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)

DAB486IL-2 is a novel fusion toxin in which the ADP-ribosyltransferase and membrane-translocating domains of diphtheria toxin have been combined with the interleukin-2 (IL-2) gene, creating a recombinant protein capable of selectively intoxicating cells bearing the high-affinity IL-2 receptor. Clinical activity has been documented in Hodgkin disease and the non-Hodgkin lymphomas; toxicities have been minimal and include mild hepatic transaminitis, proteinuria, and hypersensitivity reactions. In this report, a patient with tumor-stage cutaneous T-cell lymphoma developed clinical adrenal failure with bilateral adrenal hemorrhage and necrosis 7 weeks after completing a 5-day course of treatment with DAB486IL-2. The relationship of fusion toxin therapy to the development of this unusual toxicity is discussed.
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PMID:Bilateral adrenal hemorrhage and adrenal insufficiency in a patient with lymphomatous adrenal infiltration following administration of a fusion toxin (DAB486 interleukin-2). 783 23

We have previously shown that malignant B cells from non-Hodgkin's lymphomas (NHL) are resistant to Fas-mediated apoptosis. To determine the mechanisms underlying this resistance, we analysed by Western blotting the expression of several apoptotic regulators, caspase 3, caspase 8, FADD and poly(ADP-ribose) polymerase (PARP) in fresh lymphoma cells, isolated from 16 B-NHL biopsy samples of different histological subtypes, and displaying variable levels of Fas expression. The profiles of expression of these apoptotic regulators were monitored in cell lysates at different times following Fas with or without CD40 stimulation. Expression of FADD and of the uncleaved forms of PARP, caspase 3 and caspase 8 were detected in all untreated NHL samples. Low levels of PARP cleavage were noted in three untreated samples. Fas stimulation alone induced neither significant apoptosis nor significant changes in the expression profiles of FADD, caspases 3 and 8 and PARP in the 16 samples, except for variations in FADD and caspase 8 expression levels in a minority of samples. Fas/CD40 co-stimulation induced apoptosis and cleavage of caspase 3, caspase 8 and PARP in the five NHLs tested; expression of FADD was not modified. Our results showed (1) that induction of apoptosis in B-NHLs by Fas/CD40 co-stimulation used the same caspase executioner machinery as the normal Fas pathway, and (2) that NHL cells which resisted Fas-mediated apoptosis displayed no defect in either expression or functionality of caspases 3 and 8, nor in FADD expression. The dysfunction underlying NHL resistance to apoptosis must therefore lie upstream of caspase 8, or could alternatively be influenced by anti-apoptotic regulators of the Bcl-2 family.
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PMID:FADD expression and caspase activation in B-cell lymphomas resistant to Fas-mediated apoptosis. 1046 53

One of the major characteristics of anaplastic large cell lymphomas (ALCL) is the expression of the Ki-1/CD30 antigen. While the receptor mediates NF-kappaB-activation in Hodgkin's lymphomas, some data suggest the CD30-mediated apoptosis of other CD30-expressing cells. We were able to demonstrate that activation of CD30 leads to different effects regarding cell proliferation of the ALCL-derived cell lines Karpas 299 and JB6. Western and Northern blotting analysis revealed that CD30-induced growth inhibition of Karpas 299 cells correlated with a strong upregulation of the cell cycle inhibitor p21(CIP1/WAF1). We found a non activating point mutation at codon 273 in exon 8 of the p53 gene in Karpas 299 cells which indicates an p53-independent mechanism for induced p21 expression. Abundant p21 protein expression resulted in hypophosphorylation of the retinoblastoma protein (Rb) and inhibition of the proliferating cell nuclear antigen (PCNA). CD30-stimulated cells showed no indications of apoptotic cell death, like genomic DNA fragmentation or cleavage of the caspase-3 target protein poly (ADP-ribose) polymerase (PARP). Our results indicate that CD30 is able to mediate an p21-associated cell cycle arrest in ALCL with possible implications for prognosis and clinical treatment.
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PMID:CD30-mediated cell cycle arrest associated with induced expression of p21(CIP1/WAF1) in the anaplastic large cell lymphoma cell line Karpas 299. 1131 91

