RESUMO
Efficacy of lenalidomide was investigated in 103 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) treated on the prospective, multicenter randomized phase-II CLL-009 trial. Interphase cytogenetic and mutational analyses identified TP53 mutations, unmutated IGHV, or del(17p) in 36/96 (37.5%), 68/88 (77.3%) or 22/92 (23.9%) patients. The overall response rate (ORR) was 40.4% (42/104). ORRs were similar irrespective of TP53 mutation (36.1% (13/36) vs 43.3% (26/60) for patients with vs without mutation) or IGHV mutation status (45.0% (9/20) vs 39.1% (27/68)); however, patients with del(17p) had lower ORRs than those without del(17p) (21.7% (5/22) vs 47.1% (33/70); P=0.049). No significant differences in progression-free survival and overall survival (OS) were observed when comparing subgroups defined by the presence or absence of high-risk genetic characteristics. In multivariate analyses, only multiple prior therapies (⩾3 lines) significantly impacted outcomes (median OS: 21.2 months vs not reached; P=0.019). This analysis indicates that lenalidomide is active in patients with relapsed/refractory CLL with unfavorable genetic profiles, including TP53 inactivation or unmutated IGHV. (ClinicalTrials.gov identifier: NCT00963105).
Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Fatores Imunológicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Talidomida/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Lenalidomida , Leucemia Linfocítica Crônica de Células B/genética , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Recidiva , Retratamento , Análise de Sobrevida , Talidomida/uso terapêutico , Resultado do Tratamento , Proteína Supressora de Tumor p53/genéticaRESUMO
This review considers available evidence for mechanisms of conferred adaptive advantages in the face of specific infectious diseases. In short, we explore a number of genetic conditions, which carry some benefits in adverse circumstances including exposure to infectious agents. The examples discussed are conditions known to result in resistance to a specific infectious disease, or have been proposed as being associated with resistance to various infectious diseases. These infectious disease-genetic disorder pairings include malaria and hemoglobinopathies, cholera and cystic fibrosis, tuberculosis and Tay-Sachs disease, mycotic abortions and phenylketonuria, infection by enveloped viruses and disorders of glycosylation, infection by filoviruses and Niemann-Pick C1 disease, as well as rabies and myasthenia gravis. We also discuss two genetic conditions that lead to infectious disease hypersusceptibility, although we did not cover the large number of immunologic defects leading to infectious disease hypersusceptibilities. Four of the resistance-associated pairings (malaria/hemogloginopathies, cholera/cystic fibrosis, tuberculosis/Tay-Sachs, and mycotic abortions/phenylketonuria) appear to be a result of selection pressures in geographic regions in which the specific infectious agent is endemic. The other pairings do not appear to be based on selection pressure and instead may be serendipitous. Nonetheless, research investigating these relationships may lead to treatment options for the aforementioned diseases by exploiting established mechanisms between genetically affected cells and infectious organisms. This may prove invaluable as a starting point for research in the case of diseases that currently have no reliably curative treatments, e.g., HIV, rabies, and Ebola.
RESUMO
This manuscript considers available evidence that a specific Salmonella strain could be used as an effective orally-administered option for cancer therapy involving the brain. It has been established that Salmonella preferentially colonizes neoplastic tissue and thrives as a facultative anaerobe in the intra-tumor environment. Although Salmonella accumulates in tumors by passive processes, it is still possible for lipopolysaccharide to cause sepsis and endotoxic shock during the migration of bacteria to the tumor site. An LPS-free version of a recently identified Salmonella isolate may have the capability to circumvent the blood brain barrier and provide a safer method of reaching brain tumors. This isolate merits further research as a "Trojan horse" for future oral biotherapy of brain cancer.
