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PLENARY PAPER
From the Department of Adult Oncology, Dana-Farber
Cancer Institute, and Department of Medicine, Harvard Medical School,
Boston, MA; and Celgene Corporation, Warren, NJ.
Although thalidomide (Thal) was initially used to treat
multiple myeloma (MM) because of its known antiangiogenic effects, the
mechanism of its anti-MM activity is unclear. These studies demonstrate
clinical activity of Thal against MM that is refractory to conventional
therapy and delineate mechanisms of anti-tumor activity of Thal and its
potent analogs (immunomodulatory drugs [IMiDs]). Importantly, these
agents act directly, by inducing apoptosis or G1 growth arrest, in MM
cell lines and in patient MM cells that are resistant to melphalan,
doxorubicin, and dexamethasone (Dex). Moreover, Thal and the IMiDs
enhance the anti-MM activity of Dex and, conversely, are inhibited by
interleukin 6. As for Dex, apoptotic signaling triggered by Thal and
the IMiDs is associated with activation of related adhesion focal
tyrosine kinase. These studies establish the framework for the
development and testing of Thal and the IMiDs in a new treatment
paradigm to target both the tumor cell and the microenvironment,
overcome classical drug resistance, and achieve improved outcome in
this presently incurable disease.
(Blood. 2000;96:2943-2950) Thalidomide (Thal) was originally used in Europe
for the treatment of morning sickness in the 1950s but was withdrawn
from the market in the 1960s because of reports of teratogenicity and phocomelia associated with its use. The renewed interest in Thal stems
from its broad spectrum of pharmacologic and immunologic effects.1 Because of its immunomodulatory and
antiangiogenic effects, it has been used to effectively treat erythema
nodosum leprosum, an inflammatory manifestation of
leprosy.2 Potential therapeutic applications span a wide
spectrum of diseases, including cancer and related conditions,
infectious diseases, autoimmune diseases, dermatologic diseases, and
other disorders such as sarcoidosis, macular degeneration, and diabetic
retinopathy.3 Recent reports of increased bone marrow
(BM) angiogenesis in multiple myeloma (MM),4,5
coupled with the known antiangiogenic properties of Thal,6
provided the rationale for its use to treat MM.7 Importantly, Thal induced clinical responses in 32% of MM patients whose disease was refractory to conventional and high-dose
therapy,7 suggesting that it can overcome drug resistance
because of its alternative mechanisms of anti-MM activity. Besides
alkylating agents and corticosteroids, Thal now, therefore, represents
the third distinct class of agents useful in the treatment of MM.
Given its broad spectrum of activities, Thal may be acting against MM
in several ways.8 First, Thal may have a direct effect on
the MM cell and/or BM stromal cell to inhibit their growth and
survival. For example, free radical-mediated oxidative DNA damage may
play a role in the teratogenicity of Thal9 and may also
have anti-tumor effects. Second, adhesion of MM cells to BM stromal
cells both triggers secretion of cytokines that augment MM cell growth
and survival10-12 and confers drug
resistance13; Thal modulates adhesive
interactions14 and, thereby, may alter tumor cell growth,
survival, and drug resistance. Third, cytokines secreted into the BM
microenvironment by MM and/or BM stromal cells, such as interleukin
(IL)-6, IL-1 In this study, we have begun to characterize the mechanisms of activity
of Thal and these analogs against human MM cells. Delineation of their
mechanisms of action, as well as mechanisms of resistance to these
agents, will both enhance understanding of MM disease pathogenesis and
derive novel treatment strategies.
MM-derived cell lines and patient cells
Thal and analogs
DNA synthesis DNA synthesis was measured as previously described.19 MM cells (3 × 104 cells/well) were incubated in 96-well culture plates (Costar, Cambridge, MA) in the presence of media, Thal, SelCID1, SelCID2, SelCID3, SelCID4, IMiD1, IMiD2, IMiD3, and/or recombinant IL-6 (50 ng/mL) (Genetics Institute, Cambridge, MA) for 48 hours at 37°C. DNA synthesis was measured by [3H]-thymidine (3H-TdR; NEN Products, Boston, MA) uptake. Cells were pulsed with 3H-TdR (0.5 µCi/well) during the last 8 hours of 48-hour cultures, harvested onto glass filters with an automatic cell harvester (Cambridge Technology, Cambridge, MA), and counted by using the LKB Betaplate scintillation counter (Wallac, Gaithersburg, MD). All experiments were performed in triplicate.Colorimetric assays were also performed to assay drug activity. Cells from 48-hour cultures were pulsed with 10 µL of 5 mg/mL 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide (MTT; Chemicon International Inc, Temecula, CA) to each well for 4 hours, followed by 100 µL isopropanol that contained 0.04 HCl. Absorbance readings at a wavelength of 570 nm were taken on a spectrophotometer (Molecular Devices Corp., Sunnyvale, CA). Cell cycle analysis MM cells (1 × 106) cultured for 72 hours in media alone, Thal, IMiD1, IMiD2, and IMiD3 were harvested, washed with phosphate-buffered saline (PBS), fixed with 70% ethanol, and pretreated with 10 µg/mL of RNAse (Sigma). Cells were stained with propidium iodide (PI; 5 µg/mL; Sigma), and cell cycle profile was determined by using the program M software on an Epics flow cytometer (Coulter Immunology, Hialeah, FL), as in prior studies.20Detection of apoptosis In addition to identifying sub-G1 cells as described above, apoptosis was also confirmed by using annexin V staining. MM cells were cultured in media (0.01% DMSO) or with 10 µmol/L of Thal or 1 µmol/L IMiD1, IMiD2, and IMiD3 at 37°C for 72 hours, with addition of drugs at 24-hour intervals. Cells were then washed twice with ice-cold PBS and resuspended (1 × 106 cells/mL) in binding buffer (10 mmol/L HEPES, pH 7.4, 140 mmol/L NaCl, 2.5 mmol/L CaCl2). MM cells (1 × 105) were incubated with annexin V-FITC (5 µL; Pharmingen, San Diego, CA) and PI (5 µg/mL) for 15 minutes at room temperature. Annexin V+PI
apoptotic cells were enumerated by using the Epics cell sorter (Coulter).
