Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The principle of alkylating agent dose intensity, especially with melphalan-based tandem autotransplants, has been effective in increasing the rate of complete remission beyond 40% and effecting 10-year survivorship in about 40% of the three fourths of patients presenting without cytogenetic abnormalities (Total Therapy I). Further dose escalation and post-transplant consolidation therapy, as practiced with Total Therapy II, seems to further improve results in these patients, but not in those with chromosome 13 abnormalities or lactate dehydrogenase elevation. Phase III trials for post-transplant relapse indicate higher complete remission and near-complete remission rates among patients randomized to thalidomide added to dexamethasone versus dexamethasone alone. In a phase I/II study, thalidomide derivative CC-5013, with less sedative and neurotoxic effects, promoted responses in eight of 15 patients with post-transplant relapse, refractory to other salvage therapies, at dose levels of > or = 25 mg daily. Based on a profound graft-vs-myeloma effect with allografts, mini-allotransplants were evaluated in 31 high-risk patients with cytogenetic abnormalities and prior autotransplants; all nine with responsive disease and only one prior autotransplant remain disease-free and alive. Such mini-allotransplants are now offered as consolidation after one standard autotransplant to patients with cytogenetic abnormalities. The systematic application of gene expression profiling attempts to classify multiple myeloma (MM) patients according to molecular features and to dissect the genetic basis for drug sensitivity or resistance. Given the availability of an expanding treatment armamentarium (eg, thalidomide, CC-5013, the proteasome inhibitor PS-341, farnesyltransferase inhibitors, IL-6 receptor antibody, endothelial receptor inhibitor), gene expression profiling is anticipated to help in the selection of agents with the greatest probability of activity toward individualized treatment. Careful scrutiny of gene expression will also help in the identification of unrecognized targets for therapeutic intervention.
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PMID:High-dose therapy and immunomodulatory drugs in multiple myeloma. 1252 Apr 82

Multiple myeloma (MM) cells home to and adhere to extracellular matrix proteins and to bone marrow stromal cells (BMSCs); and in the BM microenvironment, grow, survive, resist drugs, and migrate under the influence of cytokines including interleukin-6, vascular endothelial growth factor, tumor necrosis factor alpha, and insulin-like growth factor (IGF)-1. Proliferation is via the Ras/Raf MAPK cascade, drug resistance via PI3-K/Akt signaling, and migration via PKC dependent pathways. Novel therapies that target not only the MM cell, but also the BM microenvironment, can overcome drug resistance in vitro and in vivo in murine human MM models. For example, immunomodulatory derivatives of thalidomide (IMiDs) and the proteasome inhibitor PS-341 both induce apoptosis of MM cell lines and patient cells refractory to melphalan, doxorubicin, and dexamethasone; abrogate MM cell binding to fibronectin and BMSCs and related protection against immune- and drug-induced apoptosis; block production of cytokines which promote MM cell growth, survival, drug resistance, and migration; inhibit angiogenesis; and stimulate host anti-tumor immunity. In the setting of relapsed refractory MM, a Phase I trial of the IMiD CC5013 shows stable paraprotein or better in 20 of 24 (79%) patients, with a favorable toxicity profile. In this same patient population 85% of 54 patients treated in a Phase II trial of PS-341 achieved either paraprotein response (50%) or stable disease (35%). Cellular and gene microarray studies comparing PS-341 and an IkappaB kinase inhibitor, PS-1145, suggest that selective NF-kappaB blockade cannot account for all the anti-MM activity of PS-341. Finally, cellular and signaling studies provide the preclinical rationale for combining these novel agents with conventional therapies, or with each other, to enhance efficacy. These novel therapeutics therefore represent a new treatment paradigm in MM targeting the tumor cell in its microenvironment to overcome classical drug resistance and improve patient outcome. Future studies should define the utility of these agents as primary therapy, treatment for first relapse, and maintenance therapy.
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PMID:Moving disease biology from the lab to the clinic. 1254 78

