SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on November 7, 2002; DOI 10.1182/blood-2002-06-1768. This Article Abstract Full Text (PDF) All Versions of this Article: 2002-06-1768v1 101/6/2377    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mitsiades, N. Articles by Anderson, K. C. Search for Related Content PubMed PubMed Citation Articles by Mitsiades, N. Articles by Anderson, K. C. Related Collections Neoplasia Apoptosis Signal Transduction Gene Expression Genomics Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 March 2003, Vol. 101, No. 6, pp. 2377-2380 NEOPLASIA Brief report The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications Nicholas Mitsiades, Constantine S. Mitsiades, Paul G. Richardson, Vassiliki Poulaki, Yu-Tzu Tai, Dharminder Chauhan, Galinos Fanourakis, Xuesong Gu, Charles Bailey, Marie Joseph, Towia A. Libermann, Robert Schlossman, Nikhil C. Munshi, Teru Hideshima, and Kenneth C. Anderson From the Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston MA; Department of Medicine, Harvard Medical School, Boston, MA; Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA; Beth Israel Deaconess Medical Center (BIDMC) Genomics Center, BIDMC, Harvard Institutes of Medicine, Boston, MA; Boston VA Health Care System, Boston, MA.     Abstract Top Abstract Introduction Study design Results and discussion References The proteasome inhibitor PS-341 inhibits nuclear factor-B (NF-B) activation, induces apoptosis in cancer cells, including multiple myeloma (MM) cells, and has marked clinical activity as a monotherapy for MM. In this study, we found that subtoxic concentrations of PS-341 potently sensitized MM cell lines and patient cells to DNA-damaging chemotherapeutic agents such as doxorubicin and melphalan, including cells resistant to these drugs and those isolated from a patient who had relapsed after PS-341 monotherapy. Moreover, PS-341 abolished cell adhesion-mediated drug resistance. Using gene expression profiling and proteomic analysis, we demonstrate that PS-341, among its other proapoptotic effects, down-regulates the expression of several effectors involved in the cellular response to genotoxic stress. These data suggest that, in addition to down-regulating the expression of apoptosis inhibitors, PS-341 inhibits genotoxic stress response pathways and thereby restores sensitivity to DNA-damaging chemotherapeutic agents. These studies, therefore, provide the framework for clinical use of this agent in combination with conventional chemotherapy. (Blood. 2003;101:2377-2380) © 2003 by The American Society of Hematology.     Introduction Top Abstract Introduction Study design Results and discussion References PS-341, a boronic acid dipeptide proteasome inhibitor, inhibits the activation of the transcription factor NF-B (nuclear factor-B),1,2 down-regulates the expression of several apoptosis inhibitors,3 induces caspase-dependent apoptosis of drug resistant multiple myeloma (MM) cell lines and patient cells,3,4 inhibits MM cell binding to bone marrow stromal cells (BMSCs), and inhibits production of MM growth and survival factors in the BM milieu.5 In a murine plasmacytoma model, PS-341 inhibits tumor growth in a dose-dependent fashion and prolongs host survival.6 In a phase 2 clinical trial of PS-341 in patients with relapsed, refractory MM, objective responses, including some complete responses, were observed.7 In this study, we characterized the effect of PS-341 combined with doxorubicin and melphalan on MM cells. We found that PS-341 lowered the apoptotic threshold to these chemotherapeutic agents and even reversed drug resistance. Gene expression profiling using oligonucleotide microarrays, as well as proteomic analysis, detected down-regulation of several effectors mediating the response to genotoxic stress. These studies, therefore, provide the framework for the future use of PS-341 combined with conventional chemotherapy.     Study design Top Abstract Introduction Study design Results and discussion References Tissue culture Human MM cell lines included MM.1S,8 RPMI-8226/S, and its doxorubicin (Dox40)- and melphalan (LR5)-resistant sublines,8 ARP-1,8 S6B45,8 NCI-H929 (American Type Culture Collection, Manassas, VA), and INA6 (a gift from Renate Burger, University of Erlangen-Nuernberg, Germany). Tumor cells were freshly isolated from the bone marrow of MM patients as previously described.8 Case report A 58-year-old woman, with relapsed refractory immunoglobulin G (IgG) lambda MM, had received prior therapy with melphalan and prednisone; vincristine, doxorubicin, and dexamethasone (VAD) plus cyclophosphamide; high-dose melphalan and autologous stem cell transplantation; -interferon; and thalidomide. After informed consent, she received cyclic PS-341, 1.3 mg/m2 intravenously twice a week for 2 weeks with 1 week off, per approved protocol of the institutional review board (IRB). Although serum paraprotein decreased from 5.1 g/dL to 3.3 g/dL after 3 cycles of PS-341, she developed fatigue and exacerbation of a preexisting peripheral neuropathy. PS-341 dose was, therefore, reduced to 1 mg/m2, and she completed 4 cycles of therapy. Because of progressive disease evidenced by increasing paraprotein (5.0 g/dL) and circulating plasma cells, dexamethasone (40 mg twice a week for 2 weeks each cycle) was added. Although her M-component slightly decreased (to 4.7 g/dL) and circulating plasma cells transiently cleared, she developed rapidly progressive disease, with 48% circulating plasma cells after the sixth cycle; PS-341 protocol treatment was discontinued. Subsequent therapy with intravenous cyclophosphamide, thalidomide, thalidomide alone, dexamethasone, and biaxin, as well as Doxil with thalidomide and dexamethasone, was ineffective. At this time, MM cells were isolated by BM aspiration and purified