RESUMO
Macular lymphocytic arteritis describes a recently reported entity, clinically characterized by asymptomatic hyperpigmented macules on the lower limbs, without association of systemic diseases. Histopathologically it is characterized by a lymphocytic arteritis with a hyalinized fibrin ring. We report a new case presenting with ulceration, a finding not previously described. A 25-year-old Hispanic woman was evaluated for a 1-year history of a gradually progressive, asymptomatic eruption that begins at level of both knees and progressively affects both legs and feet. She also referred recently appeared ulcers on inner right ankle without previous traumatism. Physical examination revealed multiple fairly well-defined light brown and faint pink patches with petechiae on as well as retiform crusts and livedoid lesions on inner right ankle. Both types of lesions were biopsied showing lymphocytic arteritis with fibrinoid necrosis and thrombus. There were no relevant laboratory alterations. The clinical peculiarity of our case is the clinical image of the lesions mimicking a pigmented purpuric dermatosis and the presence of a non-traumatic ulcer which could be explained because chronic lymphocytic damage may cause ischemic damage. Ulceration in our case supports consideration of macular arteritis as a latent form of cutaneous polyarteritis nodosa.
Assuntos
Arterite/patologia , Linfócitos/patologia , Poliarterite Nodosa/patologia , Dermatopatias Vasculares/patologia , Úlcera Cutânea/patologia , Adulto , Feminino , Humanos , Transtornos da Pigmentação/patologia , Púrpura/patologia , Pele/irrigação sanguíneaRESUMO
Tumor antigen-specific T-cell tolerance limits the efficacy of therapeutic cancer vaccines. Antigen-presenting cells mediate the induction of T-cell tolerance to self-antigens. We therefore assessed the fate of tumor-specific CD4+ T cells in tumor-bearing recipients after in vivo activation of antigen-presenting cells with antibodies against CD40. Such treatment not only preserved the responsiveness of this population, but resulted in their endogenous activation. Established tumors regressed in vaccinated mice treated with antibody against CD40 at a time when no response was achieved with vaccination alone. These results indicate that modulation of antigen-presenting cells may be a useful strategy for enhancing responsiveness to immunization.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Antígenos CD40/imunologia , Vacinas Anticâncer , Carcinoma de Células Renais/prevenção & controle , Neoplasias Renais/prevenção & controle , Neoplasias Pulmonares/secundário , Glicoproteínas de Membrana/imunologia , Transferência Adotiva , Animais , Ligante de CD40 , Carcinoma de Células Renais/imunologia , Tolerância Imunológica , Neoplasias Renais/imunologia , Neoplasias Pulmonares/prevenção & controle , Transfusão de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Células Tumorais CultivadasRESUMO
Macrophages from mice bearing large D1-DMBA-3 mammary tumors have a decreased capacity to kill tumor targets. This effect is due to an impaired ability to produce nitric oxide (NO) in response to lipopolysaccharide (LPS) stimulation. Here we report that the DA-3 tumor cell line, derived from the in vivo adenocarcinoma D1-DMBA-3, produces a factor that inhibits both NO production/release and cytotoxicity of LPS-activated peritoneal exudate macrophages (PEM). However, other complex macrophage functions such as phagocytosis, superoxide production, mitochondrial dehydrogenase activity, and synthesis of proteins were not reduced by this factor. The NO inhibitor has been found to be lipid in nature. Lipid extracts from DA-3 cell culture supernatants were purified by repeated silica gel column chromatography. The active molecule was unambiguously characterized as phosphatidyl serine (PS) by fast atom bombardment tandem mass spectrometry. Preliminary results indicate a lack of induced NO synthase (iNOS) activity in the lysates of LPS-activated PEM pretreated with PS. The ubiquity of PS in the inner leaflet of biological membranes and its NO inhibitory property, suggest that this phospholipid may be one of the long elusive molecules responsible for regulating physiological levels of NO in the host and hence preventing cellular dysfunction and/or tissue damage. Furthermore, the possible overexpression and shedding of PS by DA-3 tumor cells may represent a novel mechanism to impair macrophage cytotoxicity, a host function that contributes to the protection against developing neoplasms.
