The scatter factor/hepatocyte growth factor (HGF)-c-Met axis is involved in the malignant phenotype of various tumor types via activation of a wide range of autocrine and paracrine processes. Autocrine activation of tumor cell c-Met receptors enhances tumor cell proliferation, angiogenesis, invasion/metastasis and resistance to apoptosis and cytotoxic therapies. In addition, tumor and stroma cell-derived HGF functions as a potent angiogenic factor. Therefore, the HGF-c-Met axis is critically involved in multiple facets of normal cellular growth and homeostasis and activated in a dysregulated manner in a variety of cancers. Consequently, inhibiting the HGF-c-Met axis would be anticipated to have potent anti-tumor effects in many cancers through multiple complimentary mechanisms including increased sensitivity to current cytotoxic chemo-and radiotherapies. The acceptance of c-Met as a tractable target for cancer therapy has fostered intensive drug discovery efforts across the pharmaceutical industry. This research has led to 20 published crystal structures (with and without ligands) that revealed two distinct binding modes for ATP-competitive inhibitors: Type I ligands which assumes a U shape geometry through interactions with both hinge and activation loop residue Y1230, and Type II ligands which adopt a more extended orientation, either binding a conventional DFG-out conformation or protein conformations with varying degrees of 'DFG-out' character. Nearly a dozen small molecule c-Met inhibitors have entered human clinical trials ranging from Type I inhibitors solely selective for c-Met to Type I inhibitors with broader kinase activities to Type II inhibitors with "spectrum selective" kinase activity. The identification, profiles and properties of these clinical candidates are summarized in this review.
The effect of the potent and selective poly(ADP-ribose) (PAR) polymerase-1 [and PAR polymerase-2] inhibitor CEP-8983 on the ability to sensitize chemoresistant glioblastoma (RG2), rhabdomyosarcoma (RH18), neuroblastoma (NB1691), and colon carcinoma (HT29) tumor cells to temozolomide-and camptothecin-induced cytotoxicity, DNA damage, and G 2 -M arrest and on the potentiation of chemotherapy-induced myelotoxicity was evaluated using in vitro assays. In addition, the effect of the prodrug CEP-9722 in combination with temozolomide and/or irinotecan on PAR accumulation and tumor growth was also determined using glioblastoma and/or colon carcinoma xenografts relative to chemotherapy alone. CEP-8983 sensitized carcinoma cells to the growth-inhibitory effects of temozolomide and/or SN38 increased the fraction of and/ or lengthened duration of time tumor cells accumulated in chemotherapy-induced G 2 -M arrest and sensitized tumor cells to chemotherapy-induced DNA damage and apoptosis. A granulocyte-macrophage colony-forming unit colony formation assay showed that coincubation of CEP-8983 with temozolomide or topotecan did not potentiate chemotherapy-associated myelotoxicity. CEP-9722 (136 mg/kg) administered with temozolomide (68 mg/kg for 5 days) or irinotecan (10 mg/kg for 5 days) inhibited significantly the growth of RG2 tumors (60%) or HT29 tumors (80%) compared with temozolomide or irinotecan monotherapy, respectively. In addition, CEP-9722 showed ''stand alone'' antitumor efficacy in these preclinical xenografts. In vivo biochemical efficacy studies showed that CEP-9722 attenuated PAR accumulation in glioma xenografts in a dose-and time-related manner. These data indicate that CEP-8983 and its prodrug are effective chemosensitizing agents when administered in combination with select chemotherapeutic agents against chemoresistant tumors. [Mol Cancer Ther 2007;6(8):2290-302]
Pancreatic ductal adenocarcinoma is one of the major causes of cancer mortality in the industrialized world, having among the poorest prognosis of any malignancy. Mutations or alterations in the p53 tumor suppressor gene/protein are observed in 50 ± 70% of these cancers, yet little information is available regarding the phenotypic e ects of restoration of wild-type (wt) p53 function in pancreatic ductal carcinoma cells. The consequences of stable reintroduction of wt p53 on apoptosis and di erentiation was examined in a poorly di erentiated pancreatic carcinoma cell line (Panc-1), possessing only mutant (mt) p53 (codon 273 mutation). Cells were transfected with a temperature-sensitive mouse p53 val135 (tsp53) vector under additional control of a geneticallymodi®ed metallothionein promoter. This tsp53 has a`mt' phenotype at 37.58C, and a`wt' phenotype at 32.58C and the presence of 100 mM ZnCl 2 . Stable expression of wt p53 caused upregulation of the p21/WAF1 gene, and G 1 growth arrest as shown by¯ow cytometry and BrdU labeling. Additionally, apoptosis was induced 8 ± 12 postinduction in the majority of the cells (60 ± 70%), as demonstrated by morphological changes, in situ TdT labeling and internucleosomal laddering. However, a subpopulation (30%) of the transfectants survived this apoptotic fate. Unlike the epithelial parental Panc-1 cells, these cells exhibited the appearance of a neuroendocrine-like phenotype with extensive branch-like processes, and marked cytoplasmic and cytoskeletal immunostaining for tau-2, synaptophysin, and chromogranin A. These studies suggest that stable and regulated expression of wt p53 can have multiple phenotypic consequences (apoptosis and altered di erentiation to a neuroendocrine-like phenotype) in poorly-di erentiated pancreatic carcinoma cells.
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