as previously described.8 Materials PS-341 was provided by Millennium Pharmaceuticals (Cambridge, MA). Dexamethasone, doxorubicin, melphalan, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were obtained from Sigma Chemical (St Louis, MO). Ku 70 and 80 antibodies were acquired from Lab Vision (Fremont, CA). Methods RNA isolation, gene expression profiling, and data analysis were performed as previously described.3 High-throughput global proteomic analysis of the signaling state of PS-341-treated MM cells was performed by multiplex-immunoblotting arrays using the KPKS-1.0 and KPSS-1.0 platforms, as previously described.9,10 Immunoblotting analysis and quantification of cell survival with the MTT assay were performed as previously described.11 All experiments were repeated at least 3 times, and each experimental condition was repeated at least in quadruplicate wells. Results from representative experiments are shown. LD50 values were calculated with the use of the SPSS-11.0 statistical package. Statistical significance was examined by a 2-way analysis of variance, followed by Duncan post hoc test. In all analyses, P < .05 was considered statistically significant.     Results and discussion Top Abstract Introduction Study design Results and discussion References Synergistic anti-MM activity between PS-341 and conventional chemotherapeutics NF-B confers resistance to DNA-damaging chemotherapy12; conversely, specific inhibition of NF-B sensitizes MM cells to subtoxic concentrations of doxorubicin.13 We now investigated whether the proteasome inhibitor PS-341, which inhibits NF-B activity,1 sensitizes MM cells to conventional chemotherapy. As shown in Figure 1A, PS-341, at a subtoxic concentration, markedly enhances sensitivity of MM.1S cells to subtoxic concentrations of doxorubicin and to melphalan (P < .001 in both cases). However, the subtoxic concentration of PS-341 did not increase the anti-MM effect of dexamethasone (P > .05), in agreement with our previous finding of only additive cytotoxicity between these 2 agents.5 Dose-response analysis demonstrated that the LD50 for doxorubicin in MM.1S cells was 150 nM in the absence and 26 nM in the presence of PS-341 (2 nM) (Figure 1B). The concentration of PS-341 is 10 to 30 nM in patients' serum, with peaks of 100 nM, which is sufficient to achieve this synergistic effect in vivo. View larger version (50K): [in this window] [in a new window]   Figure 1. PS-341 sensitizes MM cells to DNA-damaging chemotherapy. (A) MM.1S cells were pretreated with doxorubicin (Doxo; 40 nM), melphalan (Mel; 1 µM), or dexamethasone (Dex; 0.5 µM) for 24 hours, and then PS-341 (2 nM) was added for additional 24 hours (black bars, without PS-341; white bars, with PS-341). PS-341 sensitizes MM.1S cells to DNA-damaging chemotherapy. (B) Dose-response analysis for the effect of doxorubicin on MM.1S cells in the presence () or absence () of PS-341 (2 nM) reveals that PS-341 decreases the LD50 of doxorubicin from 150 to 26 nM. (C) MM.1S cells were pretreated with doxorubicin (50 ng/mL) for 24 hours, and then PS-341 (2 nM) was added for an additional 24 hours (i), or pretreated with PS-341 for 24 hours and then doxorubicin for an additional 24 hours (ii), or treated with PS-341 and doxorubicin together for 24 hours (iii). In all cases a synergistic effect is found, but the strongest synergy is observed when the cells are pretreated with doxorubicin followed by PS-341 treatment (black bars, control; white bars, doxorubicin alone; grid bars, PS-341; gray bars, doxorubicin plus PS-341). (D) RPMI-8226/S, ARP-1, S6B45, NCH-H929, and INA6 cells were pretreated with doxorubicin (50 ng/mL) for 24 hours and then with PS-341 (2 nM) for an additional 24 hours (black bars, control; white bars, doxorubicin alone; grid bars, PS-341; gray bars, doxorubicin plus PS-341). (E) Primary MM cells from 4 PS-341-naive patients were pretreated with doxorubicin (50 ng/mL) for 24 hours and then with PS-341 (2 nM) for an additional 24 hours. PS-341 sensitizes all MM cells to doxorubicin (black bars, control; white bars, doxorubicin alone; grid bars, PS-341; gray bars, doxorubicin plus PS-341). (F) Doxorubicin-resistant RPMI-Dox40 cells were pretreated with (white bars) or without (black bars) doxorubicin (800 ng/mL) for 24 hours, and then PS-341 (2-10 nM) was added for an additional 24 hours (black bars, without doxorubicin; white bars, with doxorubicin). PS-341 sensitizes RPMI-Dox40 cells to doxorubicin. (G) Melphalan-resistant LR5 cells were pretreated with or without melphalan (5 µM) for 24 hours, and then PS-341 (2 nM) was added for an additional 24 hours. PS-341 sensitizes LR5 cells to melphalan. (H) MM cells isolated from a patient who had relapsed following treatment with PS-341 were pretreated with (white bars) or without (black bars) doxorubicin (100 ng/mL) for 24 hours, and then PS-341 (5-20 nM) was added for an additional 24 hours. Pretreatment with doxorubicin overcomes resistance to PS-341. (I) MM.1S cells were treated for 24 hours with doxorubicin (100-200 ng/mL) in wells coated with (white bars) or without (black bars) fibronectin (FN). PS-341 (10 nM) was added for additional 24 hours. In all cases, percentage of cell survival (mean ± SD) is quantified by MTT. All experiments were repeated at least 3 times, and each experimental condition was repeated at least in quadruplicate wells in each experiment. Results from representative experiments are shown. We next investigated whether the sequence of administration of doxorubicin and PS-341 affects their synergistic anti-MM effect. MM.1S cells were therefore (1) pretreated with doxorubicin for 24 hours and then treated with PS-341 for an additional 24 hours, (2) pretreated with PS-341 for 24 hours and then treated with doxorubicin for an additional 24 hours, or (3) treated concomitantly