Assuntos
Neoplasias Mamárias Experimentais/química , Óxido Nítrico/antagonistas & inibidores , Fosfatidilserinas/isolamento & purificação , Animais , Feminino , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/biossíntese , Fosfatidilserinas/farmacologia , Fosfolipases Tipo C/farmacologiaRESUMO
In many cases, induction of CD8(+) CTL responses requires CD4(+) T cell help. Recently, it has been shown that a dominant pathway of CD4(+) help is via antigen-presenting cell (APC) activation through engagement of CD40 by CD40 ligand on CD4(+) T cells. To further study this three cell interaction, we established an in vitro system using dendritic cells (DCs) as APCs and influenza hemagglutinin (HA) class I and II peptide-specific T cell antigen receptor transgenic T cells as cytotoxic T lymphocyte precursors and CD4(+) T helper cells, respectively. We found that CD4(+) T cells can provide potent help for DCs to activate CD8(+) T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides. Surprisingly, this help is completely independent of CD40. Moreover, CD40-independent CD4(+) help can be documented in vivo. Finally, we show that CD40-independent T cell help is delivered through both sensitization of DCs and direct CD4(+)-CD8(+) T cell communication via lymphokines. Therefore, we conclude that CD4(+) help comprises at least three components: CD40-dependent DC sensitization, CD40-independent DC sensitization, and direct lymphokine-dependent CD4(+)-CD8(+) T cell communication.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Animais , Antígenos de Diferenciação de Linfócitos T , Comunicação Celular/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Ativação Linfocitária , Linfocinas/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais , Linfócitos T Citotóxicos/imunologiaRESUMO
Stromal cells are an essential component of the bone marrow microenvironment that regulate or supports tumor survival. In this study we therefore studied the role of stromal cells in lymphoma cell survival. We demonstrated that adhesion of the B-cell lymphoma cell lines SUDH-4 and 10 to bone marrow stroma inhibited mitoxantrone-induced apoptosis. This adhesion-dependent inhibition of mitoxantrone-induced apoptosis correlated with decreased activation of caspases-8 and 9, and cleavage of caspase 3 and PARP. Electrophoretic mobility shift assays (EMSA) analysis demonstrated significantly increased NF-kappaB binding activity in lymphoma cells adhered to stroma cells compared to lymphoma cells in suspension. This DNA binding activity could be attributed to cell adhesion-mediated proteolysis of the NF-kappaB precursor, p100 (NF-kappaB2). This resulted in the generation of active p52, which translocated to the nucleus in complex with p65 and RelB. Coculture with stromal cells also induced expression of the NF-kappaB-regulated anti-apoptotic molecules, XIAP, cIAP(1) and cIAP(2). Inhibition of NF-kappaB significantly suppressed HS-5-induced protection against apoptosis in lymphoma cell lines as well as in primary lymphoma cells. Thus, bone marrow stroma protects B-cell lymphoma cells against apoptosis, at least in part through activation of NF-kappaB dependent mechanism involving up-regulation of NF-kappaB regulated antiapoptotic proteins. Consequently, this study suggests a new approach to decrease the resistance of lymphoma to chemotherapy.
