Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two new techniques were used to quantify cell death (i.e. DNA fragmentation) in situ: (1) 3' overhangs of the fragmented DNA were end labelled with biotin-7-dATP and TdT (peroxidase/DAB). (2) In situ nick translation (ISNT) was performed with DNA polymerase 1 and biotin-7-dATP, to label single strand segments of DNA (peroxidase/DAB). Both methods were tested to be negative in ischemic and tumor necrosis, and negative for mitotic figures. In 26 centroblastic Non Hodgkin lymphomas (CB) (monomorphous subtype [n = 9], polymorphous subtype [n = 7], secondary [n = 10]), 14 chronic lymphocytic leukemias and two immunocytomas these methods were employed to quantify the rate of cell death. ISNT proved to be more sensitive than end labelling. By ISNT, CB had a mean cell death rate of 250/10HPF (monomorphous type: 429/10HPF, polymorphous type: 222/10HPF, secondary: 111/10HPF). CLL showed a significantly lower rate (28/10HPF). These data suggest, that the low rate of cell turnover in CLL is indicated by a low rate of cell proliferation and a low rate of programmed cell death. In CB the high proliferation rate was accompanied by a high level of cell death. In CB/monomorphous a high turnover state with a very high proliferation and cell death rate was found, whereas CB/polymorphous represents an expansive state as indicated by a lower rate of cell death. CB/secondary showed almost no programmed cell death and therefore was interpreted as a high expansive state neoplasia.
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PMID:[Specific in situ labeling of apoptosis shows different rates of programmed cell death in non-Hodgkin lymphomas]. 788 32

Fusion proteins are recombinant molecules that combine a targeting mechanism to a cytocidal moiety. DAB(389)IL-2 (denileukin diftitox; ONTAK), with a unique mechanism of action, is the first genetically constructed fusion protein to reach the clinic. In this molecule, the interleukin-2 (IL-2) gene is genetically fused to the enzymatically active and translocating domains of diphtheria toxin. DAB(389)IL-2 is internalized into IL-2 receptor-bearing cells by endocytosis. The ADP-ribosyltransferase activity of diphtheria toxin is cleaved in the endosome and is translocated into the cytosol where it inhibits protein synthesis, leading to apoptosis. DAB(389)IL-2 and its predecessor, DAB(486)IL-2, have shown clinical activity in a variety of diseases, including B-cell non-Hodgkin's lymphoma, cutaneous T-cell lymphoma (CTCL), Hodgkin's disease, psoriasis, rheumatoid arthritis, and HIV infection. The highest response rates were observed in CTCL, and this became the focus of clinical trials leading to its subsequent approval by the United States Food and Drug Administration for this disease. The potential applications of DAB(389)IL-2 in lymphomas are reviewed.
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PMID:DAB(389)IL-2 (ONTAK): a novel fusion toxin therapy for lymphoma. 1170 18

DAB(389)IL-2 (denileukin diftitox, ONTAK) is a cytokine-targeted fusion protein that delivers the catalytic domain of diphtheria toxin to lymphoma cells expressing the interleukin-2 receptor (IL-2R). In phase I and phase III studies of DAB(389)IL-2 in patients with cutaneous T-cell lymphoma (CTCL), non-Hodgkin's lymphoma, and Hodgkin's disease in which premedications were limited to diphenhydramine and acetaminophen, acute infusion-related hypersensitivity reactions occurred in 70% of patients and vascular leak syndrome (VLS) in 27%, resulting in discontinuation of therapy in 29% of patients. There was no correlation between the dose or half-life of DAB(389)IL-2 and the occurrence of hypersensitivity events or VLS. To explore whether steroid premedication would improve the tolerability of DAB(389)IL-2, we treated 15 patients with CTCL with either dexamethasone or prednisone prior to each dose of DAB(389)IL-2. The incidence of acute infusion events was significantly decreased, with only three patients experiencing acute infusion events (one grade 4) and only two patients developing clinically apparent VLS. Grade 3 skin rash occurred in two patients and moderately severe asthenia in nine patients. A significantly improved response rate of 60% was noted with the use of steroid premedication compared to prior studies in which steroids were prohibited. We conclude that steroid premedication significantly improves the tolerability of DAB(389)IL-2 without compromising the clinical response.
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PMID:Biological correlates of acute hypersensitivity events with DAB(389)IL-2 (denileukin diftitox, ONTAK) in cutaneous T-cell lymphoma: decreased frequency and severity with steroid premedication. 1170 45

