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PURPOSE: Despite previous studies proposing shorter durations of anti-HER2 therapy for selected patients with HER2-positive early breast cancer (EBC), 12-months remains standard of care. A survey was performed to assess patient perspectives and willingness to participate in studies evaluating shorter durations of anti-HER2 therapy. METHODS: Patients with HER2-positive EBC completing or having previously completed anti-HER2 therapy, were recruited by healthcare professionals at The Ottawa Hospital Cancer Centre to participate in an anonymous online survey. The primary objective was to learn about patients' perspectives on shorter durations (less than 12-months) of anti-HER2 therapy. Secondary objectives were to explore patients' interest in clinical trials of shorter durations of anti-HER2 therapy and the degree of increased breast cancer risk they would accept with a shorter treatment duration. RESULTS: Responses were received from 94 eligible patients. Most patients received Trastuzumab alone (78%, 73/94), while 13% (12/94) received trastuzumab and pertuzumab. Side effects were experienced by 52% (46/89), the most common being; fatigue (61%, 28/46), myalgia (37%, 17/46), and diarrhea (24%, 11/46). Most patients (88%, 78/89) did not find treatment bothersome. Regarding perspectives on shorter durations of anti-HER2 therapy, most (79%, 74/94) respondents stated they would agree to less treatment if it were possible to receive fewer treatments with the same cancer benefits. 56% of patients were interested in clinical trials, however, about half stated they would not be accepting of any increase in breast cancer recurrence risk. CONCLUSION: Trials to investigate who can safely and effectively be treated with shorter durations of anti-HER2 therapy are needed. This study provides important insights to patients' perspectives on shorter durations of anti-HER2 treatment, and their concerns regarding potential increased cancer risk with less treatment.
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Neoplasias de la Mama , Receptor ErbB-2 , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Femenino , Receptor ErbB-2/metabolismo , Persona de Mediana Edad , Anciano , Adulto , Encuestas y Cuestionarios , Trastuzumab/uso terapéutico , Estadificación de Neoplasias , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano de 80 o más AñosRESUMEN
BACKGROUND: The optimal duration of filgrastim as primary febrile neutropenia (FN) prophylaxis in early breast cancer patients is unknown, with 5, 7 or 10 days being commonly prescribed. This trial evaluates whether 5 days of filgrastim was non-inferior to 7/10 days. PATIENTS AND METHODS: In this randomised, open-label trial, early breast cancer patients who were to receive filgrastim as primary FN prophylaxis were randomly allocated to 5 versus 7 versus 10 days of filgrastim for all chemotherapy cycles. A protocol amendment in November 2017 allowed subsequent patients (N = 324) to be randomised to either 5 or 7/10 days. The primary outcome was a composite of either FN or treatment-related hospitalisations. Secondary outcomes included chemotherapy dose reductions, delays and discontinuations. Analyses were carried out by per protocol (primary) and intention-to-treat, and the non-inferiority margin was set at 3% for the risk of having FN and/or hospitalisation per cycle of chemotherapy. RESULTS: Patients (N = 466) were randomised to receive 5 (184, 39.5%), or 7/10 (282, 60.5%) days of filgrastim. In our primary analysis, the difference in risk of either FN or treatment-related hospitalisation per cycle was -1.52% [95% confidence interval (CI): -3.22% to 0.19%] suggesting non-inferiority of a 5-day filgrastim schedule compared with 7/10-days. The difference in events per cycle for FN was 0.11% (95% CI: -1.05 to 1.27) while for treatment-related hospitalisations it was -1.68% (95% CI: -2.73% to -0.63%). The overall proportions of patients having at least one occurrence of either FN or treatment-related hospitalisation were 11.8% and 14.96% for the 5- and 7/10-day groups, respectively (risk difference: -3.17%, 95% CI: -9.51% to 3.18%). CONCLUSION: Five days of filgrastim was non-inferior to 7/10 days. Given the cost and toxicity of this agent, 5 days should be considered standard of care. CLINICALTRIALS. GOV REGISTRATION: NCT02428114 and NCT02816164.
