as bevecizumab, sunitinib and many others in Phase III clinical trials.  3-D organotypic cultures of tumor cells, fibroblasts and normal and/or tumor vasculature would provide an extremely useful tool for screening new compounds or improving on the efficacy and specificity of already approved drugs. 

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