Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
 11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The incidence of non-Hodgkin's lymphoma has been increasing at a rate of 4% per year since 1950; more than 62,000 cases will be diagnosed in the United States in 2000. Diffuse large cell lymphoma (DLCL) is the prototype of curable non-Hodgkin's lymphoma. Empirically designed chemotherapy regimens did not increase the cure rate of 30-40% achieved by the original four-drug regimen introduced in the 1970s [cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)]. We studied the antitumor effects of the CHOP regimen alone or in combination with a unique protein kinase C activator, bryostatin 1, on a xenograft model for resistant DLCL in mice with severe combined immune deficiency (WSU-DLCL2-SCID). In this model, the efficacy of bryostatin 1 given at 75 microg/kg, i.p., alone for 1 or 2 days [B(1x) and B(2x)]was compared with the efficacy of CHOP alone, bryostatin 1 + CHOP (B+CHOP) given concurrently, bryostatin 1 for 1 day followed by CHOP on day 2 [B(1x)-CHOP], and bryostatin 1 for 2 days followed by CHOP on day 3 [B(2x)-CHOP]. CHOP doses were as follows: (a) cyclophosphamide, 40 mg/kg, i.v.; (b) doxorubicin, 3.3 mg/kg, i.v.; (c) vincristine, 0.5 mg/kg, i.v.; and (d) prednisone, 0.2 mg/kg, every day for 5 days, p.o. Tumor growth inhibition (T/C), tumor growth delay (T-C), and log10 kill for B(1x), B(2x), CHOP, B+CHOP, B(1x)-CHOP and B(2x)-CHOP were 49%, 39%, 25.8%, 15.1%, 14.6%, and 12%; 6, 7, 16, 25, 12, and 15 days; and 0.6, 0.5, 2.2, 3.6, 1.7, and 2.0, respectively. To begin elucidating the mechanism whereby bryostatin 1 potentiated the effects of CHOP in the mouse model; we studied the effect of bryostatin 1 on Bax, Bcl-2, and poly(ADP-ribose) polymerase proteins in vitro and in vivo. Bax protein increased in a time-dependent manner without any measurable change in Bcl-2 expression. However, significant cleavage of the preapoptotic marker poly(ADP-ribose) polymerase was not recorded, and the percentage of apoptotic cells detected by flow cytometry increased only slightly (approximately 8%) after 96 h of bryostatin 1 exposure. The in vitro and in vivo results emphasize the superiority of combining bryostatin 1 with the CHOP regimen against the WSU-DLCL2 model. One possible mechanism may be the modulatory effects of bryostatin 1 on the Bax:Bcl-2 family of apoptosis-regulatory proteins. The use of this combination should be further explored clinically in the treatment of lymphoma.
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PMID:The addition of bryostatin 1 to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy improves response in a CHOP-resistant human diffuse large cell lymphoma xenograft model. 1115 56

The anti-CD20 monoclonal antibody rituximab (Rituxan, IDEC-C2B8) has shown promising results in the clinical treatment of a subset of patients with low grade or follicular non-Hodgkin's lymphoma (NHL). However, chemotherapy- and rituximab-refractory NHL patients may benefit from a regimen in which rituximab acts as a sensitizing agent. This study examined the apoptotic signaling mediated by rituximab on rituximab- and paclitaxel-resistant CD20(+) NHL B cell lines (Ramos, Raji, Daudi, and 2F7). Treatment with either rituximab (20 micro g/ml) or paclitaxel (0.1-1000 nM) inhibited viable cell recovery of NHL lines. Neither rituximab nor paclitaxel induced significant apoptosis, although the combination treatment resulted in synergy in apoptosis. Rituximab selectively down-regulated Bcl-xL and induced apoptosis protease activating factor 1 (Apaf-1) expressions in Ramos cells. Paclitaxel down-regulated the expression of Bcl-xL and inhibitor of apoptosis proteins (c-IAP-1) and up-regulated the expression of Bad and Apaf-1. The combination treatment resulted in the formation of truncated Bid, cytosolic accumulation of cytochrome c and second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low PI, activation of caspase-9, caspase-7, caspase-3, and cleavage of poly(ADP-ribose) polymerase. The findings identify two potential novel intracellular targets of rituximab-mediated signaling in Ramos NHL cells (i.e., Bcl-xL and Apaf-1). Further, the findings show that both rituximab and paclitaxel selectively modify the expression pattern of proteins involved in the apoptosis signal transduction pathway and, through functional complementation, the combination results in synergy in apoptosis. The potential therapeutic significance of these findings is discussed.
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PMID:Rituximab (anti-CD20) selectively modifies Bcl-xL and apoptosis protease activating factor-1 (Apaf-1) expression and sensitizes human non-Hodgkin's lymphoma B cell lines to paclitaxel-induced apoptosis. 1461 92