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Neoplasias de la Mama , Neutropenia Febril Inducida por Quimioterapia , Neutropenia Febril , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neutropenia Febril Inducida por Quimioterapia/epidemiología , Neutropenia Febril Inducida por Quimioterapia/etiología , Neutropenia Febril Inducida por Quimioterapia/prevención & control , Neutropenia Febril/inducido químicamente , Neutropenia Febril/epidemiología , Neutropenia Febril/prevención & control , Filgrastim/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes/uso terapéuticoRESUMEN
BACKGROUND: Taxane acute pain syndrome (TAPS) is characterized by myalgias and arthralgias starting 2-3 days after taxane-based chemotherapy and lasting up to 7 days. In the absence of validated tools, many studies use the presence of both the myalgia and arthralgia components of the Common Terminology Criteria for Adverse Events (CTCAE) to define TAPS. The present study prospectively evaluated the frequency, severity, and impact of TAPS in patients with breast or prostate cancer. PATIENTS AND METHODS: In this prospective, non-randomized study, patients with breast or prostate cancer commencing taxane-based chemotherapy completed the CTCAE (version 4.03), the Functional Assessment of Cancer Therapy-Taxane (FACT-T), and Brief Pain Inventory (BPI) questionnaires at baseline and once between days 5 and 7 of each chemotherapy cycle. RESULTS: From March 2015 to April 1, 2016, 75 patients (breast n = 66, prostate n = 9) were enrolled; 83% received docetaxel and 16% paclitaxel and 1% withdrew. After the first cycle of taxane, TAPS was reported by 25/69 (36.2%) patients; a further 8/69 (18.2%) reporting TAPS after a subsequent chemotherapy treatment. Overall incidence of TAPS was 33/75 (44%). While associated with detrimental scores on FACT-T and BPI as well as increased use of analgesics in 63% (21/33) of patients with TAPS, TAPS did not lead to alterations in chemotherapy dosing. CONCLUSIONS: TAPS is common after taxane-based chemotherapy, and its presence is associated with reduced quality of life and increased analgesic requirements. Prospective patient-reported outcome assessments are crucial to help individualize treatment strategies and improve management of TAPS.
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Dolor Agudo/tratamiento farmacológico , Artralgia/inducido químicamente , Neoplasias de la Mama/complicaciones , Hidrocarburos Aromáticos con Puentes/efectos adversos , Mialgia/inducido químicamente , Neoplasias de la Próstata/complicaciones , Taxoides/efectos adversos , Dolor Agudo/psicología , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Neoplasias de la Próstata/tratamiento farmacológico , Calidad de Vida , SíndromeRESUMEN
Background: Despite advances in systemic therapy choices for patients with early-stage breast cancer, optimal practices for intravenous (IV) access remain unknown. That lack of knowledge holds particularly true for the use of central venous access devices (cvads) such as peripherally inserted central catheters (piccs) and implanted vascular access devices (ports). Methods: Using a survey of Canadian oncologists and oncology nurses responsible for the care of breast cancer patients, we evaluated current access practices, perceptions of complications, and perceptions of risk, and we estimated complication rates and evaluated perceived risk factors for lymphedema. Results: Survey responses were received from 25 physicians and 57 oncology nurses. Administration of trastuzumab or an anthracycline was associated with a higher likelihood of a cvad being recommended. Other factors associated with recommendation of a cvad included prior difficult IV access and a recommendation from the chemotherapy nurse. Although the complication rates perceived to be associated with the use of piccs and ports remained high, respondents felt that cvads might improve patient quality of life. Risk factors perceived to be associated with the risk of lymphedema were axillary lymph node dissection, radiation to the axilla, and line-associated infection. Factors known to be unrelated to lymphedema risk (specifically, blood draws and blood pressure measurement) continue to be perceived as posing a higher risk. Conclusions: Despite widespread use of chemotherapy for patients with breast cancer, the type of venous access used for treatment varies significantly, as do perceptions about the risks of cvad use and the risk for lymphedema development. Further prospective studies are needed to identify best-practice strategies.