Assuntos
Proteínas Reguladoras de Apoptose/genética , Apoptose , Linfoma não Hodgkin/patologia , Subunidade p52 de NF-kappa B/metabolismo , Células Estromais/fisiologia , Fator de Transcrição RelB/metabolismo , Células da Medula Óssea , Caspases/metabolismo , Adesão Celular , Comunicação Celular/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular , Técnicas de Cocultura , Humanos , NF-kappa B/metabolismo , Regulação para Cima/genéticaRESUMO
Objective: To elucidate the expression levels of key immune biomarkers, phosphate and tension homology deleted on chromosome ten (PTEN) and programmed cell death protein1(PD-1),of different immune tolerance pathway in classic Hodgkin's lymphoma (CHL) to further determine their clinical role and prognostic significance. Methods: The clinical features and prognostic factors of 56 CHL patients, who were admitted to the TianJin Medical University Cancer Institute from February 2003 to August 2013, were retrospectively analyzed. PTEN and PD-1 protein expression levels were analyzed by immunohistochemistry, Epstein-Barr virus encoded RNA (EBER) was performed by in situ hybridization assay. Correlations between the expression of biomarkers and clinicopathologic parameters were examined and survival analyses were performed. Results: This cohort of 56 CHL patients included 34 males and 22 females with a median age of 25 years (ranged from 7 to 71 years). In a univariate analysis, age≥45, IPS score >2, EBER positive, high expression of PTEN protein conferred inferior 5-year OS and 5-year PFS; In a multivariate model, age≥45, IPS score >2, EBER positive, high expression of PTEN protein were identified as the independent adverse prognostic factors for CHL. Conclusions: This study suggested for the first time that PTEN was independent prognostic immune biomarkers in CHL, which provided the novel therapeutic strategy of immune therapy for CHL.
Assuntos
Doença de Hodgkin , PTEN Fosfo-Hidrolase/análise , Receptor de Morte Celular Programada 1/análise , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
Objective: To explore the mechanism of ibrutinib on drug resistance diffuse large B-cell lymphoma (DLBCL) cells. Methods: DLBCL cell line was cultured with mesenchymal stem cells (MSC) , and DLBCL cells which migrated and adhered to MSC under microscope was counted. The secretion of CXCL12 by MSC were measured by ELISA. The expression of CXCR4 on DLBCL cells were measured by flow cytometry, HBL-1 cells were transfected with a CXCR4-lentivector. An Annexin â ¤-binding assay was used to detect the induction of apoptosis. Clonogenic growth of DLBCL cells was evaluated on MethoCult media. Ibrutinib was injected into NOD/SCID mice, tumor growth was assessed via caliper measurements every 3 days. Results: MSC promoted migration and adhesion of DLBCL cells to MSC. Ibrutinib inhibited migration and adhesion of DLBCL cells to MSC in a dose-dependent manner (P<0.05) . CXCL12 secreted by MSC and CXCR4 expressed on DLBCL cells could induce each other, which upgraded the levels of secretion and expression. Ibrutinib could inhibit the secretion of CXCL12 (SUDHL10: 660 pg/ml vs 1 400 pg/ml, P=0.004; HBL-1: 720 pg/ml vs 1 490 pg/ml, P=0.018; DLBCL:850 pg/ml vs 1 450 pg/ml, P=0.004) and expression of CXCR4 (P<0.05) . When co-cultured with MSC, the ratio of HBL-1 cells apoptosis in the group of control, mitoxantrone, ibrutinib, mitoxantrone+ibrutinib were respectively 15.1%, 17.5%, 23.5%, 58.7%. After transfected with a CXCR4-lentivector and overexpressed CXCR4, the ratios of HBL-1 cells apoptosis were 14.2%, 16.1%, 22.5%, 38.3% respectively. The ratio of DLBCL cells apoptosis induced by mitoxantrone was lower when co-cultured with MSC (P<0.05) . But with the addition of ibrutinib, the ratio of apoptosis was increaed and it was similar to cultivation without MSC, which suggested ibrutinib could inhibit drug-resistance induced by MSC. But after transfected with a CXCR4-lentivector, the overexpression of CXCR4 was detected and the ratio of apoptosis was significantly lower when co-cultured with MSC which demonstrated that ibrutinib inhibited drug-resistance by inhibiting the expression of CXCR4. MSC enhanced lymphoma clonogenicity in vitro and lymphoma cell growth in vivo. The number of colonies of control, MSC, Ibrutinib, MSC+Ibrutinib were 113±5, 205±4, 62±9, 123±3 (2.5×10(3)/well, x±s) , respectively. The tumor volume of NOD/SCID mice were respectively 6 500, 17 000, 4 000, 10 000 mm(3). Ibrutinib inhibited lymphoma clonogenicity in vitro and lymphoma cell growth in vitro. Conclusion: Ibrutinib targeted the CXCL12/CXCR4 axis, inhibited the expression of CXCR4 and inhibited MSC-mediated drug resistance. Ibrutinib also inhibited lymphoma clonogenicity in vitro and lymphoma cell growth in vivo. These results provided a scientific rationality for relapsed/refractory DLBCL treatment with ibrutinib.