Assuntos
Neoplasias Encefálicas/microbiologia , Salmonella/fisiologia , Animais , Antineoplásicos/administração & dosagem , Barreira Hematoencefálica , Encéfalo/patologia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/terapia , Bovinos , Modelos Animais de Doenças , Humanos , Hipóxia , Lipopolissacarídeos/química , Mutação , Neoplasias/complicações , Neoplasias/microbiologia , Neoplasias/terapia , Sepse/fisiopatologia , Choque Séptico/fisiopatologia , SuínosRESUMO
BACKGROUND: Despite improvement with intensive multi-agent chemotherapy, 2-year progression-free survival (PFS) rates for adults with high-risk Burkitt's lymphoma (BL) remains <55%. PATIENTS AND METHODS: We conducted a phase II trial for newly diagnosed classic BL utilizing liposomal doxorubicin (Adriamycin) in lieu of doxorubicin and incorporating intravenous rituximab (at 500 mg/m(2) twice/cycle) into the CODOX-M/IVAC regimen. Correlative analyses included paired serum and cerebrospinal fluid (CSF) rituximab levels and close examination of cardiac function. RESULTS: Among 25 BL patients, the median age was 44 years (23-70) and 4 patients were HIV positive. There were 20 high-risk and 5 low-risk patients. At baseline, 40% of high-risk patients had bone marrow involvement, 35% had bulky disease and 15% had central nervous system involvement. The overall response rate was 100% (complete remission 92%). At 34-month median follow-up, the 2-year PFS and overall survival (OS) rates for all patients were 80% and 84%, respectively (low-risk: both 100%; high-risk: 76% and 81%, respectively). Furthermore, the 2-year PFS, OS, and disease-specific survival (DSS) rates for high-risk, HIV-negative patients were 84%, 89% and 100%, respectively. Adverse events (AEs) appeared to be consistent with prior CODOX-M/IVAC data, although there were several grade 3 cardiac events noted (all declined ejection fraction without clinical symptoms). The mean serum rituximab levels at 24 h after cycles 1 and 3 for patients without relapse were 258 and 306 µg/ml, respectively, versus 131 and 193 µg/ml, respectively, for patients with early progression (P = 0.002 and 0.002, respectively). The mean CSF rituximab levels for all patients were 0.11 and 0.24 µg/ml, respectively, at cycle 1 (24/72 h), which equated to serum:CSF ratios of 0.05% and 0.20%, respectively. CONCLUSIONS: The integration of rituximab into CODOX-M/IVAC for adult BL was feasible and tolerable, while changes in cardiac function warrant continued examination. This regimen was associated with excellent survival rates for HIV-negative BL. Further investigation of the predictive value of serum rituximab is needed. Clinicaltrials.gov NCT00392990.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Burkitt/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Linfoma de Burkitt/mortalidade , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Etoposídeo/administração & dosagem , Feminino , Humanos , Ifosfamida/administração & dosagem , Estimativa de Kaplan-Meier , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Rituximab , Trombocitopenia/induzido quimicamente , Resultado do Tratamento , Vincristina/administração & dosagem , Adulto JovemRESUMO
Exploiting the antitumor effect of natural killer (NK) cells has regained interest in light of data from preclinical and clinical work on the potential of alloreactive NK cells. Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) represent the two most prevalent adult hematological malignancies in the western hemisphere. To evaluate the role of NK cells in the immune surveillance and their therapeutic potential for CLL and MM, tumor cell susceptibility to NK-mediated killing was investigated. Results show relative resistance of tumor cells from CLL as well as MM (73 and 70% of the patients, respectively) to NK-mediated killing. To gain insight into molecular mechanisms of this resistance, the expression of the tolerogenic HLA-G molecule in CLL and MM and its relevance to susceptibility to NK-mediated killing were investigated. HLA-G transcript was found in tumor cells from 89% (n=19) of CLL and 100% (n=9) of MM patients examined. HLA-G1 surface expression was observed in CLL and was very low or undetectable in MM. Notably, blocking of HLA-G1 with specific antibody on CLL samples increased their susceptibility to NK-mediated killing, demonstrating that HLA-G participates in protecting CLL cells from NK-mediated killing and may thus contribute to their immune escape in vivo.