Immunoblotting MM cells were cultured with 10 µmol/L of Thal, IMiD1, IMiD2, or IMiD3; harvested; washed; and lysed using lysis buffer: 50 mmol/L HEPES (pH 7.4), 150 mmol/L NaCl, 1% Triton-X 100, 30 mmol/L sodium pyrophosphate, 5 mmol/L EDTA, 2 mmol/L Na3VO4, 5 mmol/L NaF, 1 mmol/L phenylmethyl sulfonyl fluoride (PMSF), 5 µg/mL leupeptin, and 5 µg/mL aprotinin. For detection of p21, cell lysates were subjected to SDS-PAGE, transferred to polyvinylidene difluoride (PVDF) membrane, and immunoblotted with anti-p21 antibody (Ab; Santa Cruz Biotech, Santa Cruz, CA). The membrane was stripped and reprobed with anti-alpha tubulin Ab (Sigma) to ensure equivalent protein loading. For detection of p53, cell lysates were prepared from MM cells (2 × 107) with the use of lysis buffer. Lysates were incubated with anti-mutant (mt) or wild-type (wt) p53 monoclonal Abs (Calbiochem, San Diego, CA) and then immunoprecipitated overnight with protein A Sepharose (Sepharose CL-4B; Pharmacia, Uppsala, Sweden). Immune complexes were analyzed by immunoblotting with horseradish peroxidase-conjugated anti-p53 Ab reactive with both mt and wt p53 (Calbiochem).To characterize growth signaling, immunoblotting was also done with anti-phospho-specific MAPK Ab (New England Biolabs, Beverly, MA) in the presence or absence of IL-6 (Genetics Institute) and/or the MEK 1 inhibitor PD98059 (New England Biolabs), as in prior studies.21 Antigen-antibody complexes were detected by using enhanced chemiluminescence (Amersham, Arlington Heights, IL). Blots were stripped and reprobed with anti-ERK2 Ab (Santa Cruz Biotech) to ensure equivalent protein loading. To characterize apoptotic signaling, MM cells were cultured with 100 µmol/L of Thal, IMiD1, IMiD2, or IMiD3; harvested; washed; and lysed in 1 mL of lysis buffer (50 mmol/L Tris, pH 7.4, 150 mM NaCl, 1% NP-40, 5 mmol/L EDTA, 2 mmol/L Na3VO4, 5 mmol/L NaF, 1 mmol/L PMSF, 5 µg/mL leupeptin, and 5 µg/mL aprotinin), as in prior studies.22 Lysates were incubated with anti-related adhesion focal tyrosine kinase (RAFTK) Ab for 1 hour at 4°C and then for 45 minutes after the addition of protein G-agarose (Santa Cruz Biotech). Immune complexes were analyzed by immunoblotting with anti-P-Tyr Ab (RC20; Transduction Laboratories, Lexington, KY) or anti-RAFTK Abs. Proteins were separated by electrophoresis in 7.5% SDS-PAGE gels, transferred to nitrocellulose paper, and analyzed by immunoblotting. The antigen-antibody complexes were visualized by chemiluminescence. Statistical analyses Statistical significance of differences observed in drug-treated versus control cultures was determined by using the Student t test. The minimal level of significance was P < .05.
Treatment of MM patients with Thal Seventeen (39%) of 44 patients with MM treated at our institute responded to Thal (Table 1). This response included 6 men and 11 women. These patients had received a median of 4 (1-9) prior treatment regimens, and 10 patients had a prior high-dose therapy and hematopoietic stem cell transplant. One patient achieved complete response (absence of monoclonal protein on immunofixation and normal BM biopsy), 11 patients achieved partial response (> 50% decrease in monoclonal protein), and 5 patients achieved stable disease (< 50% decrease in monoclonal protein). Patients received a median of 400 mg (range, 100-800 mg) maximum dose of daily Thal for a median of 6 months (range, 1.5-13 months). As of January 1, 2000, 11 patients have continued response at a median of 6 months (range, 4-13 months), and 6 patients have progressed at a median of 4.5 months (range, 1.5-10 months).
Effect of Thal and analogs on DNA synthesis by MM cell lines and patient MM cells The effect of Thal and its analogs, including IMiD1, IMiD2, IMiD3, SelCID1, SelCID2, SelCID3, and SelCID4, on DNA synthesis of MM cell lines (MM.1S, Hs Sultan, U266, and RPMI-8226) was determined by measuring 3H-TdR uptake during the last 8 hours of 48-hour cultures, in the presence or absence of drug at various concentrations. IMiD1, IMiD2, and IMiD3 inhibited 3H-TdR uptake of MM.1S (Figure 1A) and Hs Sultan (Figure 1B) cells in a dose-dependent fashion. Fifty percent inhibition of proliferation of MM.1S cells was noted at 0.01-0.1 µmol/L IMiD1, 0.1-1.0 µmol/L IMiD2, and 0.1-1.0 µmol/L IMiD3 (P < .001). Fifty percent inhibition of proliferation of Hs Sultan cells was noted at 0.1 µmol/L IMiD1, 1.0 µmol/L IMiD2, and 1.0 µmol/L IMiD3 (P < .001). In contrast, only 15% and 20% inhibition in MM.1S and Sultan cells, respectively, were observed in cultures at even higher concentrations (100 µmol/L) of Thal. No significant inhibition of DNA synthesis of U266 MM cells was noted in cultures with 0.001 to 100 µmol/L Thal or these IMiDs (data not shown). The effects of these drugs on proliferation were confirmed by using MTT assays for MM.1S cells (Figure 1A) and Hs Sultan cells (Figure 1B). Although there was also a dose-dependent inhibition of proliferation of MM.1S cells by SelCIDs, 50% inhibition was observed only at high doses (100 µmol/L) for only 2 of the 4 SelCIDs (SelCIDs 1 and 3, Figure 1C). Further studies, therefore, focused on Thal and the IMiDs.