Assuntos
Linfoma Difuso de Grandes Células B , Células-Tronco Mesenquimais , Adenina/análogos & derivados , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Piperidinas , Pirazóis , Pirimidinas , Receptores CXCR4Assuntos
Conscientização , Terapia Biológica/efeitos adversos , Antígenos de Superfície da Hepatite B/sangue , Hepatite B/induzido quimicamente , Psoríase/tratamento farmacológico , Antivirais/uso terapêutico , DNA Viral/sangue , Hepatite B/sangue , Hepatite B/tratamento farmacológico , Vírus da Hepatite B/genética , Humanos , Psoríase/sangue , Psoríase/imunologiaRESUMO
The formation of a blood supply (angiogenesis) is critical to the growth of solid tumors. The naturally occurring steroid tetrahydrocortisol, the synthetic cyclodextrin derivative beta-cyclodextrin tetradecasulfate, and the tetracycline derivative minocycline have antiangiogenic activity. Tetrahydrocortisol and beta-cyclodextrin tetradecasulfate in a 1:1 molar ratio by continuous infusion over 14 days and minocycline administered i.p. over 14 days from day 4 to day 18 postimplantation of the Lewis lung carcinoma significantly increased the growth delay of the primary tumor after treatment with cis-diamminedichloroplatinum(II), melphalan, cyclophosphamide, Adriamycin, bleomycin, and radiation therapy administered in standard regimens. Addition of the antiangiogenic agents to treatment with the cytotoxic therapies not only reduced the number of lung metastases formed from the primary tumor but also reduced the number of large metastases. Five of 12 animals treated with the antiangiogenic modulators and cyclophosphamide were long-term survivors (> 120 days). Thus, antiangiogenic therapies can potentiate the efficacy of standard anticancer therapies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclodextrinas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Minociclina/farmacologia , Tetra-Hidrocortisol/farmacologia , beta-Ciclodextrinas , Animais , Bleomicina/administração & dosagem , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Neoplasias Pulmonares/radioterapia , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Células Tumorais CultivadasRESUMO
We are developing complexes of negatively charged PtCl4 with positively charged nuclear dyes as new antitumor agents for use alone and in conjunction with hyperthermia and/or radiation. Elemental analysis has shown that the complex PtCl4(Fast Black)2 is a tight ion pair. In experimentally growing EMT6 cells in vitro, PtCl4(Fast Black)2 killed cells in a log-linear manner which increased as the temperature of the exposures was increased from 37 to 42 degrees C or 43 degrees C. In addition, cell kill was also increased under conditions of low pH (6.45), especially in hypoxic cells treated at elevated temperature. Measurement of intracellular platinum levels after exposure to 25 microM cisplatin or PtCl4(Fast Black)2 demonstrated that platinum levels were between 170- and 200-fold higher after exposure to PtCl4(Fast Black)2. In vivo studies in the FSaIIC murine fibrosarcoma showed, again, that PtCl4(Fast Black)2 killed in a log-linear manner. Treatment of tumors placed in the thigh with 43 degrees C, 30-min hyperthermia immediately following i.p. injection of PtCl4(Fast Black)2 was dose modifying. One hundred mg/kg of PtCl4(Fast Black)2 produced a 4.6-day tumor growth delay which increased to 6.4 days with 43 degrees C, 30-min hyperthermia immediately following i.p. injection of PtCl4(Fast Black)2 was does modifying. One hundred mg/kg of PtCl4(Fast Black)2 produced a 4.6-day tumor growth delay which increased to 6.4 days with 43 degrees C, 30-min hyperthermia (growth delay for hyperthermia alone was 1.4 days), and 500 mg/kg produced a 5.6-day delay which increased to 11.0 days with hyperthermia. In contrast, cisplatin (5 mg/kg) produced a 4.4-day delay which increased to 5.9 days with hyperthermia. PtCl4(Fast Black)2 was well tolerated by animals, and the maximally tolerated dose was approximately 650 mg/kg. This new complex appears quite active as an antitumor agent alone and in conjunction with hyperthermia, and, since other studies have shown it to interact positively with radiation, this agent seems a very appropriate candidate for further development as a clinical anticancer drug.