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Administración Intravenosa/métodos , Neoplasias de la Mama/tratamiento farmacológico , Cateterismo Venoso Central/métodos , Neoplasias de la Mama/patología , Femenino , Humanos , Enfermeras y Enfermeros , Médicos , Encuestas y CuestionariosRESUMEN
Background: The choice of vascular access for systemic therapy administration in breast cancer remains an area of clinical equipoise, and patient preference is not consistently acknowledged. Using a patient survey, we evaluated the patient experience with vascular access during treatment for early-stage breast cancer and explored perceived risk factors for lymphedema. Methods: Patients who had received systemic therapy for early-stage breast cancer were surveyed at 2 Canadian cancer centres. Results: Responses were received from 187 patients (94%). The route of vascular access was peripheral intravenous line (IV) in 24%, a peripherally inserted central catheter (picc) in 42%, and a surgically inserted central catheter (port) in 34%. Anthracycline-based regimens were associated with a greater use of central vascular access devices (cvads- that is, a picc or port; 86/97, 89%). Trastuzumab use was associated with greater use of ports (49/64, 77%). Although few patients (7%) reported being involved in the decisions about vascular access, most were satisfied or very satisfied (88%) with their access type. Patient preference centred mainly on avoiding delays in the initiation of chemotherapy. Self-reported rates of complications (183 evaluable responses) were infiltration with peripheral IVs (9/44, 20%), local skin infections with piccs (7/77, 9%), and thrombosis with ports (4/62, 6%). Perceived risk factors for lymphedema included use of the surgical arm for blood draws (117/156, 75%) and blood pressure measurement (115/156, 74%). Conclusions: Most patients reported being satisfied with the vascular access used for their treatment. Improved education and understanding about the evidence-based requirements for vascular access are needed. Perceived risk factors for lymphedema remain variable and are not evidence-based.
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Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/tratamiento farmacológico , Infusiones Intravenosas/métodos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Femenino , Humanos , Linfedema/etiología , Linfedema/patología , Persona de Mediana Edad , Factores de Riesgo , Encuestas y Cuestionarios , Adulto JovenRESUMEN
IMPORTANCE: Clinical equipoise exists around the optimal time to start adjuvant endocrine therapy in patients who will receive post-operative radiotherapy for breast cancer. Concerns continue to exist regarding potential reduced efficacy, or increased toxicity, when radiation, and endocrine therapy are administered concurrently. OBJECTIVE: To perform a systematic review of studies comparing outcomes between sequential and concurrent adjuvant radiation and endocrine therapy in early-stage breast cancer. All modalities of radiation therapy were considered, and endocrine therapy could be either tamoxifen or an aromatase inhibitor. Outcomes of interest included; local, regional or distant recurrence, overall survival and treatment-related toxicities. EVIDENCE REVIEWED: PubMed, Ovid Medline, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from 1946 to December 2017. Two reviewers independently assessed each citation using the criteria outlined above. Study quality was assessed using the Cochrane Collaboration's tool for prospective studies, and the Newcastle-Ottawa scale for retrospective studies. FINDINGS: Of 2137 unique citations identified, 13 met eligibility criteria. Eleven were unique studies (7569 patients), while 2 of the studies were updated analyses of previous studies. Studies evaluated the timing of adjuvant radiation, and tamoxifen (5 studies, 1550 patients), or aromatase inhibitors (6 studies, 6019 patients). We identified 1 complete randomized clinical trial (150 patients), and 5 retrospective studies (1580 patients), in addition to conference abstracts (5 studies, 5839 patients). Overall, none of the studies showed a significant difference in efficacy, or toxicity, with concurrent versus sequential treatment. However, given the significant heterogeneity of the study populations, it was not possible to conduct a meta-analysis. CONCLUSIONS AND RELEVANCE: In the absence of high quality data, adequately powered randomized trials are required to answer this important clinical question.
