RESUMO
Huntingtin interacting protein 1 (HIP1) is an inositol lipid, clathrin, and actin binding protein that is overexpressed in a variety of epithelial malignancies. Here, we report for the first time that HIP1 is elevated in non-Hodgkin's and Hodgkin's lymphomas and that patients with lymphoid malignancies frequently had anti-HIP1 antibodies in their serum. Moreover, p53-deficient mice with B-cell lymphomas were 13 times more likely to have anti-HIP1 antibodies in their serum than control mice. Furthermore, transgenic overexpression of HIP1 was associated with the development of lymphoid neoplasms. The HIP1 protein was induced by activation of the nuclear factor-kappaB pathway, which is frequently activated in lymphoid malignancies. These data identify HIP1 as a new marker of lymphoid malignancies that contributes to the transformation of lymphoid cells in vivo.
Assuntos
Proteínas de Ligação a DNA/biossíntese , Linfoma/metabolismo , Animais , Anticorpos Antineoplásicos/sangue , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Modelos Animais de Doenças , Doença de Hodgkin/genética , Doença de Hodgkin/metabolismo , Humanos , Linfoma/genética , Linfoma/patologia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/metabolismo , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genéticaRESUMO
Non-Hodgkin's lymphoma (NHL) is an increasingly common disease that, despite advances in antibody-targeted therapy, still requires novel therapeutic approaches. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) activates a major nonmitochondrial pathway for tumor cell killing through binding to a receptor family, some activating and some decoy. Agonistic antibodies to the receptors TRAIL-R1 and TRAIL-R2 can mimic many of the effects of TRAIL. We are investigating the effects of such agonistic antibodies, mapatumumab directed at TRAIL-R1 and lexatumumab directed at TRAIL-R2, on NHL cell lines. These antibodies induce apoptosis through caspase-8 but also activate BID to involve the mitochondrial pathway and activate caspase-9. In addition, we find signaling through both the nuclear factor-kappaB and c-Jun NH2-terminal kinase pathways. Because the proteasome inhibitor bortezomib also affects these pathways, we have investigated the combination of TRAIL-R antibodies and bortezomib and show enhanced apoptosis and signaling as well as enhanced killing of NHL cells in a severe combined immunodeficient mouse/human NHL cell line xenograft system. The combination of bortezomib and TRAIL signaling warrants further investigation as a therapeutic regimen. Understanding the multiple intracellular pathways of TRAIL activation may lead to rationally designed therapeutic trials.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Ácidos Borônicos/uso terapêutico , Linfoma não Hodgkin/patologia , Pirazinas/uso terapêutico , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/imunologia , Animais , Anticorpos Monoclonais Humanizados , Western Blotting , Bortezomib , Caspase 9/metabolismo , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma não Hodgkin/metabolismo , Camundongos , Camundongos SCID , Fosforilação/efeitos dos fármacos , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
BACKGROUND: Despite exciting new targeted therapeutics against non-Hodgkin's lymphoma (NHL), chemotherapy remains a cornerstone of therapy. While purine nucleoside analogs have significant activity in low grade NHL, the pyrimidine nucleoside analog gemcitabine has been less extensively studied, but has important activity. Use of the anti-CD20 monoclonal antibody rituximab in combination with chemotherapy for B-NHL is becoming prevalent in clinical practice, but has not been extensively studied in pre-clinical models. METHODS: We have tested the activity of gemcitabine +/- rituximab in vitro and in scid/human NHL xenograft models. We used two t(14;18)+, CD20+ follicular B cell NHL cell lines, DoHH2 a transformed NHL line and WSU-FSCCL isolated from pleural fluid of a patient with indolent NHL. RESULTS: Gemcitabine is cytotoxic to DoHH2 and WSU-FSCCL cells in vitro, and the IC50 is 2-3 fold lower in the presence of rituximab. Apoptosis is also enhanced in the presence of rituximab. Clearance of NHL cells from ascites in scid mice is prolonged by the combination, as compared with either agent alone. Most importantly, survival of scid mice bearing human NHL cells is significantly prolonged by the combination of gemcitabine + rituximab. CONCLUSION: Based on our pre-clinical data showing prolonged survival of mice bearing human lymphoma cell line xenografts after treatment with gemcitabine + anti-CD20 antibody, this combination, expected to have non-overlapping toxicity profiles, should be explored in clinical trials.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antígenos CD20/imunologia , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Linfoma não Hodgkin/terapia , Animais , Anticorpos Monoclonais Murinos , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Corantes/farmacologia , Terapia Combinada , Desoxicitidina/administração & dosagem , Técnicas In Vitro , Concentração Inibidora 50 , Linfoma não Hodgkin/imunologia , Camundongos , Camundongos SCID , Transplante de Neoplasias , Poli(ADP-Ribose) Polimerases/metabolismo , Rituximab , Sais de Tetrazólio/farmacologia , Tiazóis/farmacologia , Translocação Genética , GencitabinaRESUMO
