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PURPOSE: Interferon alfa-2b (IFN alpha-2b) exhibits antitumor activity in metastatic melanoma and on this basis has been evaluated as an adjuvant therapy following surgery for deep primary (T4) or regionally metastatic (N1) melanoma. METHODS: A randomized controlled study of IFN alpha-2b (Schering-Plough, Kenilworth, NJ) administered at maximum-tolerated doses of 20 MU/m2/d intravenously (i.v.) for 1 month and 10 MU/m2 three times per week subcutaneously (SC) for 48 weeks versus observation, was conducted by the Eastern Cooperative Oncology Group (ECOG) in 287 patients. RESULTS: A significant prolongation of relapse-free survival (P = .0023, one-sided) and prolongation of overall survival (P = .0237, one-sided) was observed with IFN alpha-2b therapy in this trial, which is now mature with a median follow-up time of 6.9 years. The impact of treatment on relapse rate is most pronounced early during the treatment interval. The overall benefit of treatment in this trial was analyzed stratified by tumor burden and the presence or absence of microscopic nonpalpable and palpable regional lymph node metastasis. The benefit of therapy with IFN alpha-2b was greatest among node-positive strata. Toxicity of IFN alpha-2b required dose modification in the majority of patients, but treatment at > or = 80% of the scheduled dose was feasible in the majority of patients through the IV phase of treatment, and for more than 3 months of SC maintenance therapy. Discontinuation of treatment due to toxicity was infrequent after the fourth month of therapy. CONCLUSION: IFN alpha-2b prolongs the relapse-free interval and overall survival of high-risk resected melanoma patients. The increment in median disease-free survival (from 1 to 1.7 years) and overall survival (from 2.8 to 3.8 years) that results from this therapy is associated with a 42% improvement in the fraction of patients who are continuously disease-free after treatment with IFN (from 26% to 37%) in comparison to observation. IFN alpha-2b is the first agent to show a significant benefit in relapse-free and overall survival of high-risk melanoma patients in a randomized controlled trial.
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The Notch pathway is an evolutionary conserved signaling cascade that has an essential role in melanoblast and melanocyte stem cell homeostasis. Notch signaling is emerging as a key player in melanoma, the most deadly form of skin cancer. In melanoma, Notch1 is inappropriately reactivated and contributes to melanoma tumorigenicity. Here, we propose a novel mechanism by which Notch1 promotes the disease. We found that Notch1 directly regulates the transcription of neuregulin1 (NRG1) by binding to its promoter region. NRG1 is the ligand for ERBB3 and 4, members of the epidermal growth factor family of receptors that are involved in the genesis and progression of a number of cancers. Notch1 and NRG1 expression are associated in melanoma and inhibition of NRG1 signaling leads to melanoma cell growth inhibition and tumor growth delay. Mechanistically, these effects are associated with the inhibition of the PI3Kinase/Akt signaling pathway and with the accumulation of p27(Kip1). On the other end, addition of recombinant NRG1 can partially restore melanoma cell growth that is inhibited by Notch1 ablation. Taken together, our findings underline a new, previously undescribed autocrine signaling loop between Notch1 and NRG1 that controls melanoma growth and provide experimental evidence that the targeting of Notch and ERBB signaling may represent a novel potential therapeutic approach in melanoma.
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Melanoma/patología , Neurregulina-1/metabolismo , Receptor Notch1/metabolismo , Transducción de Señal , Neoplasias Cutáneas/patología , Humanos , Melanoma/metabolismo , Neurregulina-1/genética , Regiones Promotoras Genéticas , Neoplasias Cutáneas/metabolismoRESUMEN
Hormonally regulated survival factors can have an important role in breast cancer. Here we elucidate G1P3, a survival protein induced by interferons (IFNs), as a target of estrogen signaling and a contributor to poor outcomes in estrogen receptor-positive (ER(+)) breast cancer. Compared with normal breast tissue, G1P3 was upregulated in the malignant epithelium (50 × higher) and was induced by estrogen ex vivo. In accord with its overexpression in early stages of breast cancer (hyperplasia and ductal carcinoma in situ), in morphogenesis assays G1P3 enhanced the survival of MCF10A acinar luminal cells causing hyperplasia by suppressing detachment-induced loss of mitochondrial potential and apoptosis (anoikis). In cells undergoing anoikis, G1P3 attenuated the induction of Bim protein, a proapoptotic member of the Bcl-2 family and reversed the downmodulation of Bcl-2 protein. Downregulation of G1P3 induced spontaneous apoptosis in BT-549 breast cancer cells and significantly reduced the growth of ER(+) breast cancer cell MCF7 (P≤0.01), further suggesting its prosurvival activity. In agreement with its induction by estrogen, G1P3 antagonized tamoxifen, an inhibitor of ER in MCF7 cells. More importantly, elevated expression of G1P3 was significantly associated with decreased relapse-free and overall survival in ER(+) breast cancer patients (P≤0.01). Our studies suggest that elevated expression of G1P3 may perturb canonical tumor-suppressing activity of IFNs partly by affecting the balance of pro- and antiapoptotic members of Bcl-2 family proteins, leading to breast cancer development and resistance to therapies.