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Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/terapia , Quimioterapia Adyuvante , Esquema de Medicación , Femenino , Humanos , Pronóstico , Radioterapia AdyuvanteRESUMEN
OBJECTIVES: Because of difficulty experienced in assessing pain in frail older patients and the lack of pain assessment tools with standardization in the elderly, the Functional Pain Scale (FPS), an instrument incorporating both subjective and objective components to assess pain, was developed and evaluated. DESIGN, SETTING, PARTICIPANTS, AND MEASURES: One hundred subjects more than 65 years old participated in the validity, reliability, and responsiveness (the clinical sensitivity of the instrument to change) testing of the Functional Pain Scale. Subjects were recruited from a geriatrics inpatient setting, a geriatrics outpatient setting, and a local hospice (residing in their homes). Ninety-four of the subjects completed all phases of testing. Reliability was tested using a test-retest format and a correlation matrix. Criterion-related validity was established as compared with the Visual Analog Scale (VAS), the Present Pain Intensity (PPI), the McGill Short Form Questionnaire (MPQ-SF), and the Numeric Pain Scale (NPS) instruments. Responsiveness for the FPS, the VAS, the PPI, the MPQ-SF, and the NPS instruments was determined using five previously described techniques: effect size, standardized response means, relative efficiency, direct comparison of t test scores, and direct comparison of P values. A cumulative index was developed to rank each scale. Cumulative responsiveness index scores were based on individual scale performance for each separate responsiveness test. The lowest score in the cumulative responsiveness index indicated the most responsive scale. RESULTS: Interrater reliability for instruments tested exceeded 0.95 for all instruments tested. Validity testing showed high correlations as well (r = 0.62, r = 0.85, r = 0.80, r = 0.90 for the VAS, the PPI, the MPQ-SF, and the NPS respectively). Responsiveness evaluated overall by the responsiveness index was best for the Functional Pain Scale (7) followed by the Visual Analog Scale (12), the Present Pain Intensity (13), the McGill Pain Questionnaire-Short Form (19), and the Numerical Pain Questionnaire (24). CONCLUSIONS: The Functional Pain Scale was determined to be reliable, valid, and responsive. The responsiveness of the Functional Pain Scale was superior to the other instruments tested. The Functional Pain Scale is an acceptable instrument for assessing pain in older adults and may reflect changes in pain better than other instruments tested. Further testing in other populations is warranted.
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The changes in lipoprotein(a) concentration that occur with age as a result of its association with an increased risk of coronary artery disease were investigated. Lipoprotein(a) concentrations were measured in serum samples from healthy volunteers, individuals with premature coronary artery disease, individuals with hyperlipidaemia but without evidence of premature coronary artery disease, and also in elderly men and women who had hyperlipidaemia. Concentrations in individuals with premature coronary artery disease were the same as those of the healthy volunteers, while in both these groups they were lower than those found in hyperlipidaemic elderly men and women, and those found in hyperlipidaemic women aged 36-68 years. No association between raised lipoprotein(a) concentration and mortality as a result of premature coronary artery disease was demonstrated. Raised lipoprotein(a) levels found in the hyperlipidaemic individuals also suggested that it may not be an independent risk factor.
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Colesterol/sangre , Enfermedad Coronaria/sangre , Hiperlipidemias/sangre , Lipoproteína(a)/sangre , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
pT1 G3 bladder carcinomas are heterogeneous with respect to tumor recurrence and progression. Whereas some urologists treat these carcinomas by repeated transurethral resections often followed by intravesical chemotherapy or BCG instillation, others recommend cystectomy after tumor recurrence or early cystectomy after the initial diagnosis. Our goal was to determine the prognostic value of p53, p21/WAF1, Bcl-2, Bax, Bak, and Ki-67 immunoreactivity in these tumors. There were 30 patients with a new histopathological diagnosis of pT1 G3 urothelial carcinoma based on a transurethral resection specimen. Representative sections of these specimens were examined for the above markers. All patients were followed up regularly and were classified as being tumor free or having tumor recurrence or progression. The mean follow-up period was 43 months (range: 8-102 months). Twenty-five patients underwent radical cystectomy and 7 of these (28%) suffered from tumor progression and died of bladder cancer. In 5 patients, surgery was limited to a transurethral resection and 4 of these patients developed superficial tumor recurrence. There was a significant difference in tumor-free survival between patients with p53-immunoreactive (mean: 30 months) and p53-negative tumors (mean: 82 months; p = 0.0341). Bcl-2 positivity was also associated with decreased tumor-free survival (p = 0.043). The other markers had no significant prognostic impact. We conclude that p53 and Bcl-2 immunoreactivity labels the most aggressive pT1 G3 bladder carcinomas.