Increased nuclear factor kappaB (NF-kappaB) activity is associated with increased tumor cell survival in multiple myeloma. The function of NF-kappaB is inhibited through binding to its inhibitor, IkappaB. Release of activated NF-kappaB follows proteasome-mediated degradation of IkappaB resulting from phosphorylation of the inhibitor and, finally, conjugation with ubiquitin. We report that myeloma cells have enhanced IkappaBalpha phosphorylation and increased NF-kappaB activity compared with normal hematopoietic cells. The proteasome inhibitor PS-341 blocked nuclear translocation of NF-kappaB, blocked NF-kappaB DNA binding, and demonstrated consistent antitumor activity against chemoresistant and chemosensitive myeloma cells. The sensitivity of chemoresistant myeloma cells to chemotherapeutic agents was markedly increased (100,000-1,000,000-fold) when combined with a noncytotoxic dose of PS-341 without affecting normal hematopoietic cells. Similar effects were observed using a dominant negative super-repressor for IkappaBalpha. Thus, these results suggest that inhibition of NF-kappaB with PS-341 may overcome chemoresistance and allow doses of chemotherapeutic agents to be markedly reduced with antitumor effects without significant toxicity.
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PMID:The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. 1263 19

Waldenstrom's macroglobulinemia (WM) remains an incurable B-cell malignancy, necessitating urgent development of novel treatment strategies. Building on our experience on bed-to-bedside translational studies for multiple myeloma (mm), we identified a constellation of novel classes of anti-WM agents, including the proteasome inhibitor PS-341; the ansamycin family of inhibitors (eg, geldanamycin and its analogues) of the heat-shock protein 90 (hsp90) molecular chaperone; histone deacetylase inhibitors, such as suberoylanilide hydroxamic acid (SAHA); and the thiazolidinedione group of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists (eg, ciglitazone or rosiglitazone). Our preclinical data show that these classes of agents induce growth arrest and apoptosis of WM cells, at concentrations relevant to those achieved in previous clinical uses of these drugs, and suggest that novel therapeutic strategies for WM can be designed to include combinations of these agents, to simultaneously target multiple levels of diverse pathways important for tumor cell growth and survival, and thus maximize the pro-apoptotic activities of these agents and/or neutralize protective responses of WM against their effects. These molecular studies provide a framework for rational design of the next generation of combination therapies for WM.
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PMID:Novel biologically based therapies for Waldenstrom's macroglobulinemia. 1272 Jan 59

The discovery of the activity of thalidomide in myeloma in the late 1990s transformed the therapy of myeloma dramatically. Apart from providing a useful treatment option for patients with myeloma, it has spurred clinical investigation of several other nonchemotherapeutic agents for this disease. These active, promising agents include CC-5013 (a thalidomide analog) and bortezomib (a proteasome inhibitor), as well as other agents, such as arsenic trioxide, ENMD 0995 and 2-methoxyestradiol. Preliminary data show that a number of these agents are active in treating disease that has relapsed after conventional chemotherapy as well as after high-dose therapy and transplantation, and some agents are active even after other novel agents have failed. The only novel drug that is commercially available currently is thalidomide, which has a therapeutically relevant benefit at all stages of the disease. A therapeutic trial of thalidomide is essential for all patients with myeloma. There are in vitro and in vivo data showing synergy between some of the novel agents. Although these novel drugs are typically used for treating disease that is refractory to or has relapsed after cytotoxic therapy, it is likely that they will start being used as part of frontline therapy, either by themselves or in combination with chemotherapy.
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PMID:Novel therapies in multiple myeloma. 1273 64

The proteasome inhibitor bortezomib (VELCADE; formerly PS-341, LDP-341, MLN341) is a novel dipeptide boronic acid. In cell culture and xenograft models, bortezomib showed potent activity, enhanced the sensitivity of cancer cells to traditional chemotherapeutics, and appeared to overcome drug resistance. In vitro, bortzomib downregulated the NF-kappaB pathway. NF-kappaB is a transcription factor that enhances the production of growth factors (e.g., IL-6), cell-adhesion molecules, and anti-apoptotic factors, all of which contribute to the growth of the tumor cell and/or protection from apoptosis. Phase II trials have been conducted in patients with relapsed and refractory multiple myeloma (SUMMIT trial, 202 patients) or relapsed myeloma (CREST trial, n=54) using a 1.3mg/m(2) dose given twice weekly for 2 weeks (days 1, 4, 8, 11; rest days 12-21). Both trials showed responses (including complete responses) with manageable toxicities, forming the basis for an ongoing phase III trial comparing response to bortezomib versus high-dose dexamethasone.
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PMID:Clinical update: proteasome inhibitors in hematologic malignancies. 1273 41