with PS-341 and doxorubicin for 24 hours. Although the combination of PS-341 and doxorubicin was more potent than either drug alone under any of these conditions (P < .05 in all cases), the most pronounced synergy was observed when MM cells are pretreated with doxorubicin followed by PS-341 (Figure 1C). We extended our studies to additional MM cell lines (RPMI-8226/S, ARP-1, S6B45, NCI-H929, and INA6, Figure 1D) and primary patient MM cells (Figure 1E) and confirmed that PS-341 sensitizes MM cells to doxorubicin. Importantly, the same sensitizing effect is observed in cells that have been selected for resistance to doxorubicin (RPMI-Dox40 cells, Figure 1F) or melphalan (LR5 cells, Figure 1G), indicating that PS-341 increases chemosensitivity in both drug-sensitive and -resistant MM cells. We next assessed the effect of PS-341 on the chemosensitivity of primary MM cells isolated from a patient who had relapsed following conventional and high-dose chemotherapy, interferon-, thalidomide alone and combined with cytotoxic drugs or steroids, liposomal doxorubicin, as well as PS-341 alone and in combination with dexamethasone. These patient MM cells have low sensitivity to either PS-341 (IC50 > 50 nM compared with IC50 < 5 nM in PS-341-sensitive patient MM cells2) or doxorubicin monotherapy in vitro. Nonetheless, the combination of these 2 agents results in significant MM cell death (Figure 1H). Therefore, synergy between PS-341 and chemotherapy can reverse resistance to either agent alone. PS-341 abolishes cell adhesion-mediated drug resistance (CAM-DR) Previous studies have shown that sensitivity of MM cells to doxorubicin is decreased on tumor cell binding to extracellular matrix components, in particular fibronectin.14-17 This CAM-DR is associated with increased availability of caspase inhibitor FLICE-inhibitory protein (FLIP) for binding to the death receptor Fas and decreased activation of caspase-8.18 Because we have demonstrated that PS-341 lowers FLIP expression and facilitates Fas-dependent caspase-8 activation,3 we hypothesized that PS-341 could inhibit CAM-DR. As shown in Figure 1I, MM.1S cells are less sensitive to doxorubicin in the presence than in the absence of fibronectin, but PS-341 completely overcomes this antiapoptotic effect (P < .05). Mechanism of chemosensitization by PS-341 We next investigated the mechanism of the chemosensitizing activity of PS-341. We have previously demonstrated that PS-341 decreases the expression of Bcl-2, A1, cIAP-2, X-linked inhibition of apoptosis (XIAP), and FLIP.3 These effects may be due, at least in part, to the inhibition of NF-B activation by PS-341,1,2 because specific inhibition of NF-B down-regulates these apoptosis inhibitors and sensitizes MM cells to doxorubicin.13 Our findings are consistent with the ability of NF-B to promote resistance to genotoxic agents in other models12 and suggest a possible mechanism for the chemosensitizing activity of PS-341. To further characterize the effect of the proteasome inhibitor PS-341 on the transcriptional profile of MM cells, we performed oligonucleotide gene microarray and proteomic analysis of MM.1S cells treated with PS-341 versus control cells. As we have previously reported,3 PS-341 induced changes in transcripts involved in the regulation of apoptosis, cell growth, proteasome function, and heat shock response. In this study, we specifically report the effects of PS-341 on transcripts modulating response to chemotherapy (Figure 2A). PS-341 down-regulated the transcripts for several effectors of the protective cellular response to genotoxic stress: topoisomerase II beta, that relaxes DNA torsion on replication, transcription, and cell division and is inhibited by mitoxantrone, doxorubicin, and etoposide19; the Bloom syndrome gene product, involved in maintenance of genome integrity and stability through its cooperation with p5320; 8-oxoguanine DNA glycosylase and uracil-DNA glycosylase, involved in base-excision repair and protection from oxidative DNA damage21; the mutS homologs 2 and 6, that are involved in mismatch repair22; the catalytic subunit of DNA-dependent protein kinase and Ku autoantigen, which function in the repair of DNA double-strand breaks caused by physiologic oxidation reactions, V(D)J recombination, ionizing radiation, and chemotherapeutic drugs23; the damage-specific DNA binding protein 2; and the RAD1 homolog, which is involved in nucleotide excision repair and recombination repair. Selected changes were further confirmed at the protein level. For example, our proteomic-based analysis confirms the down-regulation of DNA-dependent protein kinase (Figure 2B-C); moreover, conventional immunoblotting confirms time-dependent down-regulation of the Ku subunits (80 and 70 kD) triggered by PS-341(Figure 2D). View larger version (68K): [in this window] [in a new window]   Figure 2. PS-341 down-regulates the expression of several proteins involved in DNA repair. (A) Transcriptional profile detected by oligonucleotide-microarray analysis in MM-1S cells treated with PS-341. Transcriptional changes induced by PS-341 (100 nM, 1-8 hours) included down-regulation of a functional cluster of molecules implicated in the response to genotoxic stress. Color saturation is proportional to magnitude of the difference from the respective control. (B-C) Proteomic analysis of the signaling state of PS-341-treated MM-1S cells. Proteomic analysis detects down-regulation of DNA-PK following 8-hour incubation with PS-341 (as depicted by respective arrows). (D) Immunoblotting confirms that PS-341 decreases protein expression of Ku 80 and Ku 70. In a phase 2 multicenter clinical trial of PS-341 treatment of patients with relapsed, refractory MM, remarkable antitumor activity has been demonstrated, including some complete responses.7 Our prior