Effect of Thal and analogs in DNA synthesis of MM cells resistant to conventional therapy To examine whether there was cross-resistance between Thal and the IMiDs with conventional therapies, RPMI-8226 MM cells resistant to Dox (Dox6 and Dox40 cells), Mit (MR20 cells), or Mel (LR5 cells), and MM.1R cells resistant to Dex were similarly studied. Proliferation of Dox6 and Dox40, MR20, LR5, or MM1.R cells is unaffected by culture with 60 nmol/L and 400 nmol/L Dox, 20 nmol/L Mit, 5 µmol/L Mel, and 1 µmol/L Dex, respectively (data not shown). Importantly, 3H-TdR uptake of Dox6, Dox40, MR20, or LR5 was inhibited in cultures with Thal and the IMiDs in a dose-dependent manner (1-100 µmol/L) versus media alone cultures (Figure 2A-D). For example, 10 µmol/L IMiD1 blocked proliferation of Dox6, Dox40, MR20, and LR5 cells by 20%, 33%, 32%, and 21%, respectively (P < .001). The IMiDs similarly inhibited DNA synthesis of MM.1R cells in a dose-dependent fashion, with more than 50% inhibition at more than 1 µmol/L IMiD1 (P < .001; Figure 2E). These data suggest independent mechanisms of resistance to Dox, Mit, Mel, and Dex versus Thal and its analogs.
Effect of Dex and IL-6 on response of MM cells to Thal and the ImiDs To determine whether the effects of Thal and the IMiDs are additive with conventional therapies, we next examined the effect of Dex (0.001-0.1 µmol/L) together with 1 µmol/L Thal or IMiDs on proliferation of Dex-sensitive MM.1S cells. As can be seen in Figure 3A, the IMiDs (1 µmol/L) significantly inhibited 3H-TdR uptake of MM.1S cells (60%-75% block, P < .01), and Dex (0.001-0.1 µmol/L) increased this inhibition in a dose-dependent fashion. For example, doses of 0.001 to 0.01 µmol/L Dex added to 1 µmol/L IMiD1 increased the inhibition of proliferation by 35% relative to cultures with 1 µmol/L IMiD1 alone (P < .01). Given the additive effects of Dex and the IMiDs, as well as the known role of IL-6 as a growth factor and specific inhibitor of Dex-induced MM cell apoptosis,19,22,23 we also examined whether exogenous IL-6 could overcome the inhibition of DNA synthesis triggered by Thal and the IMiDs. Figure 3B demonstrates that IL-6 (50 ng/mL) triggers DNA synthesis of MM.1S cells in cultures with media alone, as well as in cultures with the IMiDs (0.1 and 1 µmol/L).
Effect of Thal and analogs on DNA synthesis of patient MM cells The effect of Thal and the IMiDs on DNA synthesis of patient MM cells was next examined (Figure 4). As was true for MM.1S and Hs Sultan MM cell lines, 3H-TdR uptake of patients' MM cells was also inhibited by IMiDs (0.1-100 µmol/L) in a dose-dependent fashion, whereas the inhibitory effect of Thal, even at 100 µmol/L, was not significant. Fifty percent inhibition of MM patient cells was observed at 100 µmol/L (Figure 4A) and 1 µmol/L (Figure 4B) IMiD1, respectively (P < .001).
Effect of Thal and analogs on cell cycle profile of MM cell lines and patient MM cells To further analyze the mechanism of Thal- and IMiD-induced inhibition of DNA synthesis and to determine whether these drugs induced apoptosis of MM cells, we first examined the cell cycle profile of MM.1S, Hs Sultan cells, and patient MM cells cultured with media alone, Thal (10 µmol/L), or the IMiDs (1 µmol/L). Cells were harvested from 72-hour cultures and stained with PI. As shown in Figure 5A, all 3 IMiDs, and Thal to a lesser extent, increased sub-G1 MM.1S cells. Induction of apoptosis occurred at the dose-response curve noted for inhibition of proliferation. Twelve-hour cultures with Dex (10 µmol/L) served as a positive control for triggering increased sub-G1 cells. In contrast, no increase in sub-G1 cells was observed in cultures of Hs Sultan cells or of patient MM cells with Thal or the IMiDs. Importantly, Thal and the IMiDs induced G1 growth arrest in both Hs Sultan cells and in AS patient MM cells.
To confirm these results, we performed annexin V staining of cells in these cultures. As can be seen in Figure 5B, the percentage of annexin V-positive cells in cultures of MM.1S cells with Thal, IMiD1, IMiD2, and IMiD3 was 32%, 55%, 51%, and 43%, respectively. Forty-six percent of annexin V staining was observed in cultures with Dex, whereas only 22% annexin V-positive cells were present in cultures with media alone. The percentage of annexin V-positive Hs Sultan cells and AS patient MM cells was 4% to 7%, respectively, under all culture conditions and was not increased by Thal or the IMiDs. Effect of Thal and analogs on p21 expression in MM cell lines and patient cells We next correlated these distinct biologic sequelae of Thal and the IMiDs with p21 status in MM.1S versus Hs Sultan and patient MM cells. As can be seen in Figure 6A, p21 expression was down-regulated by the IMiDs, as well as by Dex, in MM1.S cells; and IL-6 overcomes this inhibitory effect. In contrast, the IMiDs up-regulated p21 in Hs Sultan cells and patient MM cells. Immunoblotting with anti-tubulin Ab confirmed equivalent protein loading. Wt-p53 was recognized in MM.1S cells, whereas both wt- and mt-p53 were recognized in Hs Sultan cells and patient MM cells (Figure 6B). These studies further support the observation that Thal and the IMiDs can induce either apoptosis or G1 growth arrest in sensitive MM cells, and they are consistent with Thal and IMiD p53-mediated down-regulation of p21 and susceptibility to p53-mediated apoptosis in MM.1S cells, in contrast to induction of p21 and growth arrest in Hs Sultan cells and patient MM cells, conferring protection from apoptosis.