Assuntos
Antineoplásicos/farmacologia , Compostos de Diazônio/farmacologia , Compostos Organoplatínicos/farmacologia , Células Tumorais Cultivadas/citologia , Animais , Divisão Celular/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Compostos de Diazônio/síntese química , Fibrossarcoma , Temperatura Alta , Concentração de Íons de Hidrogênio , Cinética , Neoplasias Mamárias Experimentais , Camundongos , Compostos Organoplatínicos/síntese química , Platina/análise , Espectrofotometria Atômica , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
The cytotoxicity of N,N',N''-triethylenethiophosphoramide (thiotepa) was studied in vitro in the MCF-7 human breast carcinoma cell line and in vivo using the EMT6 mouse mammary tumor model, under various conditions of oxygenation and in the presence and absence of Aroclor 1254-induced liver preparations. The cytotoxicity of thiotepa toward exponentially growing MCF-7 cells was markedly dependent on the presence of oxygen during the period of drug exposure, with 3 log greater cell kill at 500 microM thiotepa being observed when the cells were normally oxygenated compared with hypoxic cells. Incubation of thiotepa with an Aroclor 1254-induced rat liver S-9 homogenate, in the presence of a NADPH-regenerating system, resulted in an 8-fold increase in cytotoxicity towards the MCF-7 cells over a wide range of drug concentrations. Thiotepa was shown to be metabolized under these conditions in a NADPH- and O2-dependent reaction that was catalyzed by one or more microsomal cytochrome P-450 enzymes that were present in the S-9 fraction. The thiotepa metabolite triethylene phosphoramide, which hydrolyzes significantly faster than thiotepa, was significantly less cytotoxic toward the MCF-7 cells than was thiotepa itself, suggesting that it is unlikely to be the S-9 metabolite responsible for the observed increase in drug cytotoxicity. Moreover, triethylene phosphoramide cytotoxicity was only partially O2 dependent and was largely unaffected by incubation in the presence of the S-9 preparation, indicating a mechanism of action distinct from that of thiotepa. Tumor cell survival experiments with the EMT6 mouse mammary carcinoma system revealed that a 3.6-fold increase in thiotepa cytotoxicity was obtained by prior administration of the liver inducer Aroclor 1254 to the tumor-bearing animals, 5 days before drug treatment. Finally, the therapeutic effectiveness of thiotepa was significantly enhanced (3- to 5.8-fold increase in tumor growth delay) when an increase in oxygenation was achieved, by carbogen breathing, in animals given the perfluorochemical emulsion Fluosol-DA. These findings establish that the cytotoxic effects of thiotepa are oxygen dependent and may involve, at least in part, metabolic processes catalyzed by cytochrome P-450 enzymes.
Assuntos
Neoplasias da Mama/metabolismo , Fígado/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Tiotepa/metabolismo , Animais , Biotransformação , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Cinética , Neoplasias Mamárias Experimentais/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , NAD/metabolismo , NADP/metabolismo , Oxirredução , Ratos , Tiotepa/farmacologia , Tiotepa/uso terapêutico , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
The median survival for metastatic melanoma is in the realm of 8-16 months and there are few therapies that offer significant improvement in overall survival. One of the recent advances in cancer treatment focuses on epigenetic modifiers to alter the survivability and immunogenicity of cancer cells. Our group and others have previously demonstrated that pan-HDAC inhibitors induce apoptosis, cell cycle arrest and changes in the immunogenicity of melanoma cells. Here we interrogated specific HDACs which may be responsible for this effect. We found that both genetic abrogation and pharmacologic inhibition of HDAC6 decreases in vitro proliferation and induces G1 arrest of melanoma cell lines without inducing apoptosis. Moreover, targeting this molecule led to an important upregulation in the expression of tumor associated antigens and MHC class I, suggesting a potential improvement in the immunogenicity of these cells. Of note, this anti-melanoma activity was operative regardless of mutational status of the cells. These effects translated into a pronounced delay of in vivo melanoma tumor growth which was, at least in part, dependent on intact immunity as evidenced by the restoration of tumor growth after CD4+ and CD8+ depletion. Given our findings, we provide the initial rationale for the further development of selective HDAC6 inhibitors as potential therapeutic anti-melanoma agents.