DAB(389)IL-2 (denileukin diftitox, ONTAK) is an interleukin-2 receptor (IL-2R)-specific ligand fusion protein that may potentially be selective for IL-2R-expressing malignancies. The activity of DAB(389)IL-2 in the treatment of cutaneous T-cell lymphoma has established the feasibility of utilizing such a targeted therapeutic in disseminated disease with acceptable toxicity. Data from the phase I trial suggest that the definition of activity in other cancer types, including other non-Hodgkin's lymphomas (NHL), is warranted. Three NHL patients in this study responded, two of whom had follicular lymphomas, with the third having a primary intermediate-grade B-cell NHL that was refractory to chemotherapy and stem cell transplant. This patient has remained in complete remission over 3 years after treatment with DAB(389)IL-2. Patients treated to date have had IL-2R-positive tumors, but this remains a very complex clinical issue. The need for a threshold level of receptor expression, the difficulty in obtaining representative tissue, the lack of an assay that accurately reflects high-affinity receptor, and the potential difficulty of observer variability in evaluating the assays should point us toward examining response rates in cancer patients where IL-2R cannot be detected or is unknown. The potential to target the high-affinity IL-2R supports the development of this agent in transplantation and in autoimmune diseases. Targeting IL-2R-expressing lymphocytes may be an effective strategy for the prevention of graft rejection and to treat or prevent graft-versus-host disease. DAB(389)IL-2 has been examined in clinical trials of psoriasis and rheumatoid arthritis and has shown promising results. The potential utility in other autoimmune disorders is unknown, but diseases such as systemic lupus, scleroderma, and vasculitis also may be effective candidates for such ligand fusion therapy.
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PMID:DAB(389)IL-2 (denileukin diftitox, ONTAK): other potential applications. 1170 62

DAB(389)IL-2 (ONTAK) is a fusion protein consisting of the ADP-ribosyltransferase and membrane translocating domains of native diphtheria toxin and the full-length sequence for interleukin-2 (IL-2) gene. In vitro data demonstrates that DAB(389)IL-2 is cytotoxic to cells expressing the high affinity IL-2 receptor (IL-2R). In Phases I and II clinical trials of patients whose tumor cells express a component of the IL-2R, the response rates were 18% for B-cell non-Hodgkin lymphoma (NHL) and 30% for cutaneous T-cell lymphoma (CTCL). In this study, we examined the effects of arginine butyrate on IL-2R expression and susceptibility of leukemia cells to intoxication by DAB(389)IL-2. We demonstrate that the p75 subunit of the IL-2R (IL-2Rbeta) is upregulated in the presence of low concentrations of arginine butyrate (0.06mM) which had no direct growth inhibitory effect on the cells. To explore mechanisms of this upregulation, we examined the effect of 0.06mM arginine butyrate on relevant transcriptional elements and on histone deacetylase and found activation of cAMP response element (CRE) but not NFAT or NFKB, as well as inhibition of histone deacetylase (HDAC). Our results suggest that the effects of physiologically achievable concentrations of butyrate on IL-2R expression could be exploited to enhance the susceptibility of intermediate and low-affinity IL-2R expressing leukemia cells to DAB(389)IL-2.
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PMID:Arginine butyrate increases the cytotoxicity of DAB(389)IL-2 in leukemia and lymphoma cells by upregulation of IL-2Rbeta gene. 1244 77