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Biomarcadores de Tumor/análisis , Carcinoma de Células Transicionales/patología , Ciclinas/análisis , Proteínas de la Membrana/análisis , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Proteínas Proto-Oncogénicas/análisis , Proteína p53 Supresora de Tumor/análisis , Neoplasias de la Vejiga Urinaria/patología , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/cirugía , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Supervivencia sin Enfermedad , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Antígeno Ki-67/análisis , Invasividad Neoplásica , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Factores de Tiempo , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/cirugía , Proteína Destructora del Antagonista Homólogo bcl-2 , Proteína X Asociada a bcl-2RESUMEN
Mycobacterium tuberculosis survives within host macrophages by actively inhibiting phagosome fusion with lysosomes. Treatment of infected macrophages with ATP induces both cell apoptosis and rapid killing of intracellular mycobacteria. The following studies were undertaken to characterize the effector pathway(s) involved. Macrophages were obtained from p47(phox) and inducible NO synthase gene-disrupted mice (which are unable to produce reactive oxygen and nitrogen radicals, respectively) and P2X(7) gene-disrupted mice. RAW murine macrophages transfected with either the natural resistance-associated macrophage protein gene 1 (Nramp1)-resistant or Nramp1-susceptible gene were also used. The cells were infected with bacille Calmette-Guérin (BCG), and intracellular mycobacterial trafficking was analyzed using confocal and electron microscopy. P2X(7) receptor activation was essential for effective ATP-induced mycobacterial killing, as its bactericidal activity was radically diminished in P2X(7)(-/-) macrophages. ATP-mediated killing of BCG within p47(phox-/-), inducible NO synthase(-/-), and Nramp(s) cells was unaffected, demonstrating that none of these mechanisms have a role in the ATP/P2X(7) effector pathway. Following ATP stimulation, BCG-containing phagosomes rapidly coalesce and fuse with lysosomes. Blocking of macrophage phospholipase D activity with butan-1-ol blocked BCG killing, but not macrophage death. ATP stimulates phagosome-lysosome fusion with concomitant mycobacterial death via P2X(7) receptor activation. Macrophage death and mycobacterial killing induced by the ATP/P2X(7) signaling pathway can be uncoupled, and diverge proximal to phospholipase D activation.
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Adenosina Trifosfato/farmacología , Bacteriólisis/efectos de los fármacos , Lisosomas/fisiología , Macrófagos/efectos de los fármacos , Fusión de Membrana/efectos de los fármacos , Mycobacterium bovis , Fagosomas/fisiología , Receptores Purinérgicos P2/fisiología , Animales , Bacteriólisis/fisiología , Butanoles/farmacología , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/fisiología , Línea Celular , Inhibidores Enzimáticos/farmacología , Humanos , Concentración de Iones de Hidrógeno , Macrófagos/microbiología , Macrófagos/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Noqueados , Microscopía Confocal , Microscopía Electrónica , Microscopía Fluorescente , Monocitos/microbiología , Monocitos/fisiología , NADPH Oxidasas , Óxido Nítrico Sintasa/deficiencia , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/fisiología , Óxido Nítrico Sintasa de Tipo II , Fosfolipasa D/antagonistas & inhibidores , Fosfolipasa D/fisiología , Fosfoproteínas/deficiencia , Fosfoproteínas/genética , Fosfoproteínas/fisiología , Receptores Purinérgicos P2/deficiencia , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2X7 , Vacuolas/microbiologíaRESUMEN
