more sensitive to proteasome inhibition than are be upregulated more than 2-fold in fibronectin quiescent or differentiated cells, bound MM cells. 11 are known to be NF-KB responsive. Importantly, pretreatment with either While active division does appear to increase MG-132 or bortezomib reversed adhesion-mediated sensitivity to proteasome inhibition, it is likely that drug resistance and sensitized these cells to other mechanisms contribute to the anticancer cytotoxic agents. Further studies of bortezomib activity of proteasome inhibitors activity found that proteasome inhibition decreased the binding of MM cells to BMSCs by 50% Under Inhibition of proteasomal activity results it normal circumstances, some MM cells produce TNF the accumulation of numerous regulatory a,a cytokine that enhances cell-cell interactions by proteins within the cell. Proteins stabilized by increasing the secretion of IL-6 from BMSCs and proteasome inhibition include the tumor upregulating the expression of the adhesion molecules VLA-4 and LFA-1 on MM cells and the suppressor protein p53 and the cell cycle proteins p21 and p27. It is possible that corresponding receptors VCAM-1 and ICAM-1 on BMSCs. Bortezomib prevented the TNF-a-induced proteasome inhibition triggers the apoptotic NF-KB-dependent upregulation of IL-6 and cascade, in part, by causing the rapid therefore reduced cell adhesion. Moreover the accumulation of incompatible regulatory proliferation of the remaining adherent MM cell proteins within the cell was also inhibited by bortezomib. The NF-KB pathway is constitutively active in some cancer cells and is associated with resistance to anticancer therapy. Specifically, MM tumor cells and the bone marrow of MM patients show enhanced NF KB activity, and chemoresistant MM cells have ared with chemosensitive lines. Proteasome inhibitors have ge removed for copyright reasons. See Figure 3 in andson, 2003) been shown to stabilize IKB and prevent the activation of NF-KB. In MM cells, bortezomib increased the level of phosphorylated IKB protein nd inhibited constitutive NF-KB activity. Further the tumor necrosis factor a TNF-a)-induced activation of NF-KB in MM cells This is a significant finding, since TNF-a is present in the bone marrow microenvironment and is know Preclinical studies show that bortezomib is highly to activate NF-kB-dependent gene expression and toxic against a broad range of cancer cell lines in proliferation in MM cells. Proteasome inhibition ha vitro Bortezomib may be equally effective against also been shown to block chemotherapy-and solid tumors and hematological malignancies. It also inhibits angiogenesis and when used in combination resulting in enhanced sensitivity to these tumoricidal with conventional tumoricidal agents, it enhances the agents and increased apoptosis in cancer cells in sensitivity of cancer cells to these agents vitro. However the direct inhibition of IxBa phosphorylation is insufficient to completely inhibit A study was undertaken in patients with relapsed an the proliferation of MM cells, suggesting that refractory MM disease in the United states, Of 202 bortezomib does not act through NF-kB blockade enrolled patients, evaluable. 92% had been treated with 3 or more of the classes of drugs commony used for myeloma, and 912 were refractory to Proteasome inhibitors may overcome drug their most recent therapy. The response rate(complete resistance in vivo by interfering with the protective partial, or minor response) to bortezomib was 35%.Four cent of patients had complete responses,. The media interaction between cancer cells and the bone overall survival was 16 months. with a median duration marrow. In MM. the adherence of tumor to bone response of 12 months. Also noted were improved quall marrow stromal cells(BMSC) provides protection against apoptosis, promotes tumor cell survival and progression, and confers protection against chemotherapeutic drugs. Adhesion to fibronectin this cancer, although these results may at first sight see protects cells from common chemotherapeutic modest, they actually represent a significant advance in the continuous quest for a successful treatment for this agents as well as radiation. Of the 52 genes found te other cancers and related-diseasesmore sensitive to proteasome inhibition than are quiescent or differentiated cells. While active division does appear to increase sensitivity to proteasome