in vitro preclinical studies combining PS-341 with other anti-MM agents have revealed an additive antitumor effect with dexamethasone5 and a synergistic effect with the immunomodulatory derivatives (IMiDs) of thalidomide.24 However, the magnitude of the synergy between PS-341 and conventional chemotherapy shown in the present study far exceeds these previous findings. Significant sensitization to anticancer therapies by proteasome inhibitors without increased toxicity has also been demonstrated in other animal models, independent of functional p53 status.25 Therefore, the use of PS-341 as an adjuvant to conventional chemotherapy has significant potential utility to overcome resistance, even in patients with advanced disease. In conclusion, we report that PS-341 sensitizes MM cells to chemotherapy and overcomes CAM-DR. We propose a dual mechanism for this phenomenon, related both to attenuation of the protective cellular response to genotoxic stress and to down-regulation of antiapoptotic protein expression. Our study suggests that the combination of PS-341 with conventional chemotherapy will augment clinical effectiveness and overcome resistance in patients with relapsed refractory MM.     Footnotes Submitted June 14, 2002; accepted October 17, 2002. Prepublished online as Blood First Edition Paper, November 7, 2002; DOI 10.1182/blood-2002-06-1768. Supported by the Multiple Myeloma Research Foundation (N.M., C.S.M.), Laurie Strauss Leukemia Foundation (N.M., C.S.M), National Institutes of Health Grants RO-1 50947 and PO-1 78378, National Institutes of Health Grant R24 DK58739 (T.A.L.), the Leukemia and Lymphoma Society Scholar in Translational Research Award and VA Merit Award (N.C.M.), the Myeloma Research Fund (K.C.A.), and the Doris Duke Distinguished Clinical Research Scientist Award (K.C.A.). N.M. and C.S.M. have equally contributed to this work. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Kenneth C. Anderson, Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: kenneth_anderson{at}dfci.harvard.edu.     References Top Abstract Introduction Study design Results and discussion References 1. Hideshima T, Chauhan D, Schlossman R, Richardson P, Anderson KC. The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications. Oncogene. 2001;20:4519-4527[CrossRef][Medline] [Order article via Infotrieve]. 2. Hideshima T, Chauhan D, Richardson P, et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem. 2002;277:16639-16647[Abstract/Free Full Text]. 3. Mitsiades N, Mitsiades CS, Poulaki V, et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A. 2002;99:14374-14379[Abstract/Free Full Text]. 4. Hideshima T, Mitsiades C, Akiyama M, et al. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood. 2003;101:1530-1534[Abstract/Free Full Text]. 5. Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 2001;61:3071-3076[Abstract/Free Full Text]. 6. LeBlanc R, Catley LP, Hideshima T, et al. Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res. 2002;62:4996-5000[Abstract/Free Full Text]. 7. Richardson PG, Barlogie B, Berenson J, et al. Phase II study of the proteasome inhibitor PS-341 in multiple myeloma (MM) patients (pts) with relapsed/refractory disease [abstract]. Am Soc Clin Oncol Annu Meeting Proc. 2002:11a. 8. Mitsiades CS, Treon SP, Mitsiades N, et al. TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. Blood. 2001;98:795-804[Abstract/Free Full Text]. 9. Zhang H, Shi X, Zhang Q-J, et al. Nocodazole-induced p53-dependent c-Jun N-terminal kinase activation reduces apoptosis in human colon carcinoma HCT116 cells. J Biol. Chem. 2002;277:43648-43658[Abstract/Free Full Text]. 10. Mitsiades CS, Mitsiades N, Poulaki V, Akyiama M, Treon SP, Anderson KC. High-throughput global proteomic analysis of the signaling state of human multiple myeloma cells [abstract]. Blood. 2001;98:733a. 11. Mitsiades N, Poulaki V, Kotoula V, Leone A, Tsokos M. Fas ligand is present in tumors of the Ewing's sarcoma family and is cleaved into a soluble form by a metalloproteinase. Am J Pathol. 1998;153:1947-1956[Abstract/Free Full Text]. 12. Wang CY, Mayo MW, Baldwin AS Jr. TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. Science. 1996;274:784-787[Abstract/Free Full Text]. 13. Mitsiades N, Mitsiades CS, Poulaki V, et al. Biologic sequelae of NF-B blockade in multiple myeloma: therapeutic applications. Blood. 2002;99:4079-4086[Abstract/Free Full Text]. 14. Damiano JS, Dalton WS. Integrin-mediated drug resistance in multiple myeloma. Leuk Lymphoma. 2000;38:71-81[Medline] [Order article via Infotrieve]. 15. Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS. Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood. 1999;93:1658-1667[Abstract/Free Full Text]. 16. Hazlehurst LA, Dalton WS. Mechanisms associated with cell adhesion mediated drug resistance (CAM-DR) in hematopoietic malignancies. Cancer Metastasis Rev. 2001;20:43-50[CrossRef][Medline] [Order article via Infotrieve]. 17. Hazlehurst LA, Damiano JS, Buyuksal I, Pledger WJ, Dalton WS. Adhesion to fibronectin via beta1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene. 2000;19:4319-4327[CrossRef][Medline] [Order article via Infotrieve]. 18. Shain KH, Landowski TH, Dalton WS. Adhesion-mediated intracellular redistribution of c-Fas-associated death domain-like IL-1-converting enzyme-like inhibitory protein-long confers resistance to CD95-induced apoptosis in hematopoietic cancer cell lines. J Immunol. 2002;168:2544-2553[Abstract/Free Full Text]. 19. Hazlehurst LA, Valkov N, Wisner L, et al. Reduction in drug-induced DNA double-strand breaks associated with beta1 integrin-mediated adhesion correlates with drug resistance in U937 cells. Blood. 2001;98:1897-1903[Abstract/Free Full Text]. 20. Garkavtsev IV, Kley N, Grigorian IA, Gudkov AV. The Bloom syndrome protein interacts and cooperates with p53 in regulation of transcription and cell growth control. Oncogene. 