Proliferation, cell neoplasia

Perry, C., Sklan, E.H., Soreq, H. (2004). CREB regulates AChE-R-induced proliferation of human glioblastoma cells. Neoplasia 6 279-86. 

Interaction of compounds with a toxicity target can result in a wide variety of in cell phenotypes (22). Deregulation of gene expression can result in inappropriate cell division (neoplasia, teratogenesis), apoptosis, and protein synthesis (e.g., peroxisome proliferation). Cell death can result from stimuli resulting in apoptosis, which has been defined as pro-... 

Hughes SJ, Morse MA, Weghorst CM, Kim H, Watkins PB, Guengerich FP, Orringer MB, Beer DG (1999) Cytochromes P450 are expressed in proliferating cells in Barrett s metaplasia. Neoplasia 1 145-153... 

Carcinogenicity Studies. These are generally inappropriate for biotechnology-derived pharmaceuticals however, some products may have the potential to support or induce proliferation of transformed cells... possibly leading to neoplasia. When this concern is present, further studies in relevant animal models may be needed. 

Looked at another way, the four major carcinogenic mechanisms are DNA damage, cell toxicity, cell proliferation and oncogene activation. Any effective program to identify those drags which have the potential to cause or increase the incidence of neoplasia in humans must effectively screen for these mechanisms (Kitchin, 1999). 

The control of cell numbers is regulated by cell proliferation, differentiation and apoptosis. Increased proliferation and/or decreased apoptosis result in neoplasia. In addition to inhibition of proliferation or induction of differentiation, the modulation of apoptosis can be employed for treatment for cancer. Several anticancer agents in use are potent inducers of apoptosis (Dive and Hickman, 1991 Fisher, 1994). Tumor promotion may result in decreased apoptosis. Because PKC activation by TPA induces carcinogenesis, it seems that PKC may be involved in apoptosis. There are many reports on the effects of PKC on apoptosis. However, the results are very controversial. Here an overview of these data is presented. 

Members of the myc gene family have been implicated in the control of normal cell proliferation as well as in neoplasia. A more direct role for myc genes in transformation is indicated by their ability to transform primary rat embryo fibroblasts in association with the c-H-ras oncogene. 

Products that may have the potential to stimulate growth or induce proliferation or clonal expansion of cell types, in particular, transformed cells, all processes that may eventually lead to neoplasia should be evaluated with respect to receptor expression in various malignant and normal human cells that are relevant to the patient population under study [27], In such cases normal human cell lines and multiple human cancer cell lines expressing the relevant receptor, as well as primary cells derived from human tumor explants, should be used for in vitro assessment. When in vitro data demonstrate enhanced growth, further studies in relevant in vivo xenograft animal models with receptor expressing tumor cell lines may be needed. In addition incorporation of sensitive indexes of cellular proliferation in long-term repeat-dose toxicity studies may provide useful information. 

A classical example is alcoholic cirrhosis, which in the case of chronic alcohol abuse, leads to multiple, polyclonal areas of liver cell hyperplasia and an increased risk for development of hepatocellular neoplasia. In both preneoplasia and certain forms of hyperplasia, the antecedent lesions typically have a higher rate of cell proliferation than the surrounding normal cells and, thus, these cells are at increased risk to sustain additional genetic damage and progress to the next stage in the carcinogenic process. 

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