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

Solid tumor growth consists of an avascular and a subsequent vascular phase. Several studies have now shown that, as in solid tumors, angiogenesis also plays a critical role in the progression of hematological malignancies. Monoclonal gammopathy of undetermined significance (MGUS) and non-active to active multiple myeloma (MM) progress when plasma cells induce angiogenesis and this in turn promotes progression. The increased bone marrow neovascularization, increased angiogenic and proteolytic potential of plasma cells may explain the frequent occurrence of extramedullary localization in MM. As observed in active MM, enhanced bone marrow neovascularization is apparent in acute untreated lymphoblastic leukemia. In B-cell non-Hodgkin's lymphomas, angiogenesis is significantly enhanced in relation to progression. Angiostatic molecules, such as thalidomide, could also be considered for the clinical management of hematological tumors.
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PMID:Angiogenesis, angiogenic factor expression and hematological malignancies. 1190 88

Gemcitabine is a pyrimidine nucleoside analog with antitumor activity against solid tumor malignancies and leukemia. We evaluated its activity as a single agent and combining it with cisplatin in relapsed-refractory multiple myeloma (MM). Sixteen patients with advanced MM received intravenous gemcitabine 1250 mg/mq (days 1, 8 and 15) as a single agent for a total of 3 monthly courses. The responders received another three courses, and the non-responders received three courses of gemcitabine 1000 mg/mq (days 1, 8 and 15) plus cisplatin 80 mg/mq (day 1). No grade 4 hematological toxicity was seen after gemcitabine treatment, whereas > or = 3 grade neutropenia and thrombocytopenia were seen in 21 and 13% of the gemcitabine-cisplatin infusions, respectively. Non-hematological toxicity was negligible for both the regimens. After three courses of gemcitabine as a single agent, th e response rate was 31% (1 complete response, 1 partial response and 3 minimal response). Eight patients (50%) achieved stable disease and 3 (19%) had disease progression. Ten patients received gemcitabine-cisplatin and were evaluable for the response. Two patients progressed, four maintained stable disease whereas four patients, unresponsive to gemcitabine, obtained a response (3 partial response and 1 minimal response). With a median follow-up of 13 months (range 8-17.5), 7 patients (44%) died, 5 (31%) had disease progression, 1 (6%) relapsed, 1 was still in partial response (+11 months) and 2 (13%) had a stable disease. Median time to treatment failure (TTF) was 8 months (CI95%: 7.6-8.4) and median overall survival (OS) was 16 months (CI95%: 10-22). These results showed that gemcitabine and gemcitabine-cisplatin were feasible regimens and well tolerated in advanced relapsed-refractory MM. The response rates, the TTF and OS were similar to other salvage chemotherapy regimens; nevertheless, the quality of response was modest particularly after gemcitabine alone. Better results might be obtained combining gemcitabine with other chemotherapy compounds or with biologically based therapies.
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PMID:Gemcitabine alone or combined with cisplatin in relapsed or refractory multiple myeloma. 1215 96

The multiple tumor syndrome is an unusual pathologic condition, which consists in association of multiple malignancies in the same patient. Seven cases are discussed: two women, five men, aged 32-70 years. The period between the two neoplasias was 2-23 years (in 6 cases). In one case the two malignancies appeared concomitantly. The hematological malignancies were: multiple myeloma: 2 cases; chronic granulocytic leukemia: 2 cases; chronic lymphatic leukemia: 3 cases. In four cases, the solid tumor followed the hematological malignancy at variable periods (2 and 4 years). In other two cases, the solid tumors preceded the hematological malignancy with 2 years, 23 years respectively. The solid tumors were genital cancers, malignant melanoma, spino-cellular carcinoma, thyroid cancer, hemangiosarcoma. In a single case the second tumor was a hematological malignancy too (NHL-diffuse lymphocytic lymphoma). Possible implications of previous therapy and environmental factors are discussed.
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PMID:The multiple tumor syndrome. Personal experience. 1263 87

PRAME (Preferentially expressed antigen of melanoma), highly expressed in various solid tumor cells and normal testis, was first isolated as a human melanoma antigen recognized by cytotoxic T cells (CTL). This gene was also expressed in some of the hematological malignancies, including acute myelogenous leukemia (AML) and multiple myeloma. We and others have extensively evaluated the PRAME expression in various hematological malignancies and demonstrated high expression of the PRAME gene in subsets of AML, chronic myelogenous leukemia, acute lymphocytic leukemia, lymphoma and multiple myeloma. In addition, we have demonstrated that PRAME was a useful marker for detection of minimal residual disease (MRD) in patients with leukemia, particularly those leukemias in which tumor specific markers are currently unavailable. Since PRAME was first identified as a tumor antigen recognized by T cells, the possibility that PRAME is a leukemia antigen recognized by T cells was evaluated, and it was found that PRAME-positive leukemia cell lines and fresh leukemia cells were susceptible to lysis by the PRAME-specific CTL. Five CTL epitopes associated with either HLA-A*0201 or HLA-A*2402 have recently been identified. It is, therefore, an attractive strategy to apply PRAME specific immunotherapy on patients with PRAME positive leukemia in MRD condition.
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PMID:Preferentially expressed antigen of melanoma (PRAME) in the development of diagnostic and therapeutic methods for hematological malignancies. 1268 12