Effect of Thal and analogs on growth and apoptotic signaling in MM.1S and MM.1R cells We have previously characterized signaling cascades mediating MM cell growth and apoptosis, as well as the antiapoptotic effect of IL-6.19,22-25 Because we have shown that IL-6-induced proliferation is mediated by the ras-dependent mitogen-activated protein kinase (MAPK) cascade,19 we next examined the effect of Thal and the IMiDs on tyrosine phosphorylation of MAPK in IL-6-responsive MM.1S cells. Constitutive tyrosine phosphorylation of MAPK in MM.1S cells was down-regulated by the MEK1 inhibitor PD98059 (50 µmol/L), which served as a positive control (Figure 6A), and to a lesser extent by the IMiDs (1 µmol/L; Figure 7A) or Thal (10 µmol/L; data not shown). Treatment of MM.1S cells with IL-6 increased MAPK tyrosine phosphorylation, which was partially blocked by PD98059 but was unaffected by the IMiDs (Figure 7A) or Thal (data not shown). Stripping the blot and reprobing with anti-ERK2 Ab confirmed equivalent protein loading.
The observation that IL-6 can overcome the effects of Thal, the IMiDs, and Dex, coupled with our prior studies delineating signaling cascades mediating Dex-induced apoptosis and the protective effects of IL-6,22,23,25 suggested that RAFTK activation may be induced during apoptosis triggered by Thal and IMiDs. MM.1S and MM.1R cells were, therefore, next cultured with 1 µmol/L Thal, IMiD1, IMiD2, or IMiD3 for 12 hours. Twelve-hour cultures with Dex (10 µmol/L) served as a positive control for activation of RAFTK. Total cell lysates were subjected to immunoprecipitation with anti-RAFTK Ab and analyzed by immunoblotting with anti-P-Tyr Ab or anti-RAFTK Ab. As can be seen in Figure 7B, Dex induced tyrosine phosphorylation of RAFTK in MM.1S cells but not in MM.1R cells. Importantly, IMiD1 induced RAFTK tyrosine phosphorylation in both MM.1S and MM.1R cells, correlating with its effects on both Dex-sensitive and Dex-resistant MM cells.
This study demonstrates for the first time a direct dose-dependent effect of Thal and these analogs on tumor cells. Thal has demonstrated clinical anti-MM activity at the University of Arkansas7 and in this study, and Thal at high concentrations (100 µmol/L) resulted in a modest (< 20%) inhibition of in vitro DNA synthesis of MM cells. SelCIDs also induced a dose-dependent inhibition of MM cells, but only 2 of 4 SelCIDs tested achieved 50% inhibition of proliferation, even at 100 µmol/L concentrations. Importantly, all 3 IMiDs tested achieved 50% inhibition of DNA synthesis at concentrations (0.1-1.0 µmol/L) corresponding to serum levels that are readily achievable, both confirming their direct action on tumor cells and suggesting their potential clinical utility. Moreover, the IMiDs inhibited the proliferation of Dox-, Mit-, and Mel-resistant MM cells by 20% to 35%, and of Dex-resistant MM cells by 50%. These in vitro effects correlate with the observed clinical activity of Thal in patients with MM that is refractory to conventional therapies, both at the University of Arkansas7 and reported in this study, and suggest their clinical utility to overcome drug resistance. Moreover, our studies further suggest that Dex can add to the antiproliferative effect of Thal and the IMiDs in vitro, suggesting the potential utility of coupling these agents therapeutically. Finally, our study also identified MM cells resistant to Thal and the analogs (U266 cells), which, therefore, can be used to study mechanisms of Thal resistance. Our studies demonstrate that Thal and the IMiDs are acting directly on
MM cells, in the absence of accessory BM or T cells. It is also
possible that these agents may be mediating their anti-MM effect by
cytokines, given their known inhibitory effects on TNF- Having shown the inhibitory effects of Thal and the IMiDs on 3H-TdR uptake of tumor cells, we next examined their effect on MM cell cycle. Interestingly, these drugs had distinct functional sequelae in MM cells. Specifically, the IMiDs, and to a lesser extent Thal, induced apoptosis of MM.1S cells, evidenced both by increased sub-G1 cells on PI staining and increased annexin V-positive cells. In these cells that have wt p53, these agents (and Dex) down-regulate p21, thereby facilitating G1-to-S transition and susceptibility to apoptosis. This apoptotic effect may correlate with the clinical observation that complete response to Thal is rarely observed. IL-6 overcomes the down-regulation of p21 induced by these agents, consistent with the increase in DNA synthesis triggered by IL-6 even in the presence of these drugs. In contrast, in Hs Sultan cells (wt and mt p53) and patient cells (wt p53 and mt p53), the IMiDs and Thal induce p21 and related G1 growth arrest, thereby conferring protection from apoptosis, as has been observed in other systems.28,29 In our prior study,20 p21 was also constitutively expressed in the majority of MM cells and also inhibited proliferation in both p53-dependent and -independent mechanisms. Previous reports that cells overexpressing p21 protein demonstrate chemoresistance30 further support the protective effect of G1 growth arrest induced by these agents in Hs Sultan MM cells and patient MM cells. Conversely, the frequent regrowth of progressive MM noted clinically on discontinuation of Thal treatment may correlate with release of drug-related G1 growth arrest. An ongoing clinical trial is correlating response to Thal with laboratory parameters (ie, serum IL-6 or the surrogate marker C reactive protein) and will gain further insights into its mechanisms of in vivo anti-tumor activity. Finally, our prior studies have characterized apoptotic signaling
cascades in MM, as well as the protective effect of IL-6, especially
against Dex-induced apoptosis.22,23,25,31 Specifically, we
have shown that Dex down-regulates growth kinases, such as MAPK and
p70RSK;23 importantly, it activates RAFTK,
which is required for Dex-induced apoptosis and abrogated by
IL-6.22 The current studies show that IMiD1 acts similarly
to Dex, because it activates RAFTK and apoptosis in MM.1S cells,
sequelae that are blocked by IL-6. Given our prior studies, which
demonstrate that apoptosis of MM cells induced by UV irradiation, In conclusion, the results of this study, therefore, demonstrate evidence for direct activity of Thal and the IMiDs against human MM cells. To confirm their in vivo mechanism of action, these compounds and SelCIDs will be examined in an animal model. Importantly, these studies provide the framework for the development and testing of a new biologically based treatment paradigm that uses these novel agents, either alone or together with conventional therapies, to target both the tumor cell and its microenvironment, overcome classical drug resistance, and achieve improved outcome in this presently incurable disease.