PURPOSE: We conducted a Phase II trial of bryostatin-1, an inhibitor of protein kinase C, in advanced renal cell carcinoma to measure toxicity, response rate, time to progression, and induction of cytokines. EXPERIMENTAL DESIGN: A total of 32 patients (26 male and 6 female) received bryostatin-1 at 35-40 microg/m(2) i.v. over 1 h on days 1, 8, and 15 of each 4-week cycle. Plasma interleukin-6, tumor necrosis factor-alpha, and C-reactive protein levels were assayed pretreatment, 1 and 23 h after completion of bryostatin-1 infusion at weeks 1 and 5. RESULTS: Cycles (102) of bryostatin-1 were given (median 2, range 1-8). The most common grade 1 or 2 toxicities were myalgias (46.8%), fatigue (59.3%), and dyspnea (18.8%). Grade 3-4 toxicity included myalgias (40.6%), ataxia (9.3%), and dyspnea (15.6%). Four (12%) patients experienced cardiac events while on study (cardiac arrhythmias and congestive heart failure occurred in 2 patients, and 2 patients had fatal cardiac arrests). Of 32 patients evaluable for response, 2 (6.3%) had partial responses lasting 9 with 6 months. A total of 15 patients (46.8%) had stable disease, and 6 (18.8%) patients had stable disease for >or=6 months. Plasma interleukin-6 increased >or=2-fold over baseline measurements in 5 of 17 patients (29.4%) but did not correlate with response or toxicity. CONCLUSIONS: Although weekly bryostatin-1 at 35-40 microg/m(2) produced a low proportion of objective responses, prolonged (>6 months) stable disease or partial remission in 25% of patients suggests that this agent, or other inhibitors of protein kinase C, may have a role in the treatment of renal cell carcinoma, perhaps in combination with other agents.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Lactonas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Briostatinas , Proteína C-Reativa/biossíntese , Carcinoma de Células Renais/patologia , Progressão da Doença , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Interleucina-6/sangue , Neoplasias Renais/patologia , Lactonas/administração & dosagem , Macrolídeos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Monoclonal anti-CD20 antibody (rituximab) is active, but not curative, therapy for B-cell non-Hodgkin's lymphoma. BCL-2 is an antiapoptotic protein whose expression is dysregulated in most indolent B-cell malignancies. Antisense oligonucleotides (AS-ODNs) that down-regulate BCL-2 expression induce apoptosis and chemosensitize B-cell lymphoma cells. We hypothesized that BCL-2 down-regulation by AS-ODNs would sensitize cells to rituximab and improve therapeutic results. There is enhanced apoptosis and reduction in cell numbers when DoHH2 cells are treated in vitro with rituximab plus BCL-2 AS-ODNs, compared with either agent alone. There is little in vitro effect on WSU-FSCCL cells by rituximab, AS-ODNs that down-regulate BCL-2 by targeting the immunoglobulin portions of the BCL-2-immunoglobulin fusion molecule, or a combination of the two. The combination is more effective than either agent alone in clearing DoHH2 cells from ascites in scid mice. Combination therapy with AS-BCL-2-ODNs and rituximab significantly prolongs survival in both the DoHH2 and WSU-FSCCL models. With higher and repeated doses, this combination could be curative. We conclude that the combination of rituximab and antisense-mediated down-regulation of BCL-2 has enhanced activity against human lymphoma, prolongs survival, and could cure mice bearing human lymphoma. This merits investigation in clinical trials.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linfoma de Células B/terapia , Linfoma Folicular/terapia , Oligonucleotídeos Antissenso/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/uso terapêutico , Animais , Anticorpos Monoclonais Murinos , Antígenos CD20/imunologia , Terapia Combinada , Regulação para Baixo , Feminino , Humanos , Linfoma de Células B/genética , Linfoma de Células B/imunologia , Linfoma Folicular/genética , Linfoma Folicular/imunologia , Camundongos , Camundongos SCID , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Rituximab , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The development and clinical testing of drug combinations for the treatment of Non-Hodgkin Lymphoma (NHL) and other cancers has recently shown great promise. However, determining the optimum combination and its associated dosages for maximum efficacy and minimum side effects is still a challenge. This paper describes a parametric analysis of the dynamics of malignant B-cells and the effects of an anti-sense oligonucleotide targeted to BCL-2 (as-bcl-2), anti-CD-20 (rituximab) and their combination, for a SCID mouse human lymphoma xenograft model of NHL. Our parametric model is straightforward. Several mechanisms of malignant B-cell birth and death in the nodal micro-environment are simulated. Cell death is accelerated by hypoxia and starvation induced by tumor scale, by modification of anti-apoptosis with as-bcl-2, and by direct kill effects of rituximab (cell kill by cytotoxic immune cells is not included, due to the absence of an immune system in the corresponding experiments). We show that the cell population dynamics in the control animals are primarily determined by K*, the ratio of rate constants for malignant cell death, K(d), and cell birth, K(b). Tumor growth with independent treatments is reproduced by the model, and is used to predict their effect when administered in combination. Malignant cell lifetimes are derived to provide a quantitative comparison of the efficacy of these treatments. Future experimental and clinical applications of the model are discussed.