Assuntos
Antígenos HLA/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Células Matadoras Naturais/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Mieloma Múltiplo/imunologia , Evasão Tumoral , Antígenos de Neoplasias , Citotoxicidade Imunológica , Antígenos HLA/análise , Antígenos HLA/genética , Antígenos HLA-G , Antígenos de Histocompatibilidade Classe I/análise , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Vigilância Imunológica , RNA Neoplásico/análiseRESUMO
New insights into prognostic markers and the pathophysiology of chronic lymphocytic leukemia (CLL) are beginning to change the concept of CLL treatment. Alemtuzumab has evolved as a potent and effective therapeutic option for patients with CLL. Specifically, alemtuzumab has demonstrated substantial efficacy in fludarabine-refractory patients and has shown impressive responses when administered subcutaneously in first-line therapy. A group of experts gathered to discuss new data related to the use of alemtuzumab in CLL and to assess its place in the rapidly changing approach to treating patients with this disease. The main goals of this program were to update the management guidelines that were previously developed for alemtuzumab-treated patients and to provide community oncologists with guidance on the most effective way to integrate alemtuzumab into a CLL treatment plan.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Alemtuzumab , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos/administração & dosagem , Gerenciamento Clínico , Humanos , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/mortalidade , Guias de Prática Clínica como Assunto , Resultado do TratamentoRESUMO
BACKGROUND: Higher chemotherapy dose intensity has been studied as a way of improving the clinical outcomes in various malignancies, including non-Hodgkin's lymphoma (NHL). METHODS: We reviewed clinical trials that have studied the relation between dose and response in cancer chemotherapy, the theory behind dose-intense chemotherapy, and the clinical results with dose-escalated and dose-dense therapy in aggressive NHL. RESULTS: Myeloablative high-dose chemotherapy with stem cell transplantation produces higher 5-year survival rates than standard salvage chemotherapy in relapsed aggressive lymphoma, but its role as initial therapy is not yet clear. Nonmyeloablative dose-escalated chemotherapy is feasible with granulocyte colony-stimulating factor (G-CSF) support, but this approach does not improve outcomes. Dose-dense (14-day) CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with G-CSF support produces better results than 21-day CHOP in patients with previously untreated aggressive lymphoma, without additional toxicity. The addition of etoposide to dose-dense CHOP may provide further benefits in younger patients. The addition of rituximab to G-CSF-supported dose-dense CHOP is feasible. Preliminary data suggest the feasibility of dose-dense chemotherapy for NHL with the once-per-cycle G-CSF, pegfilgrastim. CONCLUSION: Dose-dense chemotherapy with G-CSF support produced better clinical outcomes in both younger and older patients. Phase 3 trials of dose-dense CHOP plus rituximab with CSF support are warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Medula Óssea , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Imunoterapia , Linfoma não Hodgkin/terapia , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/uso terapêuticoRESUMO
Patients with recurrent lymphoma of any grade were treated with mitoxantrone (12 mg/m2 given intravenously (IV) over 15-30 minutes on day 1) followed by fludarabine at a dose of (25 mg/m 2 given IV over 30 minutes on days 1-3) every 28 days fludarabine at a dose of (25 mg/m2 given IV over 30 minutes on days 1-3) every 28 days. All patients had failed one prior chemotherapy regimen that contained either doxorubicin or mitoxantrone, total dose not exceeding 350 mg/m2 doxorubicin or 80 mg/m2 mitoxantrone. mitoxantrone. Thirty one patients (22 with intermediate- or high-grade and 9 with low-grade NHL) were enrolled. Median age was 63 years (range: 21 to 87). The objective response rate for patients with intermediate/high-grade NHL was 55% (27% with CR) and 89% (56% with CR) for patients with low-grade NHL. Median time to disease progression was 5.1 months for patients with intermediate/high-grade NHL and 10.8 months for patients with low-grade NHL. Median time to death for patients with intermediate/high-grade disease was 11.4 months. Median time to death for patients with low-grade NHL was not calculable as only one death (due to respiratory failure) occurred in this group 6.5 months after study start. The regimen was well tolerated. Grade 3/4 neutropenia was reported in 80% (24 of 30) of patients and Grade 3/4 thrombocytopenia in 19% (6 of 31) of patients. Nine hospitalizations for adverse events (primarily fever and neutropenia) occurred among eight patients, all with intermediate/high-grade NHL, during a total of 118 cycles of therapy. Further studies of this combination regimen in patients with intermediate/high-grade NHL and studies combined with monoclonal antibodies in low-grade NHL are warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma não Hodgkin/tratamento farmacológico , Mitoxantrona/administração & dosagem , Vidarabina/análogos & derivados , Vidarabina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Estudos de Coortes , Intervalo Livre de Doença , Doxorrubicina , Feminino , Humanos , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Mitoxantrona/toxicidade , Recidiva , Indução de Remissão , Terapia de Salvação , Taxa de Sobrevida , Falha de Tratamento , Vidarabina/toxicidadeRESUMO