Submitted March 8, 2000; accepted June 28, 2000.
Supported by National Institutes of Health grant PO1 78378 and the Doris Duke Distinguished Clinical Research Scientist Award (K.C.A.).
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, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115; e-mail: kennethanderson{at}dfci.harvard.edu.
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H. Yan, P. Frost, Y. Shi, B. Hoang, S. Sharma, M. Fisher, J. Gera, and A. Lichtenstein Mechanism by Which Mammalian Target of Rapamycin Inhibitors Sensitize Multiple Myeloma Cells to Dexamethasone-Induced Apoptosis Cancer Res., February 15, 2006; 66(4): 2305 - 2313. [Abstract] [Full Text] [PDF]
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P. Richardson and K. Anderson Thalidomide and Dexamethasone: A New Standard of Care for Initial Therapy in Multiple Myeloma J. Clin. Oncol., January 20, 2006; 24(3): 334 - 336. [Full Text] [PDF]
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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]
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R. Baz, L. Li, K. Kottke-Marchant, G. Srkalovic, B. McGowan, E. Yiannaki, M. A. Karam, B. Faiman, R. A. Jawde, S. Andresen, et al. The Role of Aspirin in the Prevention of Thrombotic Complications of Thalidomide and Anthracycline-Based Chemotherapy for Multiple Myeloma Mayo Clin. Proc., December 1, 2005; 80(12): 1568 - 1574. [Abstract] [PDF]
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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]
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H. Yasui, T. Hideshima, N. Raje, A. M. Roccaro, N. Shiraishi, S. Kumar, M. Hamasaki, K. Ishitsuka, Y.-T. Tai, K. Podar, et al. FTY720 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Drug Resistance Cancer Res., August 15, 2005; 65(16): 7478 - 7484. [Abstract] [Full Text] [PDF]
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H. Yasui, T. Hideshima, M. Hamasaki, A. M. Roccaro, N. Shiraishi, S. Kumar, P. Tassone, K. Ishitsuka, N. Raje, Y.-T. Tai, et al. SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma Blood, July 15, 2005; 106(2): 706 - 712. [Abstract] [Full Text] [PDF]
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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]
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K.-R. Koh, M. Janz, M. Y. Mapara, B. Lemke, D. Stirling, B. Dorken, M. Zenke, and S. Lentzsch Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis Blood, May 15, 2005; 105(10): 3833 - 3840. [Abstract] [Full Text] [PDF]
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G. Palladini, V. Perfetti, S. Perlini, L. Obici, F. Lavatelli, R. Caccialanza, R. Invernizzi, B. Comotti, and G. Merlini The combination of thalidomide and intermediate-dose dexamethasone is an effective but toxic treatment for patients with primary amyloidosis (AL) Blood, April 1, 2005; 105(7): 2949 - 2951. [Abstract] [Full Text] [PDF]
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J. Gardyn Thalidomide With Continuous Low-Dose Dexamethasone for Multiple Myeloma J. Clin. Oncol., February 20, 2005; 23(6): 1323 - 1323. [Full Text] [PDF]
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K. Podar and K. C. Anderson The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications Blood, February 15, 2005; 105(4): 1383 - 1395. [Abstract] [Full Text] [PDF]
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B. I. Rini and E. J. Small Biology and Clinical Development of Vascular Endothelial Growth Factor-Targeted Therapy in Renal Cell Carcinoma J. Clin. Oncol., February 10, 2005; 23(5): 1028 - 1043. [Abstract] [Full Text] [PDF]
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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]
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B. Lin, L. Catley, R. LeBlanc, C. Mitsiades, R. Burger, Y.-T. Tai, K. Podar, M. Wartmann, D. Chauhan, J. D. Griffin, et al. Patupilone (epothilone B) inhibits growth and survival of multiple myeloma cells in vitro and in vivo Blood, January 1, 2005; 105(1): 350 - 357. [Abstract] [Full Text] [PDF]
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P. G. Richardson, A. Kassarjian, and W. Jing Case 38-2004 - A 40-Year-Old Man with a Large Tumor of the Skull N. Engl. J. Med., December 16, 2004; 351(25): 2637 - 2645. [Full Text] [PDF]
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N. Raje, S. Kumar, T. Hideshima, K. Ishitsuka, D. Chauhan, C. Mitsiades, K. Podar, S. Le Gouill, P. Richardson, N. C. Munshi, et al. Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma Blood, December 15, 2004; 104(13): 4188 - 4193. [Abstract] [Full Text] [PDF]
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T. Hayashi, T. Hideshima, A. N. Nguyen, O. Munoz, K. Podar, M. Hamasaki, K. Ishitsuka, H. Yasui, P. Richardson, S. Chakravarty, et al. Transforming Growth Factor {beta} Receptor I Kinase Inhibitor Down-Regulates Cytokine Secretion and Multiple Myeloma Cell Growth in the Bone Marrow Microenvironment Clin. Cancer Res., November 15, 2004; 10(22): 7540 - 7546. [Abstract] [Full Text] [PDF]