2001;20:8276-8280[CrossRef][Medline] [Order article via Infotrieve]. 21. Rosenquist TA, Zharkov DO, Grollman AP. Cloning and characterization of a mammalian 8-oxoguanine DNA glycosylase. Proc Natl Acad Sci U S A. 1997;94:7429-7434[Abstract/Free Full Text]. 22. Sixma TK. DNA mismatch repair: MutS structures bound to mismatches. Curr Opin Struct Biol. 2001;11:47-52[CrossRef][Medline] [Order article via Infotrieve]. 23. Featherstone C, Jackson SP. DNA double-strand break repair. Curr Biol. 1999;9:R759-761[CrossRef][Medline] [Order article via Infotrieve]. 24. Mitsiades N, Mitsiades CS, Poulaki V, et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs (IMiDs) in human multiple myeloma cells: therapeutic implications. Blood. 2002;99:4525-4530[Abstract/Free Full Text]. 25. Cusack JC Jr, Liu R, Houston M, et al. Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. Cancer Res. 2001;61:3535-3540[Abstract/Free Full Text]. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. Sung, A. B. Kunnumakkara, G. Sethi, P. Anand, S. Guha, and B. B. Aggarwal Curcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model Mol. Cancer Ther., April 1, 2009; 8(4): 959 - 970. [Abstract] [Full Text] [PDF] B. B. Aggarwal, R.V. Vijayalekshmi, and B. Sung Targeting Inflammatory Pathways for Prevention and Therapy of Cancer: Short-Term Friend, Long-Term Foe Clin. Cancer Res., January 15, 2009; 15(2): 425 - 430. [Abstract] [Full Text] [PDF] G. Bisping, D. Wenning, M. Kropff, D. Gustavus, C. Muller-Tidow, M. Stelljes, G. Munzert, F. Hilberg, G. J. Roth, M. Stefanic, et al. Bortezomib, Dexamethasone, and Fibroblast Growth Factor Receptor 3-Specific Tyrosine Kinase Inhibitor in t(4;14) Myeloma Clin. Cancer Res., January 15, 2009; 15(2): 520 - 531. [Abstract] [Full Text] [PDF] P. G. Richardson, C. Mitsiades, J. Laubach, D. Chauhan, T. Hideshima, and K. Anderson Realizing the Anticancer Potential of Proteasome Inhibition: The Clinical Development of Bortezomib and Second-generation Proteasome Inhibitors ASCO Educational Book, January 1, 2009; 2009(1): 163 - 170. [Abstract] [Full Text] [PDF] Y.-W. Qiang, J. D. Shaughnessy Jr, and S. Yaccoby Wnt3a signaling within bone inhibits multiple myeloma bone disease and tumor growth Blood, July 15, 2008; 112(2): 374 - 382. [Abstract] [Full Text] [PDF] C. S. Mitsiades, E. M. Ocio, A. Pandiella, P. Maiso, C. Gajate, M. Garayoa, D. Vilanova, J. C. Montero, N. Mitsiades, C. J. McMullan, et al. Aplidin, a Marine Organism-Derived Compound with Potent Antimyeloma Activity In vitro and In vivo Cancer Res., July 1, 2008; 68(13): 5216 - 5225. [Abstract] [Full Text] [PDF] A. Palumbo, F. Gay, S. Bringhen, A. Falcone, N. Pescosta, V. Callea, T. Caravita, F. Morabito, V. Magarotto, M. Ruggeri, et al. Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma Ann. Onc., June 1, 2008; 19(6): 1160 - 1165. [Abstract] [Full Text] [PDF] T. Khong, J. Sharkey, and A. Spencer The effect of azacitidine on interleukin-6 signaling and nuclear factor-{kappa}B activation and its in vitro and in vivo activity against multiple myeloma Haematologica, June 1, 2008; 93(6): 860 - 869. [Abstract] [Full Text] [PDF] Q. Chen, W. Xie, D. J. Kuhn, P. M. Voorhees, A. Lopez-Girona, D. Mendy, L. G. Corral, V. P. Krenitsky, W. Xu, L. Moutouh-de Parseval, et al. Targeting the p27 E3 ligase SCFSkp2 results in p27- and Skp2-mediated cell-cycle arrest and activation of autophagy Blood, May 1, 2008; 111(9): 4690 - 4699. [Abstract] [Full Text] [PDF] R. Z. Orlowski and D. J. Kuhn Proteasome Inhibitors in Cancer Therapy: Lessons from the First Decade Clin. Cancer Res., March 15, 2008; 14(6): 1649 - 1657. [Abstract] [Full Text] [PDF] E. Colado, S. Alvarez-Fernandez, P. Maiso, J. Martin-Sanchez, M. B. Vidriales, M. Garayoa, E. M. Ocio, J. C. Montero, A. Pandiella, and J. F. San Miguel The effect of the proteasome inhibitor bortezomib on acute myeloid leukemia cells and drug resistance associated with the CD34+ immature phenotype Haematologica, January 1, 2008; 93(1): 57 - 66. [Abstract] [Full Text] [PDF] C.-K. Min, M.-J. Lee, K.-S. Eom, S. Lee, J.-W. Lee, W.-S. Min, C.-C. Kim, M. Kim, J. Lim, Y. Kim, et al. Bortezomib in Combination with Conventional Chemotherapeutic Agents for Multiple Myeloma Compared with Bortezomib Alone Jpn. J. Clin. Oncol., December 21, 2007; (2007) hym126v1. [Abstract] [Full Text] [PDF] D. J. Kuhn, Q. Chen, P. M. Voorhees, J. S. Strader, K. D. Shenk, C. M. Sun, S. D. Demo, M. K. Bennett, F. W. B. van Leeuwen, A. A. Chanan-Khan, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma Blood, November 1, 2007; 110(9): 3281 - 3290. [Abstract] [Full Text] [PDF] V. Poulaki, C. S. Mitsiades, V. Kotoula, J. Negri, D. McMillin, J. W. Miller, and N. Mitsiades The Proteasome Inhibitor Bortezomib Induces Apoptosis in Human Retinoblastoma Cell Lines In Vitro Invest. Ophthalmol. Vis. Sci., October 1, 2007; 48(10): 4706 - 4719. [Abstract] [Full Text] [PDF] R. Sitia, G. Palladini, and G. Merlini Bortezomib in the treatment of AL amyloidosis: targeted therapy? Haematologica, October 1, 2007; 92(10): 1302 - 1307. [Full Text] [PDF] E. L. Davenport, H. E. Moore, A. S. Dunlop, S. Y. Sharp, P. Workman, G. J. Morgan, and F. E. Davies Heat shock protein inhibition is associated with activation of the unfolded protein response pathway in myeloma plasma cells Blood, October 1, 2007; 110(7): 2641 - 2649. [Abstract] [Full Text] [PDF] Y. Murakawa, E. Sonoda, L. J. Barber, W. Zeng, K. Yokomori, H. Kimura, A. Niimi, A. Lehmann, G. Y. Zhao, H. Hochegger, et al. Inhibitors of the Proteasome Suppress Homologous DNA Recombination in Mammalian Cells Cancer Res., September 15, 2007; 67(18): 8536 - 8543. [Abstract] [Full Text] [PDF] R. Z. Orlowski, A. Nagler, P. Sonneveld, J. Blade, R. Hajek, A. Spencer, J. San Miguel, T. Robak, A. Dmoszynska, N. Horvath, et