Follicular lymphoma (FL) is the second most common non-Hodgkin's lymphoma and generally is incurable. Reliable prognostic markers to differentiate patients who progress rapidly from those who survive for years with indolent disease have not been established. Most cases overexpress Bcl-2, but the pathogenesis of FL remains incompletely understood. To determine whether a proteomic approach could help overcome these obstacles, we procured lymphoid follicles from 20 cases of FL and 15 cases of benign follicular hyperplasia (FH) using laser capture microdissection. Lysates were spotted on reverse-phase protein microarrays and probed with 21 antibodies to proteins in the intrinsic apoptotic pathway, including those specific for posttranslational modifications such as phosphorylation. A panel of three antibodies [phospho-Akt(Ser473), Bcl-2, and cleaved poly(ADP-ribose) polymerase] segregated most cases of FL from FH. Phospho-Akt(Ser473) and Bcl-2 were significantly increased in FL (P = 0.001 and P < 0.0001, respectively). Additionally, the Bcl-2/Bak ratio completely segregated FL from FH. High ratios of Bcl-2/Bak and Bcl-2/Bax were associated with early death from disease with differences in median survival times of 7.3 years (P = 0.0085) and 3.8 years (P = 0.018), respectively. Using protein microarrays, we identified candidate proteins that may signify clinically relevant molecular events in FL. This approach showed significant changes at the posttranslational level, including Akt phosphorylation, and suggested new prognostic markers, including the Bcl-2/Bak and Bcl-2/Bax ratios. Proteomic end points should be incorporated in larger, multicenter trials to validate the clinical utility of these protein microarray findings.
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PMID:Proteomic analysis of apoptotic pathways reveals prognostic factors in follicular lymphoma. 1611 25

Mantle cell lymphoma (MCL) is a type of aggressive B-cell non-Hodgkin's lymphoma characterized by frequent resistance to conventional chemotherapy. In this study we provided evidence that fenofibrate, which is widely known as an agonist for peroxisome proliferator-activated receptor-alpha (PPARalpha), can induce effective apoptosis in treating MCL cells. Addition of fenofibrate to MCL cell lines significantly decreased the number of viable cells by 50% at approximately 20 microM at 72 h. This decrease in cell growth was due to apoptosis, as evidenced by the cleavage of caspase 3 and poly(ADP-ribose) polymerase. The fenofibrate-mediated effects were not significantly affected by GW6471, a specific PPARalpha antagonist. Using an apoptosis pathway-specific oligonucleotide array, we found that fenofibrate significantly downregulated several pro-survival genes, including tumor necrosis factor-alpha (TNFalpha). Importantly, addition of recombinant TNF-alpha conferred partial protection against fenofibrate-induced apoptosis. Fenofibrate also decreased the nuclear translocation of nuclear factor (NF)-kappaB-p65 and significantly inhibited the DNA binding of NF-kappaB in a dose-dependent manner. To conclude, fenofibrate shows efficacy against MCL, and the mechanism can be attributed to its inhibitory effects on the TNF-alpha/NF-kappaB signaling axis. In view of the documented safety of fenofibrate in humans, it may provide a valuable therapeutic option for MCL patients.
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PMID:Fenofibrate induces effective apoptosis in mantle cell lymphoma by inhibiting the TNFalpha/NF-kappaB signaling axis. 2052 Jun 42