Interferon-alfa in combination with cytotoxic chemotherapy has been shown to be effective in treating certain types of non-Hodgkin's lymphoma (NHL) (1). However, there is no published data on upfront induction treatment of aggressive NHL with IFN-alfa containing regimens. Studies have also shown that one can overcome regrowth resistance by administering mid-cycle agents which slow tumor proliferation between courses of cytotoxic therapy (2). Based on this, we treated 32 consecutive patients between 1/93 and 9/96 with a regimen containing cyclophosphamide 750 mg/m2, mitoxantrone 12 mg/m2, and teniposide 60 mg/m2 IV on day 1 with prednisone 100 mg PO given on days 1-5. On day 15, patients received vincristine 1.4 mg/m2 (2 mg max.) and bleomycin 10 units/m2 IV. Interferon-alfa-2b 5x10(6) units/m2 SQ was administered on days 22-26. The median age was 55 (range 26-83), M:F ratio was 2.5:1, and the median International Prognostic Index was 2. 38% of patients had stages I-II and 62% had stages III-IV disease. Fifty-nine percent of the patients achieved a complete response, 22% a partial response, and 19% had progressive disease. The overall survival (OS) was 81% and the progression free survival (PFS) was 56% at 4.3 years. There were no severe (grade IV) hematologic, flu-like, GI and infectious toxicities from IFN-alpha. Leukopenia was the main severe toxicity related to the chemotherapy regimen (days 1-15), but not IFN-alpha. Severe infection secondary to the chemotherapy regimen occurred in one patient. Interferon-alfa-2b and mid-cycle chemotherapy added to an anthracycline based regimen is effective induction treatment for patients with aggressive NHL. The OS and PFS using this regimen, based on regrowth resistance, appears to be at least as or more effective than CHOP therapy for this group of patients. Severe toxicities were rare.
Assuntos
Antraciclinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Interferon-alfa/administração & dosagem , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/toxicidade , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Esquema de Medicação , Feminino , Humanos , Interferon-alfa/toxicidade , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Índice de Gravidade de Doença , Análise de Sobrevida , Equivalência Terapêutica , Resultado do TratamentoRESUMO
Twenty five patients with AML who had neither a history of toxic exposure or myelodysplasia were treated with a remission induction regimen consisting of two pulses of chemotherapy separated by 96 hrs. Each pulse consisted of cytarabine 2gm/m(2) (at t=0 and t=12 hrs) with mitoxantrone [30mg/m(2) ] administered immediately after the second cytarabine administration. Amifostine was administered three times a week [on Monday, Wednesday, and Friday] until the outcome of therapy was known. This regimen induced complete remissions in 15 of 17 patients less than 70 years of age and in 5 of 8 patients older than 70 years.
Assuntos
Antineoplásicos/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/normas , Estudos de Coortes , Citarabina/administração & dosagem , Citarabina/normas , Análise Citogenética , Esquema de Medicação , Humanos , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/genética , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Mitoxantrona/normas , Indução de Remissão , Fatores de Tempo , Resultado do TratamentoRESUMO
Chimeric CD20 monoclonal antibody as alternative therapy in relapsed low-grade non-Hodgkin's lymphoma (NHL) has produced responses in nearly 50% of patients. Augmenting CD20 expression on tumor cells and/or inducing its expression may increase the cell kill and effectiveness of antibody therapy. Peripheral blood lymphocytes from 19 patients with B-cell chronic lymphocytic leukemia (B-CLL) were incubated in vitro in the presence of interferon-alpha (IFN-alpha) (500 U/ml and 1,000 U/ml) for 24 and 72 hours. The effect on CD20 expression was studied by flow cytometry. The differences in the percentage positivity, the mean fluorescence intensity (MFI), and the product of percentage positivity and MFI were used to assess upregulation. There was a significant upregulation of CD20 expression on B cells seen at both concentrations after 24-hour priming (p < 0.01). B-CLL cells cultured for 72 hours in the presence of IFN-alpha also showed upregulation of CD20 expression; however, the degree of upregulation was much lower than that seen at 24 hours. There was no statistically significant increase in CD20 antigen expression on normal lymphocytes following cytokine exposure. These results suggest that IFN-alpha priming may augment the effectiveness of antibody therapy by directly upregulating CD20 antigen expression in addition to its indirect action through effector cells of the host.