al. Randomized Phase III Study of Pegylated Liposomal Doxorubicin Plus Bortezomib Compared With Bortezomib Alone in Relapsed or Refractory Multiple Myeloma: Combination Therapy Improves Time to Progression J. Clin. Oncol., September 1, 2007; 25(25): 3892 - 3901. [Abstract] [Full Text] [PDF] C. Jacquemont and T. Taniguchi Proteasome Function Is Required for DNA Damage Response and Fanconi Anemia Pathway Activation Cancer Res., August 1, 2007; 67(15): 7395 - 7405. [Abstract] [Full Text] [PDF] F. E. Davies, P. Wu, M. Jenner, M. Srikanth, R. Saso, and G. J. Morgan The combination of cyclophosphamide, velcade and dexamethasone (CVD) induces high response rates with comparable toxicity to velcade alone (V) and velcade plus dexamethasone (VD) Haematologica, August 1, 2007; 92(8): 1149 - 1150. [Abstract] [Full Text] [PDF] R. Manochakian, K. C. Miller, and A. A. Chanan-Khan Clinical Impact of Bortezomib in Frontline Regimens for Patients with Multiple Myeloma Oncologist, August 1, 2007; 12(8): 978 - 990. [Abstract] [Full Text] [PDF] T. Kiziltepe, T. Hideshima, L. Catley, N. Raje, H. Yasui, N. Shiraishi, Y. Okawa, H. Ikeda, S. Vallet, S. Pozzi, et al. 5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells Mol. Cancer Ther., June 1, 2007; 6(6): 1718 - 1727. [Abstract] [Full Text] [PDF] P. G. Richardson, C. Mitsiades, R. Schlossman, N. Munshi, and K. Anderson New Drugs for Myeloma Oncologist, June 1, 2007; 12(6): 664 - 689. [Abstract] [Full Text] [PDF] G. Mulligan, C. Mitsiades, B. Bryant, F. Zhan, W. J. Chng, S. Roels, E. Koenig, A. Fergus, Y. Huang, P. Richardson, et al. Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib Blood, April 15, 2007; 109(8): 3177 - 3188. [Abstract] [Full Text] [PDF] P. Richardson Toward a new therapeutic backbone in myeloma Blood, April 1, 2007; 109(7): 2672 - 2673. [Full Text] [PDF] A. Palumbo, M. T. Ambrosini, G. Benevolo, P. Pregno, N. Pescosta, V. Callea, C. Cangialosi, T. Caravita, F. Morabito, P. Musto, et al. Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma Blood, April 1, 2007; 109(7): 2767 - 2772. [Abstract] [Full Text] [PDF] J. R. Berenson, J. Matous, R. A. Swift, R. Mapes, B. Morrison, and H. S. Yeh A Phase I/II Study of Arsenic Trioxide/Bortezomib/Ascorbic Acid Combination Therapy for the Treatment of Relapsed or Refractory Multiple Myeloma Clin. Cancer Res., March 15, 2007; 13(6): 1762 - 1768. [Abstract] [Full Text] [PDF] R. Dreicer, D. Petrylak, D. Agus, I. Webb, and B. Roth Phase I/II Study of Bortezomib Plus Docetaxel in Patients with Advanced Androgen-Independent Prostate Cancer Clin. Cancer Res., February 15, 2007; 13(4): 1208 - 1215. [Abstract] [Full Text] [PDF] J. Sharkey, T. Khong, and A. Spencer PKC412 demonstrates JNK-dependent activity against human multiple myeloma cells Blood, February 15, 2007; 109(4): 1712 - 1719. [Abstract] [Full Text] [PDF] P. G. Richardson, T. Hideshima, and K. C. Anderson Plasma cell dyscrasias ASH Self-Assessment Program, January 1, 2007; 2007(1): 298 - 327. [Full Text] [PDF] F. Cardoso, V. Durbecq, J.-F. Laes, B. Badran, L. Lagneaux, F. Bex, C. Desmedt, K. Willard-Gallo, J. S. Ross, A. Burny, et al. Bortezomib (PS-341, Velcade) increases the efficacy of trastuzumab (Herceptin) in HER-2-positive breast cancer cells in a synergistic manner Mol. Cancer Ther., December 1, 2006; 5(12): 3042 - 3051. [Abstract] [Full Text] [PDF] L. Catley, E. Weisberg, T. Kiziltepe, Y.-T. Tai, T. Hideshima, P. Neri, P. Tassone, P. Atadja, D. Chauhan, N. C. Munshi, et al. Aggresome induction by proteasome inhibitor bortezomib and {alpha}-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells Blood, November 15, 2006; 108(10): 3441 - 3449. [Abstract] [Full Text] [PDF] C. S. Mitsiades, D. McMillin, V. Kotoula, V. Poulaki, C. McMullan, J. Negri, G. Fanourakis, S. Tseleni-Balafouta, K. B. Ain, and N. Mitsiades Antitumor Effects of the Proteasome Inhibitor Bortezomib in Medullary and Anaplastic Thyroid Carcinoma Cells in Vitro J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 4013 - 4021. [Abstract] [Full Text] [PDF] M.-V. Mateos, J.-M. Hernandez, M.-T. Hernandez, N.-C. Gutierrez, L. Palomera, M. Fuertes, J. Diaz-Mediavilla, J.-J. Lahuerta, J. de la Rubia, M.-J. Terol, et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study Blood, October 1, 2006; 108(7): 2165 - 2172. [Abstract] [Full Text] [PDF] C. Yu, B. B. Friday, J.-P. Lai, L. Yang, J. Sarkaria, N. E. Kay, C. A. Carter, L. R. Roberts, S. H. Kaufmann, and A. A. Adjei Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. Mol. Cancer Ther., September 1, 2006; 5(9): 2378 - 2387. [Abstract] [Full Text] [PDF] X. Dolcet, D. Llobet, M. Encinas, J. Pallares, A. Cabero, J. A. Schoenenberger, J. X. Comella, and X. Matias-Guiu Proteasome Inhibitors Induce Death but Activate NF-{kappa}B on Endometrial Carcinoma Cell Lines and Primary Culture Explants J. Biol. Chem., August 4, 2006; 281(31): 22118 - 22130. [Abstract] [Full Text] [PDF] M. Leiba, L. Cahalon, A. Shimoni, O. Lider, A. Zanin-Zhorov, I. Hecht, U. Sela, I. Vlodavsky, and A. Nagler Halofuginone inhibits NF-{kappa}B and p38 MAPK in activated T cells J. Leukoc. Biol., August 1, 2006; 80(2): 399 - 406. [Abstract] [Full Text] [PDF] B. H. Y. Yeung, D.-C. Huang, and F. A. Sinicrope PS-341 (Bortezomib) Induces Lysosomal Cathepsin B Release and a Caspase-2-dependent Mitochondrial Permeabilization and Apoptosis in Human Pancreatic Cancer Cells J. Biol. Chem., April 28, 2006; 281(17): 11923 - 11932. [Abstract] [Full Text] [PDF] M. Bazzaro, M. K. Lee, A. Zoso, W. L.H. Stirling, A. Santillan, I.-M. Shih, and R. B.S. Roden Ubiquitin-proteasome system stress sensitizes ovarian cancer to proteasome inhibitor-induced apoptosis. Cancer Res., April 1, 2006; 66(7): 3754 - 3763. [Abstract] [Full Text] [PDF] J. R. Berenson, H. H. Yang, K. Sadler, S. G. Jarutirasarn, R. A. Vescio, R. Mapes, M. Purner, S.