R prolonged er stress, and triggers an apoptotic cascade called proapoptotic/terminal upr. Several studies reveal a critical role for upr activation for tumor cell resistance to hypoxia and tumor growth promotion, and suggest that the upr may be an attractive target for antitumor modalities. It is therefore reasonable to assume that manipulation of er stress might enhance the efficacy of chemotherapeutic drugs and provide new anticancer targets. So far, data support the potential of drugs that inhibit the normal functions and homeostasis of the er in treatment of malignancies, and has lead to the development of heat shock protein 90 inhibitors. Interestingly, another novel agent, the proteasome inhibitor bortezomib, has been shown to target the er function, by inducing components of the proapoptotic/terminal upr. As part of these studies, we showed that wm cells inherently express the physiologic upr machinery compared with normal bm cells, and that increased er stress leads to proapoptotic/terminal upr in wm cells. We therefore examined tunicamycin, an er stress inducer, for potential antitumor effects in wm. Tunicamycin induced significant cytotoxicity, apoptosis and cell-cycle arrest, and inhibited dna synthesis in wm cell lines and primary bm cd19+ cells from patients with wm with an inhibitory concentration (ic50) of 0. 5 âµg/ml to 1 âµg/ml, but not in healthy donor cells. Importantly, coculture of wm cells in the context of the bm microenvironment did not inhibit tunicamycin-induced cytotoxicity. Finally, we demonstrated that er stress inducer synergized with other agents used in the treatment of wm. The results of this study were recently published (leleu et al, blood 2008). viagra for sale generic viagra online viagra without a doctor prescription viagra online viagra without a doctor prescription buy viagra online buy generic viagra viagra for sale cheap generic viagra buy generic viagra online
These preclinical studies provide a framework for further evaluation of er stress inducing agents as therapeutic agents in wm. Studies into cd70-cd27 interactions in wm. Recent studies published by us (ho et al, blood 2008) demonstrated an important role for scd27-cd70 signaling among bm lpcs and mcs in wm, and demonstrate a novel mechanism of action for scd27 as a regulator of 2 principal tnf family members (april and cd40l) whose role as growth and survival factors has previously been established by us and others in wm and other b-cell malignancies (figure 8). â â figure 8. Targeting wm cell growth and survival by use of agents that directly kill wm cells, by effecting mast cell-wm cell support networks, as well as by stimulating anti-wm cell immunity. â â â â central to these studies was the demonstration that a monoclonal ant.