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Neoplasias de la Mama/metabolismo , Proteínas Mitocondriales/metabolismo , Antineoplásicos Hormonales/uso terapéutico , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteína 11 Similar a Bcl2 , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Hiperplasia/patología , Proteínas de la Membrana/metabolismo , Neoplasias Hormono-Dependientes/metabolismo , Pronóstico , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptores de Estrógenos/metabolismo , Tamoxifeno/uso terapéutico , Regulación hacia ArribaRESUMEN
BACKGROUND: Although inhibitors of histone deacetylase inhibitors (HDACis) in combination with genotoxins potentiate apoptosis, the role of proteases other than caspases in this process remained elusive. Therefore, we examined the potentiation of apoptosis and related mechanisms of HDACis and doxorubicin combination in a panel of myeloma cell lines and in 25 primary myelomas. RESULTS: At IC(50) concentrations, sodium butyrate (an HDACi) or doxorubicin alone caused little apoptosis. However, their combination potentiated apoptosis and synergistically reduced the viability of myeloma cells independent of p53 and caspase 3-7 activation. Potentiated apoptosis correlated with nuclear translocation of apoptosis-inducing factor, suggesting the induction of caspase 3- and 7-independent pathways. Consistent with this, butyrate and doxorubicin combination significantly increased the activity of cytoplasmic cathepsin B. Inhibition of cathepsin B either with a small-molecule inhibitor or downregulation with a siRNA reversed butyrate- and doxorubicin-potentiated apoptosis. Finally, ex vivo, clinically relevant concentrations of butyrate or SAHA (suberoylanilide hydroxamic acid, vorinostat, an HDACi in clinical testing) in combination with doxorubicin significantly (P<0.0001) reduced the survival of primary myeloma cells. CONCLUSIONS: Cathepsin B has a prominent function in mediating apoptosis potentiated by HDACi and doxorubicin combinations in myeloma. Our results support a molecular model of lysosomal-mitochondrial crosstalk in HDACi- and doxorubicin-potentiated apoptosis through the activation of cathepsin B.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Catepsina B/fisiología , Doxorrubicina/administración & dosificación , Inhibidores de Histona Desacetilasas/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Caspasas/metabolismo , Caspasas/fisiología , Catepsina B/antagonistas & inhibidores , Catepsina B/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citoplasma/metabolismo , Doxorrubicina/farmacología , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/farmacología , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , ARN Interferente Pequeño/farmacología , VorinostatRESUMEN
Human melanoma cell lines, SK-MEL-3 and SK-MEL-28, despite induction of the proapoptotic cytokine, Apo2L/TRAIL, did not undergo apoptosis in response to interferons (IFN-alpha2b or IFN-beta). Postulating that genes important for apoptosis induction by IFNs might be silenced by methylation, the DNA demethylating agent 5-aza-2'-deoxycytidine (5-AZAdC) was assessed. DR4 (TRAIL-R1) was identified as one of the genes reactivated by 5-AZAdC with a >3-fold increase in 8 of 10 melanoma cell lines. Pretreatment with 5-AZAdC sensitized SK-MEL-3 and SK-MEL-28 cells to apoptosis induced by IFN-alpha2b and IFN-beta; methylation-specific PCR and bisulfite sequencing confirmed demethylation of 5'CpG islands of DR4 and flow cytometry showed an increase in DR4 protein on the cell surface. In cells with reactivated DR4, neutralizing mAB to TRAIL reduced apoptosis in response to IFN-beta or Apo2L/TRAIL. To further confirm the role of DR4, it was expressed by retroviral vector in SK-MEL-3 and SK-MEL-28 cells with reversal of resistance to IFN-beta and Apo2L/TRAIL. Thus, reexpressing DR4 by 5-AZAdC or retroviral transfection in melanoma cell in which promoter methylation had suppressed its expression, potentiated apoptosis by IFN-alpha2b, IFN-beta and Apo2L/TRAIL. Reactivation of silenced proapoptotic genes by inhibitors of DNA methylation may enhance clinical response to IFNs or Apo2L/TRAIL.