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S. Le Gouill, K. Podar, M. Amiot, T. Hideshima, D. Chauhan, K. Ishitsuka, S. Kumar, N. Raje, P. G. Richardson, J.-L. Harousseau, et al. VEGF induces Mcl-1 up-regulation and protects multiple myeloma cells against apoptosis Blood, November 1, 2004; 104(9): 2886 - 2892. [Abstract] [Full Text] [PDF]
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D. Chauhan, G. Li, K. Podar, T. Hideshima, C. Mitsiades, R. Schlossman, N. Munshi, P. Richardson, F. E. Cotter, and K. C. Anderson Targeting mitochondria to overcome conventional and bortezomib/proteasome inhibitor PS-341 resistance in multiple myeloma (MM) cells Blood, October 15, 2004; 104(8): 2458 - 2466. [Abstract] [Full Text] [PDF]
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P. Richardson and K. Anderson Immunomodulatory Analogs of Thalidomide: An Emerging New Therapy in Myeloma J. Clin. Oncol., August 15, 2004; 22(16): 3212 - 3214. [Full Text] [PDF]
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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]
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P. Richardson, R. Schlossman, S. Jagannath, M. Alsina, R. Desikan, E. Blood, E. Weller, C. Mitsiades, T. Hideshima, F. Davies, et al. Thalidomide for Patients With Relapsed Multiple Myeloma After High-Dose Chemotherapy and Stem Cell Transplantation: Results of an Open-Label Multicenter Phase 2 Study of Efficacy, Toxicity, and Biological Activity Mayo Clin. Proc., July 1, 2004; 79(7): 875 - 882. [Abstract] [PDF]
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S. Kumar, T. E. Witzig, and S. V. Rajkumar Thalidomide: Current Role in the Treatment of Non-Plasma Cell Malignancies J. Clin. Oncol., June 15, 2004; 22(12): 2477 - 2488. [Abstract] [Full Text] [PDF]
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K. Podar, L. P. Catley, Y.-T. Tai, R. Shringarpure, P. Carvalho, T. Hayashi, R. Burger, R. L. Schlossman, P. G. Richardson, L. N. Pandite, et al. GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment Blood, May 1, 2004; 103(9): 3474 - 3479. [Abstract] [Full Text] [PDF]
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D. Chauhan, G. Li, K. Podar, T. Hideshima, R. Shringarpure, L. Catley, C. Mitsiades, N. Munshi, Y. T. Tai, N. Suh, et al. The bortezomib/proteasome inhibitor PS-341 and triterpenoid CDDO-Im induce synergistic anti-multiple myeloma (MM) activity and overcome bortezomib resistance Blood, April 15, 2004; 103(8): 3158 - 3166. [Abstract] [Full Text] [PDF]
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R. LeBlanc, T. Hideshima, L. P. Catley, R. Shringarpure, R. Burger, N. Mitsiades, C. Mitsiades, P. Cheema, D. Chauhan, P. G. Richardson, et al. Immunomodulatory drug costimulates T cells via the B7-CD28 pathway Blood, March 1, 2004; 103(5): 1787 - 1790. [Abstract] [Full Text] [PDF]
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K. Zervas, M. A. Dimopoulos, E. Hatzicharissi, A. Anagnostopoulos, M. Papaioannou, Ch. Mitsouli, P. Panagiotidis, J. Korantzis, M. Tzilianos, and A. Maniatis Primary treatment of multiple myeloma with thalidomide, vincristine, liposomal doxorubicin and dexamethasone (T-VAD doxil): a phase II multicenter study Ann. Onc., January 1, 2004; 15(1): 134 - 138. [Abstract] [Full Text] [PDF]
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 J.-L. Harousseau, J. Shaughnessy Jr., and P. Richardson Multiple Myeloma Hematology, January 1, 2004; 2004(1): 237 - 256. [Abstract] [Full Text] [PDF]
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T. Hideshima, D. Chauhan, T. Hayashi, K. Podar, M. Akiyama, C. Mitsiades, N. MItsiades, B. Gong, L. Bonham, P. de Vries, et al. Antitumor Activity of Lysophosphatidic Acid Acyltransferase-{beta} Inhibitors, a Novel Class of Agents, in Multiple Myeloma Cancer Res., December 1, 2003; 63(23): 8428 - 8436. [Abstract] [Full Text] [PDF]
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M. A. Dimopoulos, A. Anagnostopoulos, and D. Weber Treatment of Plasma Cell Dyscrasias With Thalidomide and Its Derivatives J. Clin. Oncol., December 1, 2003; 21(23): 4444 - 4454. [Abstract] [Full Text] [PDF]
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D. Chauhan, G. Li, T. Hideshima, K. Podar, C. Mitsiades, N. Mitsiades, L. Catley, Y. T. Tai, T. Hayashi, R. Shringarpure, et al. Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance Blood, November 1, 2003; 102(9): 3379 - 3386. [Abstract] [Full Text] [PDF]
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C. S. Mitsiades, N. S. Mitsiades, R. T. Bronson, D. Chauhan, N. Munshi, S. P. Treon, C. A. Maxwell, L. Pilarski, T. Hideshima, R. M. Hoffman, et al. Fluorescence Imaging of Multiple Myeloma Cells in a Clinically Relevant SCID/NOD in Vivo Model: Biologic and Clinical Implications Cancer Res., October 15, 2003; 63(20): 6689 - 6696. [Abstract] [Full Text] [PDF]