-p. Lee, J. Wilson, B. Morrison, et al. Phase I/II Trial Assessing Bortezomib and Melphalan Combination Therapy for the Treatment of Patients With Relapsed or Refractory Multiple Myeloma J. Clin. Oncol., February 20, 2006; 24(6): 937 - 944. [Abstract] [Full Text] [PDF] C. S. Mitsiades, N. S. Mitsiades, C. J. McMullan, V. Poulaki, A. L. Kung, F. E. Davies, G. Morgan, M. Akiyama, R. Shringarpure, N. C. Munshi, et al. Antimyeloma activity of heat shock protein-90 inhibition Blood, February 1, 2006; 107(3): 1092 - 1100. [Abstract] [Full Text] [PDF] N. Yanamandra, N. M. Colaco, N. A. Parquet, R. W. Buzzeo, D. Boulware, G. Wright, L. E. Perez, W. S. Dalton, and D. M. Beaupre Tipifarnib and Bortezomib Are Synergistic and Overcome Cell Adhesion-Mediated Drug Resistance in Multiple Myeloma and Acute Myeloid Leukemia Clin. Cancer Res., January 15, 2006; 12(2): 591 - 599. [Abstract] [Full Text] [PDF] S. Vodanovic-Jankovic, P. Hari, P. Jacobs, R. Komorowski, and W. R. Drobyski NF-{kappa}B as a target for the prevention of graft-versus-host disease: comparative efficacy of bortezomib and PS-1145 Blood, January 15, 2006; 107(2): 827 - 834. [Abstract] [Full Text] [PDF] R. Z. Orlowski Initial Therapy of Multiple Myeloma Patients Who Are Not Candidates for Stem Cell Transplantation Hematology, January 1, 2006; 2006(1): 338 - 347. [Abstract] [Full Text] [PDF] J. San Miguel, J. Blade, M. Boccadoro, J. Cavenagh, A. Glasmacher, S. Jagannath, S. Lonial, R. Z. Orlowski, P. Sonneveld, and H. Ludwig A Practical Update on the Use of Bortezomib in the Management of Multiple Myeloma Oncologist, January 1, 2006; 11(1): 51 - 61. [Abstract] [Full Text] [PDF] T. Hideshima, J. E. Bradner, D. Chauhan, and K. C. Anderson Intracellular Protein Degradation and Its Therapeutic Implications Clin. Cancer Res., December 15, 2005; 11(24): 8530 - 8533. [Full Text] [PDF] D. Spentzos, D. A. Levine, S. Kolia, H. Otu, J. Boyd, T. A. Libermann, and S. A. Cannistra Unique Gene Expression Profile Based on Pathologic Response in Epithelial Ovarian Cancer J. Clin. Oncol., November 1, 2005; 23(31): 7911 - 7918. [Abstract] [Full Text] [PDF] T. Hideshima, D. Chauhan, P. Richardson, and K. C. Anderson Identification and Validation of Novel Therapeutic Targets for Multiple Myeloma J. Clin. Oncol., September 10, 2005; 23(26): 6345 - 6350. [Abstract] [Full Text] [PDF] G. Saunders Overview of drug therapy for multiple myeloma Journal of Oncology Pharmacy Practice, September 1, 2005; 11(3): 83 - 100. [Abstract] [PDF] H. Tatetsu, Y. Okuno, M. Nakamura, F. Matsuno, T. Sonoki, I. Taniguchi, S. Uneda, K. Umezawa, H. Mitsuya, and H. Hata Dehydroxymethylepoxyquinomicin, a novel nuclear factor-{kappa}B inhibitor, induces apoptosis in multiple myeloma cells in an I{kappa}B{alpha}-independent manner Mol. Cancer Ther., July 1, 2005; 4(7): 1114 - 1120. [Abstract] [Full Text] [PDF] T. Hideshima, J. E. Bradner, J. Wong, D. Chauhan, P. Richardson, S. L. Schreiber, and K. C. Anderson Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma PNAS, June 14, 2005; 102(24): 8567 - 8572. [Abstract] [Full Text] [PDF] M. Hamasaki, T. Hideshima, P. Tassone, P. Neri, K. Ishitsuka, H. Yasui, N. Shiraishi, N. Raje, S. Kumar, D. H. Picker, et al. Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu in vitro and in vivo Blood, June 1, 2005; 105(11): 4470 - 4476. [Abstract] [Full Text] [PDF] R. Z. Orlowski, P. M. Voorhees, R. A. Garcia, M. D. Hall, F. J. Kudrik, T. Allred, A. R. Johri, P. E. Jones, A. Ivanova, H. W. Van Deventer, et al. Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies Blood, April 15, 2005; 105(8): 3058 - 3065. [Abstract] [Full Text] [PDF] T. Ikezoe, Y. Yang, K. Bandobashi, T. Saito, S. Takemoto, H. Machida, K. Togitani, H. P. Koeffler, and H. Taguchi Oridonin, a diterpenoid purified from Rabdosia rubescens, inhibits the proliferation of cells from lymphoid malignancies in association with blockade of the NF-{kappa}B signal pathways Mol. Cancer Ther., April 1, 2005; 4(4): 578 - 586. [Abstract] [Full Text] [PDF] D. Chauhan, T. Hideshima, C. Mitsiades, P. Richardson, and K. C. Anderson Proteasome inhibitor therapy in multiple myeloma Mol. Cancer Ther., April 1, 2005; 4(4): 686 - 692. [Abstract] [Full Text] [PDF] J. Gauduchon, F. Gouilleux, S. Maillard, V. Marsaud, J.-M. Renoir, and B. Sola 4-Hydroxytamoxifen Inhibits Proliferation of Multiple Myeloma Cells In vitro through Down-Regulation of c-Myc, Up-Regulation of p27Kip1, and Modulation of Bcl-2 Family Members Clin. Cancer Res., March 15, 2005; 11(6): 2345 - 2354. [Abstract] [Full Text] [PDF] M. Nikrad, T. Johnson, H. Puthalalath, L. Coultas, J. Adams, and A. S. Kraft The proteasome inhibitor bortezomib sensitizes cells to killing by death receptor ligand TRAIL via BH3-only proteins Bik and Bim Mol. Cancer Ther., March 1, 2005; 4(3): 443 - 449. [Abstract] [Full Text] [PDF] S. V. Rajkumar, P. G. Richardson, T. Hideshima, and K. C. Anderson Proteasome Inhibition As a Novel Therapeutic Target in Human Cancer J. Clin. Oncol., January 20, 2005; 23(3): 630 - 639. [Abstract] [Full Text] [PDF] V. Poulaki, C. S. Mitsiades, C. McMullan, G. Fanourakis, J. Negri, A. Goudopoulou, I. X. Halikias, G. Voutsinas, S. Tseleni-Balafouta, J. W. Miller, et al. Human Retinoblastoma Cells Are Resistant to Apoptosis Induced by Death Receptors: Role of Caspase-8 Gene Silencing Invest. Ophthalmol. Vis. Sci., January 1, 2005; 46(1): 358 - 366. [Abstract] [Full Text] [PDF] R. Z. Orlowski The Ubiquitin Proteasome Pathway from Bench to Bedside Hematology, January 1, 2005; 2005(1): 220 - 225. [Abstract] [Full Text] [PDF] D. Spentzos, D. A. Levine, M. F. Ramoni, M. Joseph, X. Gu, J. Boyd, Towia. A. Libermann, and S. A. Cannistra Gene Expression Signature With Independent Prognostic Significance in Epithelial Ovarian Cancer J. Clin. Oncol., December 1, 2004; 