Radioimmunotherapy for Non-Hodgkin's Lymphoma

Rao, Arati V.; Akabani, Gamal; Rizzieri, David A.

doi:10.3121/cmr.3.3.157

Cited by 46 publications

(26 citation statements)

References 33 publications

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“…FL is derived from germinal center follicle lymphoid cells. 1 FL is characterized by an indolent initial course, a favorable response to first-line therapy, and also recurrences followed by a refractory phase eventually complicated by histologic transformation. Although the prognosis of FL is variable, most patients with aggressive forms of FL (high FLIPI score) ultimately die from their disease and median survival is 5 to 8 years.…”

Section: Introductionmentioning

confidence: 99%

Syk-dependent mTOR activation in follicular lymphoma cells

Leseux¹,

Hamdi²,

Saati³

et al. 2006

Blood

158

126

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The mammalian target of rapamycin (mTOR) is emerging as a promising target for antitumor therapy. However, the mechanism that contributes to its regulation in B lymphomas remains unknown. This study shows that in follicular lymphoma (FL) cells, mTOR is active because the cells displayed rapamycinsensitive phosphorylation of p70S6 kinase and 4E-BP1. Moreover, immunohistochemistry applied on lymph node tissue sections obtained from patients with FL revealed that, in most cases, p70S6 kinase was highly phosphorylated compared to normal tonsillar tissue. In FL cells, mTOR was under control of both phospholipase D (PLD) and phosphatidylinositol 3-kinase (PI3K). Moreover, we demonstrated that Syk plays a central role in mTOR activation because we found that both expression and activity are elevated compared to normal or chronic lymphocytic leukemia B cells. We also provide evidence that Syk operates through PLD-and PI3K-independent pathways. IntroductionNon-Hodgkin lymphoma (NHL) is the most commonly occurring malignant blood disease. Eighty-five percent of NHL belongs to the B lineage, and the most commonly occurring variety includes the diffuse large B-cell lymphoma (DLBCL). Follicular lymphoma (FL) is the second most common type of B-NHL and includes 35% to 40% of all adult lymphomas. FL is derived from germinal center follicle lymphoid cells. 1 FL is characterized by an indolent initial course, a favorable response to first-line therapy, and also recurrences followed by a refractory phase eventually complicated by histologic transformation. Although the prognosis of FL is variable, most patients with aggressive forms of FL (high FLIPI score) ultimately die from their disease and median survival is 5 to 8 years. 2 Despite the significant progress that has been made, mostly due to the introduction of rituximab combined with chemotherapy, further efforts are needed to identify new molecular targets in FL.In the vast majority of cases, FL cells display high expression of Bcl-2 as a consequence of t(14;18). 3,4 Based on the potent antiapoptotic properties of this protein, it has been proposed that not only is Bcl-2 a major, if not unique, causal factor for FL, but also that Bcl-2 overexpression represents a major obstacle for the eradication of tumor cells by chemotherapy, including that used in preparative regimens before stem cell transplantation. 5 However, approximately 10% to 15% of patients with FL are negative for Bcl-2. 6 Interestingly, clinical presentation, histopathologic findings, response to therapy, and clinical outcome in Bcl-2 ϩ patients are indistinguishable from those in Bcl-2 Ϫ FL patients. This observation suggests that, independently from Bcl-2, FL cells display alternative antiapoptotic pathways that ultimately interfere with the response to therapy. The recent identification of constitutively phosphorylated forms of AKT in FL histologic specimens supports this hypothesis. 7 The mammalian target of rapamycin, mTOR, is a 289-kDa evolutionarily conserved serine/threonine kinase that interacts and p...

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Section: Introductionmentioning

confidence: 99%

Syk-dependent mTOR activation in follicular lymphoma cells

Leseux¹,

Hamdi²,

Saati³

et al. 2006

Blood

158

126

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“…Radioimmunotherapy might prove to be useful in patients with molecular, but probably not hematological, relapses. While the prospects for elderly are less bright, bortezomib, thalidomide and, presumably, lenalidomide containing combinations currently seem to be the best bet (4,5).…”

Section: MCLmentioning

confidence: 99%

“…Radioimmunotherapeutic agents are monoclonal antibodies conjugated with radioactive isotopes (4). Their antitumor activity is thought to result from the combination of immunologic mechanisms triggered by antibody binding to the cell surface and effects of radiation that are not limited to the bound cells but also affect neighboring "bystander" cells.…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

E13 Non-Hodgkin lymphoma: how to proceed

Aurer

2007

Leukemia Research

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“…A very relevant field is radioimmunotherapy (RIT) using antibody-based labeled drugs. It combines the synergistic effects of radio-and immunotherapy and is an important tool in the treatment of hematologic malignancies such as Non-Hodgkins lymphoma [14,15]. Like standard chemotherapy, RIT has been optimized and standardized as a therapy for lymphomas, although not for solid tumors due to its low penetration rate and lower radiosensitivity.…”

Section: Radiotherapymentioning

confidence: 99%

Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

et al. 2014

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Owing to their large size proteinaceous drugs offer higher operative information content compared to the small molecules that correspond to the traditional understanding of druglikeness. As a consequence these drugs allow developing patient-specific therapies that provide the means to go beyond the possibilities of current drug therapy. However, the efficacy of these strategies, in particular "personalized medicine", depends on precise information about individual target expression rates. Molecular imaging combines non-invasive imaging methods with tools of molecular and cellular biology and thus bridges current knowledge to the clinical use. Moreover, nuclear medicine techniques provide therapeutic applications with tracers that behave like the diagnostic tracer. The advantages of radioiodination, still the most versatile radiolabeling strategy, and other labeled compounds comprising covalently attached radioisotopes are compared to the use of chelator-protein conjugates that are complexed with metallic radioisotopes. With the techniques using radioactive isotopes as a reporting unit or even the therapeutic principle, care has to be taken to avoid cleavage of the radionuclide from the protein it is linked to. The tracers used in molecular imaging require labeling techniques that provide site specific conjugation and metabolic stability. Appropriate choice of the radionuclide allows tailoring the properties of the labeled protein to the application required. Until the event of positron emission tomography the spectrum of nuclides used to visualize cellular and biochemical processes was largely restricted to iodine isotopes and 99m-technetium. Today, several nuclides such as 18-fluorine, 68-gallium and 86-yttrium have fundamentally extended the possibilities of tracer design and in turn caused the need for the development of chemical methods for their conjugation.

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Radioimmunotherapy for Non-Hodgkin's Lymphoma

Cited by 46 publications

References 33 publications

Syk-dependent mTOR activation in follicular lymphoma cells

Syk-dependent mTOR activation in follicular lymphoma cells

E13 Non-Hodgkin lymphoma: how to proceed

Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

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