Assuntos
Proliferação de Células/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/efeitos dos fármacos , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Animais , Linhagem Celular Tumoral , Fase G1/efeitos dos fármacos , Desacetilase 6 de Histona , Humanos , Melanoma Experimental/enzimologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Irradiated tumor cells transduced with the gene encoding the cytokine GM-CSF have been extensively studied as a vaccine formulation capable of priming systemic antitumor immune responses in the tumor-bearing host. In spite of the therapeutic promise of this vaccine strategy demonstrated in both animal models and early-phase clinical trials, clinical development has been limited by difficulties pertaining to the need to establish in culture the tumor of each patient and to perform individualized gene transfer. To circumvent these issues, we generated an HLA-negative human cell line producing large quantities of human GM-CSF for use as a universal bystander cell to be mixed with unmodified autologous tumor cells in the formulation of a vaccine. This line is easily propagated as a suspension culture in defined, serum-free medium. In a mouse model, we find that vaccination with a mixture of autologous tumor cells and an MHC-negative allogeneic GM-CSF-producing bystander cell primes antitumor immune responses that are equivalent or better than those achieved using autologous tumor cells directly transduced to secrete GM-CSF. This strategy greatly simplifies further clinical development of autologous tumor cell-based vaccines.
Assuntos
Vacinas Anticâncer , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Células Tumorais Cultivadas , Animais , Linhagem Celular , Transplante de Células , Modelos Animais de Doenças , Técnicas de Transferência de Genes , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Linfoma de Células B/terapia , Camundongos , Camundongos Endogâmicos BALB C , Transdução GenéticaRESUMO
We report single institution outcome of brief, intensive ara-C-based chemotherapy using bone marrow transplantation as primary intensification for untreated adult patients with acute lymphoblastic leukemia (ALL). Overall disease-free and overall survival were inferior to those reported with prolonged chemotherapy modeled on pediatric protocols. Survival and disease-free survival were superior for patients receiving allogeneic BMT compared with chemopurged autologous transplant or maintenance chemotherapy (patients ineligible for or declining BMT). In multivariate analysis, non-L2-FAB, higher ara-C dose, absence of CNS disease, non-Ph1+ karyotype, allogeneic BMT, T cell phenotype, and younger age were associated with improved disease-free survival. Autologous BMT was not superior to chemotherapy, and appears unlikely to provide adequate curative treatment for most adult ALL patients if not followed by maintenance.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Transplante de Medula Óssea , Citarabina/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto , Idoso , Seguimentos , Humanos , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Transplante AutólogoRESUMO
The use of chemotherapy has led to improved treatment outcome for some pediatric patients with medulloblastoma. We have used a pre-radiation chemotherapy regimen consisting of vincristine and CDDP. The 9L gliosarcoma implanted intracranially and subcutaneously in the same animals was used as a preclinical model system to assess the efficacy of treatment combinations including: vincristine, CDDP, cyclo-phosphamide, etanidazole and radiation. The experimental endpoints were percent increase-in-lifespan, tumor growth delay and tumor cell survival. Both the tumor growth delay and percent increase-in-lifespan improved as the number of agents included in the chemotherapy regimen increased. so that the chemotherapy regimen including all four agents (ETA/VIN/CDDP/CTX) resulted in the greatest tumor growth delay (23.6 +/- 1.5 days) and the greatest increase-in-lifespan (35.8%). When radiation (20 Gray, single dose) was added to the treatment regimens the combinations of ETA/CTX/X-ray and ETA/VIN/CDDP/CTX/X-ray resulted in equivalent tumor growth delays (25.2 +/- 1.3 days and 25.8 +/- 1.7 days, respectively), while the greatest increase-in-lifespan (39.1%) was obtained with the five agent combination. The response of the 9L gliosarcoma to CDDP and cyclophosphamide over a dosage range was very similar to that of the murine FSaII fibrosarcoma. Our results indicate that etanidazole may be an effective chemosensitizer of combination chemotherapy and combined modality treatment regimens for brain tumors.