Assuntos
Antígenos CD20/sangue , Linfócitos B/imunologia , Interferon-alfa/farmacologia , Leucemia Linfocítica Crônica de Células B/imunologia , Antígenos CD/sangue , Antígenos CD/genética , Antígenos CD20/genética , Linfócitos B/efeitos dos fármacos , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Interferon alfa-2 , Cinética , Leucemia Linfocítica Crônica de Células B/sangue , Proteínas Recombinantes , Valores de ReferênciaRESUMO
Twenty patients with poor prognosis AML and four patients in the blastic phase of a myeloproliferative disorder were treated with two 'pulses' of therapy each consisting of two doses of high dose araC (separated by 12 h) followed by a single dose of mitoxantrone. The pulses were separated by 96 h. Amifostine was then administered tiw. The median age of the population was 68 years with 88% of patients having had either a prior MDS, MPD or toxic exposure. The acute leukemia of 58% of patients either entered a CR or reverted to preleukemic state. For patients under 70 years of age, treatment produced 62% CRs with a leukemia free decision marrow in 77%. For patients over 70 years the CR rate was 27% with 36% of patients having a leukemia free decision marrow.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Amifostina/administração & dosagem , Citarabina/administração & dosagem , Humanos , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/fisiopatologia , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Projetos Piloto , Prognóstico , Protetores contra Radiação/administração & dosagem , Resultado do TratamentoRESUMO
Tumor necrosis factor alpha (TNF alpha) is a pleiotropic cytokine that is constitutively produced by leukemic cells in B Chronic Lymphocytic Leukemia (B-CLL). It has been shown to have autocrine and paracrine functions in normal B cells and in B lymphoproliferative diseases. This study was conducted to determine the effect of TNF alpha (in vitro) on CD20 expression on cells from patients with B-CLL. Currently, anti-CD20 monoclonal antibody therapy is becoming a second line treatment in the management of B cell disorders like low-grade non-Hodgkin's lymphoma (NHL) and B-CLL. Our results demonstrate amply that very low doses of TNF alpha (0. 0125 ng/ml) can be used to significantly increase CD20 expression on cells from patients of B-CLL as evidenced by increases in both percentage positivity and mean fluorescence intensity. The upregulation is evident as early as 24 hours and is maintained for up to 72 hours. We propose that the upregulation is a direct result of in vitro differentiation stimulated by TNF alpha. The results presented can be exploited in the designing of priming protocols prior to antibody therapy and this is discussed.
Assuntos
Antígenos CD20/análise , Leucemia Linfocítica Crônica de Células B/terapia , Fator de Necrose Tumoral alfa/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antígenos CD20/imunologia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismoRESUMO
Myelodysplastic syndromes (MDS) have previously been reported to show competitively high rates of apoptosis and proliferation in the bone marrow (BM). Using a double-labelling technique in the present study, we demonstrated that a significantly high number of S-phase cells were simultaneously apoptotic (signal antonymy; SA) in MDS (mean +/- s.e.m. 53.5 +/- 6.7%, n = 24, P < 0.001). In contrast, SA was negligible in all other specimens studied, including normal control BM (n = 13) from non-Hodgkin's lymphoma (NHL) patients, BM from patients with de novo acute myelogenous leukaemia (1'AML; n = 5), or secondary AML that had transformed from MDS (2'AML; n = 10), or the solid tumours from patients with NHL (n = 9) or head and neck squamous cell carcinoma (HNSCC; n = 10). Subsequently, the expression of a transcription factor, E2F1, was studied in density-separated BM aspirate mononuclear cells from MDS patients (n = 9) and a normal control. Two separate sets of primers were used that recognized the regulatory retinoblastoma (Rb) protein-binding region and the functional DNA-binding region of E2F1. Interestingly, although the latter manifested the expected band (280 bp) in all samples, the Rb-specific primers showed the expected band (380 bp) in the normal and in 4/9 MDS specimens. Two other MDS specimens also showed a smaller band ( approximately 325 bp), whereas 3/9 MDS patients showed exclusively the smaller band. The levels of SA were significantly higher in those MDS cases that showed the smaller Rb-specific band either alone or in addition to the expected band (median 19.5%, n = 4, P = 0.037) than in those showing exclusively the expected band (median 0.4%, n = 3). Our present studies show SA as a characteristic feature of MDS and, importantly, demonstrate its link with an altered expression of E2F1 in some MDS patients.
