Other investigators have also noted that the level of expression of EGFR in cells or tumors did not predict sensitivity to ZD. The level of EGFR expression may not indicate the degree to which any individual tumor or tumor cell line is dependent on the EGFR signaling pathway for growth.Additional biomarkers that would more specifically indicate this dependence have yet to be defined.Additionally, coexpression of other members of the erbB family that heterodimerize with EGFR but whose signaling would also be inhibited by ZD through its action on the EGFR component of such heterodimers may also play an important role in determining drug sensitivity. Increased EGFR expression is only one mechanism by which enhancement of EGFR signaling drive can be achieved: increased levels of ligand, heterodimerization of EGFR, decreased intracellular phosphatase, and mutations in EGFR that lead to constitutive activation of the TK can all contribute to signaling drive.Reverse transcriptionPCR measurements of cfos mRNA in extracts of A tumor xenografts from mice treated with ZD showed that days of drug treatment reduced cfos in a dosedependent and complete manner, paralleling drug effects on tumor size.The studies reported here have indicated the potential utility of ZD as an antitumor agent, but because patients with locally advanced or metastatic cancer undergoing treatment with cytotoxic chemotherapy are most often the target population in which new anticancer agents are tested, combinations of ZD with various cytotoxic drugs with different mechanisms of action have been investigated.These studies showed that combining ZD with platins, and topoisomerase inhibitors or the antimetabolite raltitrexed markedly potentiated cytotoxic drug activity in vitro and in vivo. They also suggest that the addition of ZD to the treatment regimen for patients undergoing cytotoxic chemotherapy might confer significant additional clinical benefits.ZD INHIBITION OF EGFR SIGNALING AND TUMOR GROWTH. Click on Request Permissions which will take you to the Copyright Clearance Centers Downloaded from cancerres.aacrjournals.org on April. American Association for Cancer Research. Androgen ablation remains the standard effective therapy for patients with advanced prostate cancer, inhibiting proliferation and inducing apoptosis in tumor cells. Unfortunately, after shortterm remissions, surviving tumor cells recur with castrateresistant prostate cancer. To significantly improve survival in men with prostate cancer, new therapeutic strategies to inhibit the appearance of this phenotype must be developed.Although Flunisolide promising, treatment resistance emerges early due to compensatory mechanisms Revefenacin involving activation of the heat shock factor HSF.OGX is a secondgeneration phosphorothioate antisense oligonucleotide currently in latestage clinical development that potently inhibits CLU expression and enhances the efficacy of anticancer therapies in various human cancers including prostate cancer. All cell lines were passaged for less than months after resurrection.AAG was kindly provided by NIH and used for in vitro and in vivo studies.OGX sequence corresponds to the initiation site in exon II of human CLU.Prostate cells were treated with siRNA or oligonucleotides, using protocols described previously. Incubation of mg of total cell lysate was done with the caspase substrate ACDEVDAMC at room temperature for hours, and caspase activity was quantified in a fluorometer with excitation and emission at and at nm, respectively.

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