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View the Table of Contents for the January 2007 issue of Molecular Cancer Therapeutics
Holder et al. Page 163
The pim-1 kinase is a true oncogene that has been implicated in the development of leukemias, lymphomas, and prostate cancer, and is the target of drug development programs. Holder et al. have used experimental approaches to identify a selective, cell-permeable small molecule inhibitor of the pim-1 kinase, to foster basic and translational studies of the enzyme. RWPE2 cells treated with quercetagetin showed pronounced growth inhibition at inhibitor concentrations that blocked pim-1 kinase activity. Furthermore, the ability of quercetagetin to inhibit the growth of other prostate epithelial cell lines varied in proportion to their levels of PIM1 protein. Quercetagetin can function as a moderately potent and selective, cell-permeable inhibitor of the pim-1 kinase, and may be useful for proof-of-concept studies to support the development of clinically useful PIM1 inhibitors.
Punchihewa et al. Page 213
The anticancer drug XR5944 was originally developed as a topoisomerase inhibitor and subsequently shown to be a transcription inhibitor. It has demonstrated exceptional anticancer activity both in vitro and in vivo and was significantly more potent than traditional topoisomerase inhibitors. Punchihewa et al. tested the ability of XR5944 to inhibit ER binding/activity in both cell-free systems and in cultured cells. Their data suggested that XR5944 is capable of specifically inhibiting the binding of ER to its consensus DNA sequence and its subsequent activity. This represents a novel mechanism of ER inhibition, which may be useful in overcoming resistance to current antiestrogens.
Page 227
Resistance of ovarian clear cell carcinoma (CCC) to platinum-based chemotherapy is associated with poor prognosis, and an effective treatment for advanced disease is urgently needed. HER2/neu is upregulated more often in CCC than in other histologic types of epithelial ovarian cancer. The purpose of this study was to assess possible treatment for ovarian CCC with the anti-HER2 antibody trastuzumab or human adenovirus type 5 E1A. E1A gene therapy, because of its ability to stabilize wild-type p53, is worth exploring as a treatment modality for women with ovarian CCC, which typically expresses wild-type p53.
Page 299
Hsp27 is a cytoprotective chaperone that sits as a hub at the center of many pathways regulating the response of a cell to stress and therapeutic stimuli. Therapeutic targeting Hsp27 is attractive as it would, in effect, affect multiple pathways implicated in cancer progression and resistance. Kamada et al. demonstrated that high levels Hsp27 increases chemoresistance in human bladder cancer cells, while Hsp27 knockdown using OGX-427 or Hsp27 siRNA increases apoptotic rates and enhances chemosensitivity in vitro and in vivo. These data are clinically relevant and timely, as a human trial to test the activity of intravesical OGX-427 in subjects with superficial bladder cancer will begin this year.