Assuntos
Apoptose , Células da Medula Óssea/patologia , Proteínas de Transporte , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA , Síndromes Mielodisplásicas/patologia , Fase S , Divisão Celular , Fatores de Transcrição E2F , Fator de Transcrição E2F1 , Humanos , Marcação In Situ das Extremidades Cortadas , Síndromes Mielodisplásicas/metabolismo , RNA Mensageiro/análise , Proteína 1 de Ligação ao Retinoblastoma , Fator de Transcrição DP1 , Fatores de Transcrição/genéticaRESUMO
Fas ligand triggers cell death after interaction with its receptor Fas. Altered expression of Fas has been associated with lymphoproliferation and autoimmune disorders in both mice and man. Apoptosis of lung and liver tissue is seen in Fas ligand transgenic mice. It is not known whether constitutive expression of Fas ligand can cause a similar human disease. Four patients with aggressive large granular lymphocyte (LGL) leukaemia involving lung and liver were studied. All four patients were severely ill with pulmonary involvement. Two patients presented with hypoxia and were oxygen dependent; the other two patients had severe pulmonary hypertension. Lung biopsies showed interstitial infiltration by leukaemic LGL. The infiltrating lymphocytes expressed both Fas and Fas ligand, whereas normal pneumocytes expressed only Fas. Similar findings were observed in liver biopsies from these patients. Features mimicking the pathological changes of graft-versus-host disease were observed, including pneumocyte apoptosis. All four patients had high levels of circulating Fas ligand. Successful treatment with oral methotrexate or 2-chlorodeoxyadenosine was associated with disappearance or marked reduction of circulating Fas ligand. These results suggest that dysregulated expression of Fas ligand can lead to human disease with pathological features resembling graft-versus-host disease.
Assuntos
Leucemia Linfoide/metabolismo , Fígado/metabolismo , Pulmão/metabolismo , Glicoproteínas de Membrana/genética , Receptor fas/genética , Adulto , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Apoptose , Proteína Ligante Fas , Feminino , Expressão Gênica , Humanos , Imunofenotipagem , Leucemia Linfoide/tratamento farmacológico , Leucemia Linfoide/patologia , Infiltração Leucêmica , Fígado/patologia , Pulmão/patologia , Masculino , Metotrexato/uso terapêutico , Camundongos , Camundongos Transgênicos , Pessoa de Meia-IdadeRESUMO
Anti-CD20 antibody is an established treatment for low-grade non-Hodgkin's lymphoma (NHL). Augmenting the expression of CD20 antigen on the tumor cells may increase the cell kill and therefore increase the effectiveness of the antibody. To study this, we incubated peripheral blood lymphocytes from CLL patients with the following cytokines: EPO, SCF, TNFalpha, TGFbeta, GMCSF, TPO, IL-1, IL-2, IL-3, IL-4, GCSF. CD20 expression was studied by flow cytometry at baseline, 24 and 72 h after exposure to these cytokines. Upregulation of CD20 antigen expression was observed with IL-4, TNFalpha and GMCSF.
Assuntos
Antígenos CD20/biossíntese , Citocinas/farmacologia , Leucemia Linfocítica Crônica de Células B/imunologia , Antígenos CD20/imunologia , Citometria de Fluxo , Humanos , Regulação para CimaRESUMO
High levels of telomerase activity and high rates of cell proliferation are associated with a poor prognosis in acute myelogenous leukemia. Furthermore, cytokine production by leukemia cells is believed to play an important role in determining the proliferative characteristics of leukemia. The in vivo effects of two noncytotoxic agents on these parameters were determined in 33 acute myelogenous leukemia patients. Three daily doses of interleukin (IL) 4 or a single dose of amifostine reduced telomerase activity in the leukemia marrow cells in 7 of 9 and 11 of 13 patients, respectively. The administration of a single dose of amifostine resulted in a reduction in tumor necrosis factor alpha and IL-6 transcript levels in the marrow cells of 10 of 13 and 12 of 13 patients in which these transcripts were present. The administration of only three doses of IL-4 or a single dose of amifostine has a significant effect on leukemia cell parameters, which are believed to have a significant impact on the in vivo biology of the disease and on its response to remission induction therapy.