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T. Hayashi, T. Hideshima, M. Akiyama, N. Raje, P. Richardson, D. Chauhan, and K. C. Anderson Ex vivo induction of multiple myeloma-specific cytotoxic T lymphocytes Blood, August 15, 2003; 102(4): 1435 - 1442. [Abstract] [Full Text] [PDF]
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C.-K. Lee, B. Barlogie, N. Munshi, M. Zangari, A. Fassas, J. Jacobson, F. van Rhee, M. Cottler-Fox, F. Muwalla, and G. Tricot DTPACE: An Effective, Novel Combination Chemotherapy With Thalidomide for Previously Treated Patients With Myeloma J. Clin. Oncol., July 15, 2003; 21(14): 2732 - 2739. [Abstract] [Full Text] [PDF]
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 P. H. Schafer, A. K. Gandhi, M. A. Loveland, R. S. Chen, H.-W. Man, P. P. M. Schnetkamp, G. Wolbring, S. Govinda, L. G. Corral, F. Payvandi, et al. Enhancement of Cytokine Production and AP-1 Transcriptional Activity in T Cells by Thalidomide-Related Immunomodulatory Drugs J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 1222 - 1232. [Abstract] [Full Text] [PDF]
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T. Hideshima, C. Mitsiades, M. Akiyama, T. Hayashi, D. Chauhan, P. Richardson, R. Schlossman, K. Podar, N. C. Munshi, N. Mitsiades, et al. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341 Blood, February 15, 2003; 101(4): 1530 - 1534. [Abstract] [Full Text] [PDF]
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 K. Podar, Y.-T. Tai, C. E. Cole, T. Hideshima, M. Sattler, A. Hamblin, N. Mitsiades, R. L. Schlossman, F. E. Davies, G. J. Morgan, et al. Essential Role of Caveolae in Interleukin-6- and Insulin-like Growth Factor I-triggered Akt-1-mediated Survival of Multiple Myeloma Cells J. Biol. Chem., February 14, 2003; 278(8): 5794 - 5801. [Abstract] [Full Text] [PDF]
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J. B. Marriott, I. A. Clarke, A. Czajka, K. Dredge, K. Childs, H.-W. Man, P. Schafer, S. Govinda, G. W. Muller, D. I. Stirling, et al. A Novel Subclass of Thalidomide Analogue with Anti-Solid Tumor Activity in Which Caspase-dependent Apoptosis is Associated with Altered Expression of bcl-2 Family Proteins Cancer Res., February 1, 2003; 63(3): 593 - 599. [Abstract] [Full Text] [PDF]
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T. Hideshima, M. Akiyama, T. Hayashi, P. Richardson, R. Schlossman, D. Chauhan, and K. C. Anderson Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu Blood, January 15, 2003; 101(2): 703 - 705. [Abstract] [Full Text] [PDF]
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M. Akiyama, T. Hideshima, T. Hayashi, Y.-T. Tai, C. S. Mitsiades, N. Mitsiades, D. Chauhan, P. Richardson, N. C. Munshi, and K. C. Anderson Nuclear Factor-{kappa}B p65 Mediates Tumor Necrosis Factor {alpha}-induced Nuclear Translocation of Telomerase Reverse Transcriptase Protein Cancer Res., January 1, 2003; 63(1): 18 - 21. [Abstract] [Full Text] [PDF]
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D. Weber, K. Rankin, M. Gavino, K. Delasalle, and R. Alexanian Thalidomide Alone or With Dexamethasone for Previously Untreated Multiple Myeloma J. Clin. Oncol., January 1, 2003; 21(1): 16 - 19. [Abstract] [Full Text] [PDF]
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S. Kumar, M. A. Gertz, A. Dispenzieri, M. Q. Lacy, S. M. Geyer, N. L. Iturria, R. Fonseca, S. R. Hayman, J. A. Lust, R. A. Kyle, et al. Response Rate, Durability of Response, and Survival After Thalidomide Therapy for Relapsed Multiple Myeloma Mayo Clin. Proc., January 1, 2003; 78(1): 34 - 39. [Abstract] [PDF]
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S. Yaccoby, C. L. Johnson, S. C. Mahaffey, M. J. Wezeman, B. Barlogie, and J. Epstein Antimyeloma efficacy of thalidomide in the SCID-hu model Blood, December 1, 2002; 100(12): 4162 - 4168. [Abstract] [Full Text] [PDF]
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S. V. Rajkumar, S. Hayman, M. A. Gertz, A. Dispenzieri, M. Q. Lacy, P. R. Greipp, S. Geyer, N. Iturria, R. Fonseca, J. A. Lust, et al. Combination Therapy With Thalidomide Plus Dexamethasone for Newly Diagnosed Myeloma J. Clin. Oncol., November 1, 2002; 20(21): 4319 - 4323. [Abstract] [Full Text] [PDF]
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K. Neben, T. Moehler, A. Benner, A. Kraemer, G. Egerer, A. D. Ho, and H. Goldschmidt Dose-dependent Effect of Thalidomide on Overall Survival in Relapsed Multiple Myeloma Clin. Cancer Res., November 1, 2002; 8(11): 3377 - 3382. [Abstract] [Full Text] [PDF]
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P. G. Richardson, R. L. Schlossman, E. Weller, T. Hideshima, C. Mitsiades, F. Davies, R. LeBlanc, L. P. Catley, D. Doss, K. Kelly, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma Blood, October 16, 2002; 100(9): 3063 - 3067. [Abstract] [Full Text] [PDF]