RESUMO
Drug resistance is a major problem in cancer therapy. The MCF-7/CDDP cell line, a subline of the MCF-7 human breast carcinoma cell line which is resistant to cis-diamminedichloroplatinum(II), is also resistant to carboplatin, D-tetraplatin and to a lesser degree to melphalan, thiotepa and BCNU compared with the MCF-7 parental cell line. This resistance persists both under normally oxygenated conditions and after 2 h of exposure to hypoxic conditions prior to exposure to the antitumor alkylating agents under normally oxygenated conditions. When the MCF-7 parental cells and MCF-7/CDDP cells were treated with SR-4233 (20 muM) or etanidazole (5 mM) for 2 h prior to and during exposure to the antitumor alkylating agents there was no change in the sensitivity and resistance patterns of the cell lines. However, if the MCF-7 parental cells and the MCF-7/CDDP cells were exposed to SR-4233 (20 muM) or etanidazole (5 mM) for 2 h under hypoxic conditions followed by release of the hypoxia and exposure to the antitumor alkylating agents for 1 h under normally oxygenated conditions the resistance of the MCF-7/CDDP was reversed so that both the MCF-7 parental and MCF-7/CDDP cell lines were essentially equally sensitive to the six antitumor alkylating agents. These results indicate that non-cytotoxic concentrations of modulators such as SR-4233 or etanidazole may be useful in reversing resistance to the.
RESUMO
The growth of the DI-DMBA-3 mammary adenocarcinoma in BALB/c mice results in a profound deficit in the tumoricidal function of their peritoneal elicited macrophages (PEM) after stimulation with lipopolysaccharide (LPS). The capacity of these macrophages to respond to stronger signals, such as a combination of LPS and low levels (5 U/ml) of interferon-gamma (IFN-gamma) is also impaired. Importantly, a combination of high levels (50 U/ml) of IFN-gamma with 10 mug/ml of LPS, is able to trigger a cytolytic response in macrophages from tumor bearing mice against mammary tumor target cells, indicating that their lytic machinery is intact. However, IFN-gamma production is severely diminished in T lymphocytes from tumor bearing mice as detected by ELISA, moreover, Northern blots revealed that the levels of IFN-gamma RNA are also decreased in T cells from tumor bearers. The cooperation between T cells and macrophages is mediated, at least in part, by IFN-gamma. Thus, mammary tumors have die potential to overcome host defenses, either by affecting the capacity of macrophages to respond adequately to activating agents, and/or by impairing the production of T-cell derived lymphokines important in macrophage activation for tumor killing.