22(23): 4700 - 4710. [Abstract] [Full Text] [PDF] G. W. Small, Y. Y. Shi, N. A. Edmund, S. Somasundaram, D. T. Moore, and R. Z. Orlowski Evidence That Mitogen-Activated Protein Kinase Phosphatase-1 Induction by Proteasome Inhibitors Plays an Antiapoptotic Role Mol. Pharmacol., December 1, 2004; 66(6): 1478 - 1490. [Abstract] [Full Text] [PDF] S. Mabuchi, M. Ohmichi, Y. Nishio, T. Hayasaka, A. Kimura, T. Ohta, J. Kawagoe, K. Takahashi, N. Yada-Hashimoto, H. Seino-Noda, et al. Inhibition of Inhibitor of Nuclear Factor-{kappa}B Phosphorylation Increases the Efficacy of Paclitaxel in in Vitro and in Vivo Ovarian Cancer Models Clin. Cancer Res., November 15, 2004; 10(22): 7645 - 7654. [Abstract] [Full Text] [PDF] R. A. Kyle and S. V. Rajkumar Multiple Myeloma N. Engl. J. Med., October 28, 2004; 351(18): 1860 - 1873. [Full Text] [PDF] M. H. Shah, D. Young, H. L. Kindler, I. Webb, B. Kleiber, J. Wright, and M. Grever Phase II Study of the Proteasome Inhibitor Bortezomib (PS-341) in Patients with Metastatic Neuroendocrine Tumors Clin. Cancer Res., September 15, 2004; 10(18): 6111 - 6118. [Abstract] [Full Text] [PDF] T. Hideshima, P. L. Bergsagel, W. M. Kuehl, and K. C. Anderson Advances in biology of multiple myeloma: clinical applications Blood, August 1, 2004; 104(3): 607 - 618. [Abstract] [Full Text] [PDF] G. Minotti, P. Menna, E. Salvatorelli, G. Cairo, and L. Gianni Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity Pharmacol. Rev., June 1, 2004; 56(2): 185 - 229. [Abstract] [Full Text] [PDF] M. Adachi, Y. Zhang, X. Zhao, T. Minami, R. Kawamura, Y. Hinoda, and K. Imai Synergistic Effect of Histone Deacetylase Inhibitors FK228 and m-Carboxycinnamic Acid Bis-Hydroxamide with Proteasome Inhibitors PSI and PS-341 against Gastrointestinal Adenocarcinoma Cells Clin. Cancer Res., June 1, 2004; 10(11): 3853 - 3862. [Abstract] [Full Text] [PDF] S. Mabuchi, M. Ohmichi, Y. Nishio, T. Hayasaka, A. Kimura, T. Ohta, M. Saito, J. Kawagoe, K. Takahashi, N. Yada-Hashimoto, et al. Inhibition of NF{kappa}B Increases the Efficacy of Cisplatin in in Vitro and in Vivo Ovarian Cancer Models J. Biol. Chem., May 28, 2004; 279(22): 23477 - 23485. [Abstract] [Full Text] [PDF] K. Sun, L. A. Welniak, A. Panoskaltsis-Mortari, M. J. O'Shaughnessy, H. Liu, I. Barao, W. Riordan, R. Sitcheran, C. Wysocki, J. S. Serody, et al. Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib PNAS, May 25, 2004; 101(21): 8120 - 8125. [Abstract] [Full Text] [PDF] J. Cortes, D. Thomas, C. Koller, F. Giles, E. Estey, S. Faderl, G. Garcia-Manero, D. McConkey, G. Patel, R. Guerciolini, et al. Phase I Study of Bortezomib in Refractory or Relapsed Acute Leukemias Clin. Cancer Res., May 15, 2004; 10(10): 3371 - 3376. [Abstract] [Full Text] [PDF] P. Bonvini, H. D. Rosa, N. Vignes, and A. Rosolen Ubiquitination and Proteasomal Degradation of Nucleophosmin-Anaplastic Lymphoma Kinase Induced by 17-Allylamino-Demethoxygeldanamycin: Role of the Co-Chaperone Carboxyl Heat Shock Protein 70-Interacting Protein Cancer Res., May 1, 2004; 64(9): 3256 - 3264. [Abstract] [Full Text] [PDF] B. Zheng, G. V. Georgakis, Y. Li, A. Bharti, D. McConkey, B. B. Aggarwal, and A. Younes Induction of Cell Cycle Arrest and Apoptosis by the Proteasome Inhibitor PS-341 in Hodgkin Disease Cell Lines Is Independent of Inhibitor of Nuclear Factor-{kappa}B Mutations or Activation of the CD30, CD40, and RANK Receptors Clin. Cancer Res., May 1, 2004; 10(9): 3207 - 3215. [Abstract] [Full Text] [PDF] S. Trudel, S. Ely, Y. Farooqi, M. Affer, D. F. Robbiani, M. Chesi, and P. L. Bergsagel Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma Blood, May 1, 2004; 103(9): 3521 - 3528. [Abstract] [Full Text] [PDF] J. Moreaux, E. Legouffe, E. Jourdan, P. Quittet, T. Reme, C. Lugagne, P. Moine, J.-F. Rossi, B. Klein, and K. Tarte BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone Blood, April 15, 2004; 103(8): 3148 - 3157. [Abstract] [Full Text] [PDF] C. S. Mitsiades, N. S. Mitsiades, C. J. McMullan, V. Poulaki, R. Shringarpure, T. Hideshima, M. Akiyama, D. Chauhan, N. Munshi, X. Gu, et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: Biological and clinical implications PNAS, January 13, 2004; 101(2): 540 - 545. [Abstract] [Full Text] [PDF] J.-L. Harousseau, J. Shaughnessy Jr., and P. Richardson Multiple Myeloma Hematology, January 1, 2004; 2004(1): 237 - 256. [Abstract] [Full Text] [PDF] H. Matta, Q. Sun, G. Moses, and P. M. Chaudhary Molecular Genetic Analysis of Human Herpes Virus 8-encoded Viral FLICE Inhibitory Protein-induced NF-{kappa}B Activation J. Biol. Chem., December 26, 2003; 278(52): 52406 - 52411. [Abstract] [Full Text] [PDF] P. M. Voorhees, E. C. Dees, B. O'Neil, and R. Z. Orlowski The Proteasome as a Target for Cancer Therapy Clin. Cancer Res., December 15, 2003; 9(17): 6316 - 6325. [Abstract] [Full Text] [PDF] D. Chauhan, G. Li, R. Shringarpure, K. Podar, Y. Ohtake, T. Hideshima, and K. C. Anderson Blockade of Hsp27 Overcomes Bortezomib/Proteasome Inhibitor PS-341 Resistance in Lymphoma Cells Cancer Res., October 1, 2003; 63(19): 6174 - 6177. [Abstract] [Full Text] [PDF] A.-H. Lee, N. N. Iwakoshi, K. C. Anderson, and L. H. Glimcher Inaugural Article: Proteasome inhibitors disrupt the unfolded protein response in myeloma cells PNAS, August 19, 2003; 100(17): 9946 - 9951. [Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) All Versions of this Article: 2002-06-1768v1 101/6/2377    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mitsiades, N. Articles by Anderson, K. C. Search for Related Content PubMed PubMed Citation Articles by Mitsiades, N. Articles by Anderson, K. C. Related Collections Neoplasia Apoptosis Signal Transduction Gene Expression Genomics Brief Reports Social Bookmarking                   What's this?

	Copyright © 2003 by American Society of Hematology         Online ISSN: 1528-0020