inhibition, it is likely that other mechanisms contribute to the anticancer activity of proteasome inhibitors. Inhibition of proteasomal activity results in the accumulation of numerous regulatory proteins within the cell. Proteins stabilized by proteasome inhibition include the tumor￾suppressor protein p53 and the cell cycle proteins p21 and p27. It is possible that proteasome inhibition triggers the apoptotic cascade, in part, by causing the rapid accumulation of incompatible regulatory proteins within the cell. The NF-κB pathway is constitutively active in some cancer cells and is associated with resistance to anticancer therapy. Specifically, MM tumor cells and the bone marrow of MM patients show enhanced NF- κB activity, and chemoresistant MM cells have increased NF-κB activity compared with chemosensitive lines. Proteasome inhibitors have been shown to stabilize IκB and prevent the activation of NF-κB. In MM cells, bortezomib increased the level of phosphorylated IκB protein and inhibited constitutive NF-κB activity. Further, bortezomib inhibited the tumor necrosis factor α (TNF-α)-induced activation of NF-κB in MM cells. This is a significant finding, since TNF-α is present in the bone marrow microenvironment and is known to activate NF-κB-dependent gene expression and proliferation in MM cells. Proteasome inhibition has also been shown to block chemotherapy- and radiotherapy-induced activation of NF-κB, resulting in enhanced sensitivity to these tumoricidal agents and increased apoptosis in cancer cells in vitro. However, the direct inhibition of IκBα phosphorylation is insufficient to completely inhibit the proliferation of MM cells, suggesting that bortezomib does not act through NF-κB blockade alone. Proteasome inhibitors may overcome drug resistance in vivo by interfering with the protective interaction between cancer cells and the bone marrow. In MM, the adherence of tumor to bone marrow stromal cells (BMSC) provides protection against apoptosis, promotes tumor cell survival and progression, and confers protection against chemotherapeutic drugs. Adhesion to fibronectin protects cells from common chemotherapeutic agents as well as radiation. Of the 52 genes found to be upregulated more than 2-fold in fibronectin￾bound MM cells, 11 are known to be NF-κB responsive. Importantly, pretreatment with either MG-132 or bortezomib reversed adhesion-mediated drug resistance and sensitized these cells to cytotoxic agents. Further studies of bortezomib activity found that proteasome inhibition decreased the binding of MM cells to BMSCs by 50%. Under normal circumstances, some MM cells produce TNF- α, a cytokine that enhances cell-cell interactions by increasing the secretion of IL-6 from BMSCs and upregulating the expression of the adhesion molecules VLA-4 and LFA-1 on MM cells and the corresponding receptors VCAM-1 and ICAM-1 on BMSCs. Bortezomib prevented the TNF-α–induced, NF-κB–dependent upregulation of IL-6 and therefore reduced cell adhesion. Moreover, the proliferation of the remaining adherent MM cells was also inhibited by bortezomib. (Image removed for copyright reasons. See Figure 3 in Richardson, 2003.) Preclinical studies show that bortezomib is highly toxic against a broad range of cancer cell lines in vitro. Bortezomib may be equally effective against solid tumors and hematological malignancies. It also inhibits angiogenesis and when used in combination with conventional tumoricidal agents, it enhances the sensitivity of cancer cells to these agents. A study was undertaken in patients with relapsed and refractory MM disease in the United States. Of 202 enrolled patients, 193 were evaluable; 92% had been treated with 3 or more of the major classes of drugs commonly used for myeloma, and 91% were refractory to their most recen therapy. The response rate (complete, partial, or minor response) to bortezomib was 35%. Four percent of patients had complete responses. The median overall survival was 16 months, with a median duration response of 12 mon hs. Also noted were improved quality￾of-life parameters, improved levels of normal immunoglobulins, decreased transfusion requirements, and improvements in hemoglobin levels. Given the severity of this cancer, although these results may at first sight seem modest, they actually represent a significant advance in the continuous quest for a successful treatment for this and other cancers and related-diseases. t t