RESUMO
Oxygen tension measurements were made in three tumors: (i) the murine FSaII fibrosarcoma, (ii) the rat 9L gliosarcoma and (iii) the rat 13672 mammary adenocarcinoma using a pO2 histograph. Tumor oxygenation measurements were made while the animals breathed air or breathed carbogen (95% oxygen/5% carbon dioxide). Pentoxifylline or a perflubron emulsion was administered to the animals and tumor oxygen measurements were repeated under both breathing conditions. Both pentoxifylline and the perflubron emulsion improved the oxygenation of the FSaII fibrosarcoma under air breathing conditions but did not alter the oxygen profiles of either rat tumor compared with air breathing alone. Carbogen breathing increased the oxygenation of all tumors. Pentoxifylline administration did not change the oxygen profiles of the tumors under carbogen breathing conditions but administration of the perflubron emulsion increased the oxygenation of all three tumors under carbogen breathing conditions compared with carbogen breathing alone. Co-administration of pentoxifylline and the perflubron emulsion enhanced the radiation response of the Lewis lung tumor to daily fractionated radiation under air breathing conditions with a dose modifying factor of 1.65 and under carbogen breathing conditions with a dose modifying factor of 2.25. Over a range of perflubron emulsion doses, pentoxifylline increased the growth delay of the Lewis lung tumor in a constant manner. These results indicate that pentoxifylline and the perflubron emulsion have the largest impact on the oxygenation of more hypoxic tumors and that administration of the perflubron emulsion/carbogen breathing is the most effective means of increasing tumor oxygenation and radiation response.
RESUMO
Rat 13672 mammary carcinoma tumors were grown subcutaneously in the hind legs of female Fischer 344 rats to a volume of about 1 cm3. Tumor oxygenation was measured using an Eppendorf PO2 histograph. Tumor oxygen measurements were made under four conditions: (a) normal air breathing, (b) carbogen breathing, (c) after intravenous administration of a perflubron emulsion (8 ml/kg) with air breathing and (d) after intravenous administration of a perflubron emulsion (8 ml/kg) with carbogen breathing. Tumor oxygenation was examined without treatment or 24 h and 48 h after treatment with cyclophosphamide (300 mg/kg, i.p.) or cisplatin (8 mg/kg, i.p.] or after the fifth dose of a daily regimen of 3-Gy irradiation (5 x 3 Gy). Under normal air-breathing conditions 49% of the tumor had a PO2 < or = 670 Pa (5 mm Hg). The degree of hypoxia in the tumors increased after each treatment such that 24 h after treatment 65%-85% of the oxygen readings were < or = 670 Pa and 48 h after treatment 60%-74% of the oxygen readings were < or = 670 Pa. Administration of the perflubron emulsion/carbogen atmosphere increased the oxygen content of the tumors both without treatment and after each of the treatments. A knowledge of tumor oxygen content over the course of treatment and the ability to increase tumor oxygen should allow for the development of more rational treatment combinations and better treatment outcomes.
Assuntos
Dióxido de Carbono/farmacologia , Cisplatino/uso terapêutico , Ciclofosfamida/uso terapêutico , Fluorocarbonos/farmacologia , Neoplasias Mamárias Experimentais/metabolismo , Oxigênio/análise , Oxigênio/farmacologia , Radiossensibilizantes/farmacologia , Animais , Emulsões , Feminino , Hidrocarbonetos Bromados , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/radioterapia , Consumo de Oxigênio/efeitos dos fármacos , Pressão Parcial , Ratos , Ratos Endogâmicos F344RESUMO
Tumor oxygen tensions were measured using a computer-controlled PO2 microelectrode in two preclinical solid tumor models, the rat 9L gliosarcoma and the rat 13672 mammary carcinoma. Tumor oxygenation profiles were determined under four conditions: (a) during normal air breathing, (b) during carbogen breathing, (c) after intravenous administration of a solution of ultrapurified polymerized bovine hemoglobin with normal air breathing and (d) after intravenous administration of a solution of ultrapurified polymerized bovine hemoglobin with carbogen breathing. Both tumors had severely hypoxic regions under normal air-breathing conditions. Although carbogen breathing increased the oxygenation of the better-oxygenated portions of the tumor, it made no impact on the severely hypoxic tumor regions. Administration of the hemoglobin solution was effective in increasing the oxygenation throughout both tumors under normal air-breathing conditions. The addition of carbogen breathing to administration of the hemoglobin solution eliminated severe hypoxia in the 9L gliosarcoma and markedly reduced the severely hypoxic regions of the 13672 mammary carcinoma. At 24 h after administration of the hemoglobin solution the 13672 mammary carcinoma showed greater hypoxia than before treatment, which was partially corrected with carbogen breathing.