Bortezomib is a ubiquitin proteasome inhibitor under development by Millennium Pharmaceuticals (formerly LeukoSite Inc) for the potential treatment of various solid tumors [312219], [392555]. In the first quarter of 2001, Millennium initiated two phase II trials evaluating bortezomib for multiple myeloma (MM). A phase II trial in patients with chronic lymphocytic leukemia (CLL) was initiated in June 2001 [400636], [412848]. By November 2001, the agent was in a number of phase I trials and combination studies for various solid tumors, including prostate, pancreatic and colorectal carcinoma [412700], [429923], [435062], [452675]. In June 2002, bortezomib was awarded Fast Track status by the FDA [453557], and in the same month pivotal phase III trials evaluating bortezomib in MM were initiated in the US, Canada and Europe [454446].
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PMID:Bortezomib (millennium pharmaceuticals). 1280 99

Bortezomib, a proteasome inhibitor, shows substantial anti-tumor activity in a variety of tumor cell lines, is in phase I, II, and III clinical trials and has recently been approved for the treatment of patients with multiple myeloma. The sequence of events leading to apoptosis following proteasome inhibition by bortezomib is unclear. Bortezomib effects on components of the mitochondrial apoptotic pathway were examined: generation of reactive oxygen species (ROS), alteration in the mitochondrial membrane potential (Delta psi m), and release of cytochrome c from mitochondria. With human H460 lung cancer cells, bortezomib exposure at 0.1 microM showed induction of apoptotic cell death starting at 24 h, with increasing effects after 48-72 h of treatment. After 3-6 h, an elevation in ROS generation, an increase in Delta psi m, and the release of cytochrome c into the cytosol, were observed in a time-dependent manner. Co-incubation with rotenone and antimycin A, inhibitors of mitochondrial electron transport chain complexes I and III, or with cyclosporine A, an inhibitor of mitochondrial permeability transition pore, resulted in inhibition of bortezomib-induced ROS generation, increase in Delta psi m, and cytochrome c release. Tiron, an antioxidant agent, blocked the bortezomib-induced ROS production, Delta psi m increase, and cytochrome c release. Tiron treatment also protected against the bortezomib-induced PARP protein cleavage and cell death. Benzyloxycarbonyl-VAD-fluoromethyl ketone, an inhibitor of pan-caspase, did not alter the bortezomib-induced ROS generation and increase in Delta psi m, although it prevented bortezomib-induced poly(ADP-ribose) polymerase cleavage and apoptotic death. In PC-3 prostate carcinoma cells (with overexpression of Bcl-2), a reduction of bortezomib-induced ROS generation, Delta psi m increase was correlated with cellular resistance to bortezomib and the attenuation of drug-induced apoptosis. The transient transfection of wild type p53 in p53 null H358 cells caused stimulation of the bortezomib-induced apoptosis but failed to enhance ROS generation and Delta psi m increase. Thus ROS generation plays a critical role in the initiation of the bortezomib-induced apoptotic cascade by mediation of the disruption of Delta psi m and the release of cytochrome c from mitochondria.
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PMID:Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic response to Bortezomib, a novel proteasome inhibitor, in human H460 non-small cell lung cancer cells. 1282 77

Multiple myeloma (MM) affects 15,000 new patients annually in the US, with 50,000 total patients, and remains incurable. Our preliminary in vitro and animal studies suggest a role for MM-host interactions in regulating MM cell growth, drug resistance, and migration in the bone marrow. Importantly, treatment strategies which target mechanisms whereby MM cells grow and survive in the bone marrow, including thalidomide and its potent immunomodulatory derivatives and proteasome inhibitor PS-341, can overcome classical drug resistance in preclinical and early clinical studies.
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PMID:Novel therapeutic approaches for multiple myeloma. 1284 14

PS-341, a potent and selective proteasome inhibitor, is the prototype for a new class of therapeutics that targets the ubiquitin-proteasome pathway. It is active as a single agent and potentiates chemotherapy and radiation in pre-clinical models. Early phase clinical studies have demonstrated tolerability and activity in multiple myeloma, lymphoma, prostate cancer and lung cancer. By its mechanism of inhibiting protein degradation, PS-341 targets a wide-range of pathways that are relevant to tumor progression and therapy resistance, and can directly modulate expression of cyclins, p27(Kip1), p53, NF-kappaB, Bcl-2 and Bax. PS-341 is currently in phase I/II clinical development in lung cancer. This paper will review the pre-clinical and clinical experience with PS-341 as it relates to lung cancer.
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PMID:Integration of the proteasome inhibitor PS-341 (Velcade) into the therapeutic approach to lung cancer. 1286 67


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