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

Rituximab is a chimeric monoclonal antibody directed at CD20 with significant activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). A variety of pathways of tumor cytotoxicity different from cytotoxic chemotherapy have been proposed for this therapeutic antibody including antibody-dependent cellular cytotoxicity and complement-mediated cell lysis. This report describes that a proportion of patients with CLL receiving rituximab treatment have in vivo activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP) cleavage in blood leukemia cells immediately following infusion of rituximab. This suggests that apoptosis using a pathway similar to fludarabine and other chemotherapeutic agents is intricately involved in the blood elimination of tumor cells after rituximab treatment. Patients having caspase-3 activation and PARP cleavage in vivo had a significantly lower blood leukemia cell count after treatment as compared to those without caspase activation. Significant down-modulation of the antiapoptotic proteins XIAP and Mcl-1 was also noted, possibly explaining in part how rituximab sensitizes CLL cells to the cytotoxic effect of chemotherapy in vivo. These findings suggest that the therapeutic benefit of antibody-based therapy in vivo for patients with CLL depends in part on induction of apoptosis and provides another area of focus for studying mechanisms of antibody-resistance in neoplastic cells.
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PMID:The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction. 1180 10

In vitro studies suggest that resistance to the apoptosis-inducing effect of chemotherapy might explain poor responses to therapy in fatal instances of Hodgkin disease (HD). Execution of apoptosis depends on proper functioning of effector caspases, in particular caspase 3, which is activated on the induction of apoptosis through either the stress-induced pathway or the death receptor-mediated pathway. Thus, high levels of caspase 3 activation should reflect proper functioning of one or both identified apoptosis pathways, resulting in chemotherapy-sensitive neoplastic cells and thus a favorable clinical response to chemotherapy. We tested this hypothesis by quantifying active caspase 3-positive tumor cells in primary biopsy specimens of HD and compared these numbers to clinical outcomes. Using an immunohistochemical assay, activation of caspase 3 was detected in 0% to 13% of neoplastic cells. High numbers of active caspase 3-positive tumor cells (5% or more) correlated with excellent clinical prognosis; 0 of 22 patients with 5% or more active caspase 3-positive cells died compared with 11 of 41 patients with less than 5% positive cells (P =.007). Proper functioning of active caspase 3 was demonstrated by the detection of one of its cleaved substrates, PARP-1/p89, in similar percentages of neoplastic cells. High levels of active caspase 3-positive neoplastic cells were associated with the expression of p53 and its downstream effector molecule p21, suggesting proper functioning of the stress-induced apoptosis pathway. In conclusion, high numbers of active caspase 3-positive neoplastic cells predict a highly favorable clinical outcome in HD patients, supporting the notion that an (at least partially) intact apoptosis cascade is essential for the cell killing effect of chemotherapy.
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PMID:High numbers of active caspase 3-positive Reed-Sternberg cells in pretreatment biopsy specimens of patients with Hodgkin disease predict favorable clinical outcome. 1207 5

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

Effector-memory T cells expressing Fas (Apo-1/CD95) are switched to an apoptotic program by cross-linking with Fas-ligand (FasL). Consequently, tumors that express FasL can induce apoptosis of infiltrating Fas-positive T lymphocytes and subdue any antitumor host immune response. Since Epstein-Barr virus (EBV)-associated tumors such as Hodgkin lymphoma (HL) and nasopharyngeal carcinoma (NPC) express FasL, we determined whether EBV-specific cytotoxic T lymphocytes (EBV-CTLs) could be modified to resist this evasion strategy. We show that long-term down-modulation of Fas can be achieved in EBV-CTLs by transduction with small interfering RNA (siRNA) encoded in a retrovirus. Modified T cells resisted Fas/FasL-mediated apoptosis compared with control cells and showed minimal cleavage of the caspase3 substrate poly(ADP-ribose) polymerase (PARP) protein after Fas engagement. Prolonged Fas stimulation selected a uniformly Fas(low) and FasL resistant population. Removal of responsiveness to this single death signal had no other discernible effects on EBV-CTLs. In particular, it did not lead to their autonomous growth since the modified EBV-CTLs remained polyclonal, and their survival and proliferation retained dependence on antigen-specific stimulation and on the presence of other physiologic growth signals. EBV-CTLs with knocked down Fas should have a selective functional and survival advantage over unmodified EBV-CTLs in the presence of tumors expressing FasL and may be of value for adoptive cellular therapy.
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PMID:Human cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis. 1571 95

