Tumor growth, proteins that inhibit

A paper detailing the properties of the multikinase inhibitor ABT-869 (7) did not indicate whether plasma protein binding data were used in the optimization leading to this highly protein-bound (mouse 98.2%, human 99.0%) compound [45]. A dose which provided a 69% reduction in tumor growth and >50% inhibition of receptor phosphorylation and pharmacodynamic response afforded plasma concentration that remained above the cellular IC50 for receptor phosphorylation in the presence of plasma for 4 of 12 h in the bid dosing cycle. 

Angiogenesis Inhibitors Proteins That Inhibit Tumor Growth... 

Finally, dietary antioxidants may affect cell growth and possible tumorigenesis. When considering the treatment of endothelial cell neoplasms, limiting cell proliferation is one key aspect of an antiangiogenic strategy. Cyclins are molecules that directly stimulate cell division, and cyclin-dependent kinases (CDK) are needed to activate cyclin molecules. Thus the cyclin pathways represent an important target for tumor suppressors to inhibit. Two known tumor suppressor proteins that act in this maimer are... 

T cells in vitro [121]. The Tat-p27 protein dose-dependently induced cell cycle arrest at Gl. Snyder et al. demonstrated that the Tat-p27 tumor suppressor protein actually inhibited tumor growth in two mouse models, such as a HI299 subcutaneous solid tumor xenograft model and a more clinical-relevant peritoneal tumor model [122]. 

Ubiquitin-proteasome pathway, involved in the degradation of tumor growth proteins, plays an important role in the treatment of cancer. Physalin B (6), the major steroidal lactone of Physalis angulata, is known to produce the ubiquitinated protein accumulation and inhibit the TNFa-induced activation of NF-KB in DLD-1 4Ub-Luc cell assay. Physalin B does not inhibit purified proteasome catalytic activities but interferes with the cellular catalytic activities of the proteasome proteins at 4—8-fold high concentration, which is required to produce significant rise in bioluminescence and ubiquitinated protein accumulation in DLD-1 4Ub-Luc cells. The results indicate that physalin B is cytotoxic and works as an apoptotic triggering agent in DLD-1 4Ub-Luc cells [95]. 

The less polar methyl ester 2 as prodrug showed better results in vivo and inhibits both farnesylation of the Ras protein and growth of Ras-transformed cells, whilst proliferation of Raf- or Mos-transformed cells was not influenced. Growth of human pancreatic adenocarcinoma cells with mutated K-Ras, c-Myc and p53 genes was inhibited by application of 2. If the compound is administered over a period of 5 days to mice with implanted Ras-dependent tumors, tumor growth can be reduced by up to 66% compared to untreated mice, whereas application of the antitumor antibiotic doxorubicin only resulted in 33% reduction under the same conditions. It is particularly noteworthy that treatment with the /1-turn mimetic - in contrast to treatment with doxorubicin - was without any visible side effects, such as weight loss. 

Blanco-Aparicio, C., Molina, M. A., Femandez-Salas, E., Frazier, M. L., Mas, J. M., Querol, E., Aviles, F. X., de Llorens, R. (1998). Potato carboxypeptidase inhibitor, a T-knot protein, is an epidermal growth factor antagonist that inhibits tumor cell growth. J. Biol. Chem., 273, 12370-12377. 

Surprisingly, a growth inhibiting and pro-apoptotic function has been demonstrated for oncogenic Ras mutants. In primary cell cultures, activation of the Ras pathway is linked to an increase in the concentration of the tumor suppressor proteins p53 and pl9ARF (Serrano, 1997), which both promote programmed cell death, or apoptosis (see Chapter 15). This example shows that, according to the cellular context, the Ras protein can promote both cell death and cell survival via interactions with distinct effector proteins. 

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