The ubiquitin-proteasome pathway has a central role in the selective degradation of intracellular proteins. Among the key proteins modulated by the proteasome are those involved in the control of inflammatory processes, cell cycle regulation, and gene expression. Consequently proteasome inhibition is a potential treatment option for cancer and inflammatory conditions. Thus far, proof of principle has been obtained from studies in numerous animal models for a variety of human diseases including cancer, reperfusion injury, and inflammatory conditions such as rheumatoid arthritis, asthma, multiple sclerosis, and psoriasis. Two proteasome inhibitors, each representing a unique chemical class, are currently under clinical evaluation. Velcade (PS-341) is currently being evaluated in multiple phase II clinical trials for several solid tumor indications and has just entered a phase III trial for multiple myeloma. PS-519, representing another class of inhibitors, focuses on the inflammatory events following ischemia and reperfusion injury. Since proteasome inhibitors exhibit anti-inflammatory and antiproliferative effects, diseases characterized by both of these processes simultaneously, as is the case in rheumatoid arthritis or psoriasis, might also represent clinical opportunities for such drugs.
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PMID:Proteasome inhibition: a new anti-inflammatory strategy. 1270 Aug 91

Although intact monoclonal antibodies (MAbs) are well suited as therapeutic reagents, their relatively slow clearance rates render them less useful for imaging applications. Over the last several years, our laboratory has developed a unique targeting approach to solid tumors that utilizes MAbs directed against DNA and its components to bind to degenerating cells and necrotic regions of tumors in a specific manner. Because these MAbs have considerable potential for the early diagnosis of cancer and for the monitoring of cytoreductive therapies, the availability of an effective imaging agent is highly desirable. To accomplish this goal, a series of genetically engineered derivatives of MAb chTNT-3 including the single-chain Fv, diabody, triabody, Fab, and F(ab')(2) were generated and expressed in NS0 myeloma cells using the Glutamine Synthetase Amplification System. Initial in vitro studies demonstrated that each of the antibody derivatives maintained its antigen binding in a stable manner. In vivo analyses after radiolabeling were then performed to evaluate their pharmacokinetic, biodistribution, and tumor-imaging properties in solid tumor-bearing mice. The results of these studies showed that compared with intact parental chTNT-3, which has a half-life of 134.2 h, the smaller derivatives were eliminated more rapidly (4.9-8.1 h). Importantly, the smaller derivatives were found to have significantly higher tumor-to-organ ratios, but lower overall uptake levels compared with parental (125)I-chTNT-3 in two different tumor models. A comparison of the five derivatives showed that the F(ab')(2) reagent consistently gave the best results in imaging and biodistribution studies. Based upon these results, further studies are warranted to demonstrate the potential of this reagent for the diagnosis and monitoring of solid tumors using noninvasive imaging techniques such as immunoscintigraphy and positron emission tomography (PET).
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PMID:Comparison of recombinant derivatives of chimeric TNT-3 antibody for the radioimaging of solid tumors. 1271 84

Recent clinical data shows that arsenic trioxide (As(2)O(3)) causes remission in patients with acute promyelocytic leukemia and multiple myeloma without severe side effects. Laboratory data suggest that As(2)O(3) induces apoptosis or cell differentiation of hematopoietic or solid tumor cells. To date, there has been no study on the effects of As(2)O(3) on glioma cells. In this study, we investigated the in vitro effect of As(2)O(3) on cell growth inhibition and cell death mechanisms in human glioma cells. As(2)O(3) significantly inhibited the proliferation of all six of the glioma cell lines (U373, U87, U251, GB1, A-172, and T98G) tested in this study in a dose-dependent manner. The IC(50) of As(2)O(3) for all of the tumor cell lines was <2 micro M. Previous studies have shown that this is a clinically safe concentration. Treatment with 2 micro M As(2)O(3) induced G(2)/M arrest in all of the glioma cell lines. Autophagy (programmed cell death type II), but not apoptosis (programmed cell death type I), was detected by electron microscopy in U-373-MG cells treated with 2 micro M As(2)O(3). Caspase inhibitors did not halt As(2)O(3)-induced cell death. Furthermore, combination of As(2)O(3) with bafilomycin A1 autophagy inhibitor enhanced the antitumor effect of As(2)O(3) through induction of apoptosis. These findings suggest that As(2)O(3) at a clinically safe concentration may be an effective chemotherapeutic agent for malignant gliomas.
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PMID:Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. 1272 26