The Hodgkin cells and Reed-Sternberg cells (HRS) of classical Hodgkin lymphoma (CHL) are derived from germinal center B cells. The pathogenesis of CHL is unclear but constitutive activation of NFkappaB may contribute. Proteasome inhibition aimed at inhibiting NFkappaB has been shown to result in apoptosis in HRS cells. Here we investigated the effects of bortezomib, a proteasome inhibitor, in HRS cells with a combination of functional assays and gene expression profiling (GEP). Exposure of KMH2 and L428 cells to bortezomib resulted in inhibition of proliferation and induction of apoptosis. Gene expression analysis of KMH2 cells by oligonucleotide cDNA microarrays showed that a limited set of genes were differentially expressed involving several key cellular pathways including cell cycle and apoptosis. Among them, the caspase 8 inhibitor cFLIP was down-regulated and confirmed by Q-PCR. Given the evidence that cFLIP in HRS cells contribute to cells' insensitive to death receptor-mediated apoptosis, we combined bortezomib and TRAIL. This combination caused further down-regulation of cFLIP protein and increased apoptosis in CHL cells demonstrated by PARP p85 immunohistochemistry and immunoblotting. Such apoptotic effects were inhibited by caspase inhibitor z-VAD-FMK, confirming the pro-apoptotic effects of bortezomib and TRAIL are caspase-dependent. Bortezomib has no detectable effect on expression of TRAIL receptor DR4/DR5 in these two cell lines. Tissue microarray analysis of primary Hodgkin lymphomas displayed that 82% cases (95/116) expressed cFLIP in Reed-Sternberg cells. The discovery of apoptotic pathways that can be manipulated by proteasome inhibition provides rationale for the combination of bortezomib and agents such as TRAIL in CHL treatment.
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PMID:Bortezomib induces caspase-dependent apoptosis in Hodgkin lymphoma cell lines and is associated with reduced c-FLIP expression: a gene expression profiling study with implications for potential combination therapies. 1765 39

The Hodgkin-Reed-Sternberg (HRS) malignant cells in Hodgkin's lymphoma (HL) originate from germinal center B lymphocytes that did not undergo apoptosis. Protein Kinase C (PKC), a family of serine/threonine kinases, plays a crucial role in signal transduction modulating cell growth, differentiation and apoptosis. Here, we report the expression of PKC isoforms in two HL-derived cell lines, L428 and KMH2 and their correlation with drug resistance to CPT and doxorubicin. Among the PKC isoforms examined, only PKCeta and PKCbetaII were preferentially expressed in the drug resistant L428 cells. We have shown correlation between the response to apoptosis of L428 and KMH2 cells and PKCeta expression in these cell lines. In order to directly demonstrate a role for PKCeta in apoptosis, its expression was knocked-down by siRNA in the resistant L428 cells. Downregulation of PKCeta rendered L428 cells more sensitive to doxorubicin and CPT. Furthermore, PKCeta knocked-down cells showed increased PARP-1 cleavage, cytochrome c release and caspase 7 activation. It appears that PKCeta functions as an anti-apoptotic protein in HL-derived cell lines, and as we show here that it is also expressed in HRS of HL biopsies, it may have therapeutic relevance in HL. Thus, PKCeta could provide a new target aimed to reduce resistance to anti-cancer treatments of HL and other cancer patients.
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PMID:PKCeta expression contributes to the resistance of Hodgkin's lymphoma cell lines to apoptosis. 1778 31


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