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B. Lin, K. Podar, D. Gupta, Y.-T. Tai, S. Li, E. Weller, T. Hideshima, S. Lentzsch, F. Davies, C. Li, et al. The Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor PTK787/ZK222584 Inhibits Growth and Migration of Multiple Myeloma Cells in the Bone Marrow Microenvironment Cancer Res., September 1, 2002; 62(17): 5019 - 5026. [Abstract] [Full Text] [PDF]
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D. Chauhan, L. Catley, T. Hideshima, G. Li, R. Leblanc, D. Gupta, M. Sattler, P. Richardson, R. L. Schlossman, K. Podar, et al. 2-Methoxyestradiol overcomes drug resistance in multiple myeloma cells Blood, August 28, 2002; 100(6): 2187 - 2194. [Abstract] [Full Text] [PDF]
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T. Hayashi, T. Hideshima, M. Akiyama, P. Richardson, R. L. Schlossman, D. Chauhan, N. C. Munshi, S. Waxman, and K. C. Anderson Arsenic Trioxide Inhibits Growth of Human Multiple Myeloma Cells in the Bone Marrow Microenvironment Mol. Cancer Ther., August 1, 2002; 1(10): 851 - 860. [Abstract] [Full Text] [PDF]
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M. Akiyama, T. Hideshima, T. Hayashi, Y.-T. Tai, C. S. Mitsiades, N. Mitsiades, D. Chauhan, P. Richardson, N. C. Munshi, and K. C. Anderson Cytokines Modulate Telomerase Activity in a Human Multiple Myeloma Cell Line Cancer Res., July 1, 2002; 62(13): 3876 - 3882. [Abstract] [Full Text] [PDF]
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S. V. Rajkumar, R. A. Mesa, R. Fonseca, G. Schroeder, M. F. Plevak, A. Dispenzieri, M. Q. Lacy, J. A. Lust, T. E. Witzig, M. A. Gertz, et al. Bone Marrow Angiogenesis in 400 Patients with Monoclonal Gammopathy of Undetermined Significance, Multiple Myeloma, and Primary Amyloidosis Clin. Cancer Res., July 1, 2002; 8(7): 2210 - 2216. [Abstract] [Full Text] [PDF]
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N. Mitsiades, C. S. Mitsiades, V. Poulaki, D. Chauhan, P. G. Richardson, T. Hideshima, N. C. Munshi, S. P. Treon, and K. C. Anderson Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications Blood, May 29, 2002; 99(12): 4525 - 4530. [Abstract] [Full Text] [PDF]
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 K. Dredge, J. B. Marriott, S. M. Todryk, G. W. Muller, R. Chen, D. I. Stirling, and A. G. Dalgleish Protective Antitumor Immunity Induced by a Costimulatory Thalidomide Analog in Conjunction with Whole Tumor Cell Vaccination Is Mediated by Increased Th1-Type Immunity J. Immunol., May 15, 2002; 168(10): 4914 - 4919. [Abstract] [Full Text] [PDF]
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F.-C. Lee ; and M. Zangari Second response to lower-dose thalidomide in a patient with multiple myeloma Blood, May 13, 2002; 99(11): 4248 - 4249. [Full Text] [PDF]
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T. Hideshima, D. Chauhan, P. Richardson, C. Mitsiades, N. Mitsiades, T. Hayashi, N. Munshi, L. Dang, A. Castro, V. Palombella, et al. NF-kappa B as a Therapeutic Target in Multiple Myeloma J. Biol. Chem., May 3, 2002; 277(19): 16639 - 16647. [Abstract] [Full Text] [PDF]
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T. Hideshima, D. Chauhan, T. Hayashi, K. Podar, M. Akiyama, D. Gupta, P. Richardson, N. Munshi, and K. C. Anderson The Biological Sequelae of Stromal Cell-derived Factor-1{alpha} in Multiple Myeloma Mol. Cancer Ther., May 1, 2002; 1(7): 539 - 544. [Abstract] [Full Text] [PDF]
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S. Lentzsch, M. S. Rogers, R. LeBlanc, A. E. Birsner, J. H. Shah, A. M. Treston, K. C. Anderson, and R. J. D'Amato S-3-Amino-phthalimido-glutarimide Inhibits Angiogenesis and Growth of B-Cell Neoplasias in Mice Cancer Res., April 1, 2002; 62(8): 2300 - 2305. [Abstract] [Full Text] [PDF]
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M. A. Hussein Nontraditional Cytotoxic Therapies for Relapsed/Refractory Multiple Myeloma Oncologist, April 1, 2002; 7(90001): 20 - 29. [Abstract] [Full Text] [PDF]
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A. F. List New Approaches to the Treatment of Myelodysplasia Oncologist, April 1, 2002; 7(90001): 39 - 49. [Abstract] [Full Text] [PDF]
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S. Majumdar, B. Lamothe, and B. B. Aggarwal Thalidomide Suppresses NF-{kappa}B Activation Induced by TNF and H2O2, But Not That Activated by Ceramide, Lipopolysaccharides, or Phorbol Ester J. Immunol., March 15, 2002; 168(6): 2644 - 2651. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
, IL-10, and tumor necrosis factor (TNF)-
, may
augment MM cell growth and survival,
) and
IL-2.
) were
purified from patient BM samples, as previously
described.
), IMiD1 (
), IMiD2
(
), and IMiD3 (
). (C) MM.1S cells were cultured with increasing
concentrations (12.5-100 µM) of SelCID1 (
) or
1 µmol/L (
), 10 µmol/L (
), 100 µmol/L (
), or 100 µmol/L (
B.
Blood.
1996;87:1104-1112