Given its role in cellular metabolism, the proteasome could prove to be a critical target that can be exploited in treating cancer. In preclinical studies, several mechanisms for bortezomib's activity in multiple myeloma cells have been identified (e.g., NF-kappaB inhibition); antitumor activity with bortezomib has been seen in myeloma patients, thereby supporting the validity of the preclinical work. Similar mechanisms may be in play in solid tumors, and cell culture and xenograft data suggest bortezomib may be active in a wide range of tumor types. One promising possibility is the use of bortezomib for the treatment of chemoresistant tumors. Chemoresistance can be caused by a number of cellular factors; NF-kappaB is a prominent instigator of chemoresistance, and proteasome inhibition was an effective means of preventing NF-kappaB activation in myeloma and several solid tumor laboratory studies. However, the inhibition of NF-kappaB may not be the only mechanism for antitumor activity. This review explores the use of proteasome inhibitors to subvert intrinsic resistance mechanisms, disrupt inducible chemoresistance, or augment the mechanisms of action of standard chemotherapeutics. Thus, in addition to providing another target for anticancer treatment, proteasome inhibition may also provide a means to treat refractory tumors.
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PMID:Rationale for the treatment of solid tumors with the proteasome inhibitor bortezomib. 1273 40

The human chemokine liver-expression chemokine (LEC) was originally found in an expressed sequence tag library, and later the LEC gene was located to chromosome 17q in the ML chemokine gene cluster. LEC has been shown to chemoattract monocytes, lymphocytes, and polymorphonuclear leukocytes (PMNs) by its binding to CCR1 and CCR8 chemokine receptors. Because of its potency as a chemoattractant for immune cells, LEC was used to genetically engineer a fusion protein with chTNT-3, a monoclonal antibody previously shown to target tumors by binding to DNA exposed in necrotic zones. Because the N-terminus of chemokines is important for their activity, the C-terminus of LEC was genetically linked to the chTNT-3 heavy chain variable region and, along with the light chain gene, cotransfected into NSO murine myeloma cells using the glutamine synthetase gene amplification system. The expressed LEC/chTNT-3 fusion protein was purified by tandem protein-A affinity and ion-exchange chromatography and chemotaxis and binding assays confirmed the bioactivity of the purified fusion protein. Pharmacokinetic and biodistribution studies in vivo showed that LEC/chTNT-3 had a biologic half-life of 3 hours and had good uptake in tumor (2.4% injected dose/g), which remained stable at 12 and 24 hours postinjection. Immunotherapy studies performed in three solid tumor models of the BALB/c mouse showed between 37% and 55% tumor reduction at 19 days post-implantation. Immunohistochemical studies using tumor sections obtained at different time points after the administration of control chTNT-3 and LEC/chTNT-3 showed heavy infiltration of CD4+ and CD8+ T cells, PMNs, B cells, and CD11c+CD11b+ dendritic cells in the LEC/chTNT-3 treated groups. The results of these studies demonstrate that this novel fusion protein has potent antitumor activity that is associated with the infiltration of different subpopulations of immune cells. The targeting of LEC to necrotic areas of tumors where the release of tumor antigens is prevalent may be a new approach for the immunotherapy of solid tumors.
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PMID:LEC/chTNT-3 fusion protein for the immunotherapy of experimental solid tumors. 1284 94

It is now well established that solid tumors depend on angiogenesis. Promoters and inhibitors of angiogenesis are in balance and antiangiogenic strategies aim at repressing the angiogenic process, thus retarding solid tumor progression. Recent data suggest the importance of angiogenesis in hematologic malignancies and several studies reveal an increased angiogenesis in active multiple myeloma. Angiogenesis seems to be a prominent feature of MM progression, and seems to be correlated with the prognosis and the resistance of MM to chemotherapy. Numerous cell populations and cytokines are involved in angiogenesis in multiple myeloma and antiangiogenic therapy with thalidomide is effective in patients with refractory or relapsed disease. The combination of thalidomide and of other immunomodulatory agents with other therapeutic regimens could lead to more effective management of patients with multiple myeloma.
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PMID:Bone marrow angiogenesis and progression in multiple myeloma: clinical significance and therapeutic approach. 1285 91


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