Promoters tumor-selective

The cost and duration of the combined chronic/cancer bioassay has limited its conduct to small numbers of selected chemicals. As a result, several short-term methods aimed at increasing predictive accuracy to enable testing of larger numbers of chemicals have been developed in attempts to successfully correlate Iheir results with evidence of carcinogenicity (or lack of carcinogenicity). This includes investigation of potential to promote tumor development, several model systems in Irans-genic and knockout models, and consideration of the predictive potential of traditional toxicity endpoints in shorter-term studies. 

HSCs need hypoxic niche to proted them from oxidative stress because reactive oxygen spedes induce p38-MAPK-mediated proliferation leading to HSC exhaustion [105]. Some CSCs may also be concealed in hypoxic microenvironments, which are common in solid tumors. Given that hypoxia seems to be important in maintaining CSCs, this provides an opportunity for tumor-selective therapy. Hypoxia-inducible factor 1 (HIF-1) is stabilized under hypoxic conditions and promotes survival of cancer cells in hypoxic niches, so several strategies to inactivate HIF-1 are currently under investigation at the preclinical level [106,107]. 

Transcriptional regulation of genes other than ElA can also confer tumor selectivity in certain tumors. For example, Branori et al. constructed a replication- selective Ad, which had either the ElB or the E2 genes controlled by the Tcf4 promoter. The E2 gene product is required for viral DNA synthesis (89). In colon... 

Under basal conditions, PKC is predominantly a cytoplasmic protein. Upon activation by Ca2+ or DAG, the enzyme associates with the plasma membrane, the site of many of its known physiological substrates, including receptors and ion channels. In fact, the translocation of PKC from the cytoplasm to the membrane has long been used as an experimental measure of enzyme activation. Such translocation has often been assayed by phorbol ester binding phorbol esters are tumor-promoting agents that selectively bind to and activate PKC. The molecular basis of the translocation of PKC from the cytoplasm to the plasma membrane has been solved. Subsequent to activation, PKC binds with high affinity to a series of membrane-associated proteins, termed receptors for... 

Level 3 of the screen is designed to determine the cytotoxic selectivity of samples for tumor cells vs. normal cells. Where possible, the same patient s tissues are used. As in Level 2, six serial dilutions (of four- to five-fold each) are assayed in triplicate for each sample. The diluted samples are then added to the tumor cell and normal cell cultures, and the IC50 is determined. A "selectivity index" (SI) is determined based on the IC50 for normal cells/IC5Q for tumor cells. Samples with an SI of three or more are advanced to Level 4 of the screen. Additionally, only purified and well-characterized compounds are promoted for further testing. 

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