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View the Table of Contents for the March 2008 issue of Molecular Cancer Therapeutics
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It is well established that mitogen activated protein kinase kinase (MKK) pathways promote the growth and metastasis of human tumors. However, little is known about the role of MKK signaling in soft tissue sarcomas. Lethal Toxin (LeTx) is a bacterial toxin that inactivates MKKs by proteolysis. Ding and colleagues found that LeTx substantially inhibited MKK activity and fibrosarcoma growth in mouse xenograft models. Ultrasound imaging revealed that LeTx caused a rapid and marked decrease in perfusion of tumor but not normal tissues. These results indicate LeTx may be a broadly effective strategy for targeting MKK signaling and neovascularization in sarcomas.
Blancafort et al. Page 688 Cancer cells develop drug resistance through dysregulation of one or more genes or cellular pathways. In order to isolate efficient regulators of drug resistance in tumor cells, Blancafort and colleagues have adopted a genome-wide scanning approach based on the screening of large libraries of artificial transcription factors (ATFs) made of three and six randomly assembled zinc finger (ZF) domains. ZF libraries were linked to a VP64 activation domain and delivered into a paclitaxel-sensitive tumor cell line. Several ATFs were isolated that promoted drug resistance. Furthermore, the authors demonstrated that a number of ATFs up-regulated targets of p53and genes participating in the p14ARF-MDM2-p53 tumor suppressor pathway. Thus, ATFs can be used to map genes and pathways involved in drug resistance phenotypes and have potential as novel therapeutic agents to inhibit drug resistance.
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