We previously demonstrated that extracellular ATP stimulated macrophage death and mycobacterial killing within Mycobacterium bovis Bacille Calmette-Guérin (BCG)-infected human macrophages. ATP increases the cytosolic Ca(2+) concentration in macrophages by mobilizing intracellular Ca(2+) via G protein-coupled P2Y receptors, or promoting the influx of extracellular Ca(2+) via P2X purinoceptors. The relative contribution of these receptors and Ca(2+) sources to ATP-stimulated macrophage death and mycobacterial killing was investigated. We demonstrate that 1) ATP mobilizes Ca(2+) in UTP-desensitized macrophages (in Ca(2+)-free medium) and 2) UTP but not ATP fails to deplete the intracellular Ca(2+) store, suggesting that the pharmacological properties of ATP and UTP differ, and that a Ca(2+)-mobilizing P2Y purinoceptor in addition to the P2Y(2) subtype is expressed on human macrophages. ATP and the Ca(2+) ionophore, ionomycin, promoted macrophage death and BCG killing, but ionomycin-mediated macrophage death was inhibited whereas BCG killing was largely retained in Ca(2+)-free medium. Pretreatment of cells with thapsigargin (which depletes inositol (1,4,5)-trisphosphate-mobilizable intracellular stores) or 1,2-bis-(2-aminophenoxy)ethane-N, N, N',N'-tetraacetic acid acetoxymethyl ester (an intracellular Ca(2+) chelator) failed to inhibit ATP-stimulated macrophage death but blocked mycobacterial killing. Using the acidotropic molecular probe, 3-(2,4-dinitroanilino)-3'-amino-N-methyl dipropylamine, it was revealed that ATP stimulation promoted the acidification of BCG-containing phagosomes within human macrophages, and this effect was similarly dependent upon Ca(2+) mobilization from intracellular stores. We conclude that the cytotoxic and bactericidal effects of ATP can be uncoupled and that BCG killing is not the inevitable consequence of death of the host macrophage.
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Adenosina Trifosfato/fisiología , Bacteriólisis , Calcio/fisiología , Macrófagos/microbiología , Mycobacterium bovis/crecimiento & desarrollo , Fagosomas/metabolismo , Fagosomas/microbiología , Adenosina Trifosfato/farmacología , Adenosina Trifosfato/toxicidad , Bacteriólisis/efectos de los fármacos , Calcio/metabolismo , Muerte Celular/efectos de los fármacos , Muerte Celular/inmunología , Células Cultivadas , Citosol/metabolismo , Ácido Egtácico/análogos & derivados , Ácido Egtácico/farmacología , Inhibidores de Crecimiento/toxicidad , Humanos , Concentración de Iones de Hidrógeno , Ionomicina/farmacología , Ionóforos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/ultraestructura , Mycobacterium bovis/efectos de los fármacos , Mycobacterium bovis/inmunología , Fagosomas/efectos de los fármacos , Fagosomas/ultraestructura , ARN Mensajero/análisis , Receptores Purinérgicos P2/biosíntesis , Receptores Purinérgicos P2/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Tapsigargina/farmacología , Uridina Trifosfato/fisiologíaRESUMEN
The death of BCG-infected human macrophages induced in vitro by ligation of surface CD95 (Fas), CD69, or complement-mediated lysis was shown not to result in the death of intracellular mycobacteria, whereas exposure to extracellular ATP initiated both macrophage death and killed the intracellular bacteria. ATP acted via P2Z receptors because these effects were mimicked by benzoylbenzoic ATP (a known agonist of P2Z receptors) and blocked by oxidized ATP, DIDS, suramin, amiloride, and KN62 (known inhibitors of P2Z-mediated responses). ATP-mediated bacterial killing was independent of reactive nitrogen and oxygen intermediates and of actinomycin D or cycloheximide inhibition. ATP-induced macrophage cell death, BCG killing, and lucifer yellow dye incorporation were minimal in 2 out of 19 healthy donors. The results suggest possible genetic heterogeneity of this mechanism of mycobacterial killing associated with P2Z-mediated pore formation.