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Azacitidina/análogos & derivados , ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , Metilación de ADN/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Silenciador del Gen/efectos de los fármacos , Interferones/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/genética , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/uso terapéutico , Apoptosis/efectos de los fármacos , Azacitidina/farmacología , Línea Celular Tumoral , ADN (Citosina-5-)-Metiltransferasa 1 , Decitabina , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Melanoma/patología , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismoRESUMEN
Interferon-alpha1 (IFN-alpha1), which may have a primary role in innate immunity, differs significantly in amino-acid sequence from IFN-alpha2, the only recombinant IFN-alpha with substantial clinical evaluation. Patients with metastatic malignancies received daily subcutaneous doses of 1.5-270 mug/m(2) of recombinant IFN-alpha1b. Gene modulation, pharmacokinetics, tolerability, and disease response were determined. Significant (P<0.01) dose and gene-dependent increases of 2-10 fold occurred in IFN-stimulated genes, including four (tumor necrosis factor-related apoptosis-inducing ligand, cig 5, p56, GEM) never previously identified as increased in patients; significant increases (P<0.01) resulted at the lowest dose (1.5 microg/m(2); 1.5 x 10(4) human antiviral units/m(2)). Increases (P<0.01) were sustainable for >4 weeks. Peak levels of IFN-alpha1b were at 3 h; an increase of approximately eightfold in both C(max) and AUC occurred between 15 microg/m(2) and 270 microg/m(2). Chronic toxicities of anorexia, weight loss, and fatigue were relatively uncommon. Eighteen patients were treated for >8 weeks; none experienced >grade 1 weight loss. Three patients at the highest dose developed grade 3 fatigue after > or =3 months, which required dose reduction or discontinuation. Patient acceptability of fatigue defined a dose for initiation of Phase II trials, 270 microg/m(2). Six patients (five with renal cell carcinoma) had progression-free survival for >1 year, including two who had partial responses. IFN-alpha1b resulted in potent stimulation of IFN-regulated genes and tumor regressions in renal cell carcinoma. Unique gene modulatory effects, when coupled with the moderate severity of side effects and a potentially central role in innate immunity, provide rationale for further clinical evaluation of IFN-alpha1 in virus infections and cancer.
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Antineoplásicos/farmacocinética , Interferón-alfa/efectos adversos , Interferón-alfa/farmacocinética , Farmacogenética , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Temperatura Corporal/efectos de los fármacos , Estudios de Cohortes , Citocinas/biosíntesis , Relación Dosis-Respuesta a Droga , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Interferón-alfa/uso terapéutico , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neopterin/biosíntesis , Análisis de Supervivencia , Ligando Inductor de Apoptosis Relacionado con TNF/biosíntesis , Ubiquitinas/biosíntesis , Microglobulina beta-2/biosíntesis , Microglobulina beta-2/genéticaRESUMEN
INTRODUCTION: Lenalidomide is an immunomodulatory derivative of thalidomide with significantly greater in vitro activity and a different toxicity profile. In preclinical trials it has shown synergy with chemotherapy. PATIENTS AND METHODS: Primary objective of this study was to determine the maximum tolerated doses of docetaxel and carboplatin when combined with oral lenalidomide in a standard phase I study design. Between September 2004 and May 2005, 14 patients with pathologically proven solid tumors, < or =2 prior chemotherapy regimens, performance status ECOG 0/1, and adequate organ function were enrolled. Dose limiting toxicities (DLT) were defined as > or = grade 3 non-hematological, or grade 4 hematological toxicity. No growth factors were used during cycle 1. RESULTS: Three of four patients treated at dose level 1, docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day 1, and lenalidomide 10 mg orally daily on Days 1-14 of a 21 day cycle experienced DLT (grade 3 electrolyte changes in two patients, and grade 4 neutropenia in one patient). Ten patients were treated at dose level -1, docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day 1, and lenalidomide 5 mg orally daily on Days 1-14 of a 21 day cycle with one DLT (Grade 4 neutropenia). There were no treatment-related deaths or irreversible toxicities. Of the 14 response-evaluable patients, five achieved a partial response (5 out of 9 patients with non-small cell lung cancer. CONCLUSIONS: Docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day 1, with lenalidomide 5 mg orally daily on Days 1-14 days of a 21 day cycle is the maximum tolerated dose without the use of prophylactic growth factors. This combination is active and further evaluation in a phase II trial is warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Administración Oral , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Docetaxel , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Lenalidomida , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Taxoides/administración & dosificación , Talidomida/administración & dosificación , Talidomida/análogos & derivados , Resultado del TratamientoRESUMEN
Bladder cancer is among the most prevalent malignancies, and is characterised by frequent tumour recurrences and localised inflammation, which may promote tissue invasion and metastasis. Microarray analysis was used to compare gene expression in normal bladder urothelium with that in tumours at different stages of progression. The innate immune response gene, interferon-stimulated gene 15 kDa (ISG15, GIP2), was highly expressed at all stages of bladder cancer as compared to normal urothelium. Western blotting revealed a tumour-associated expression of ISG15 protein. ISG15 exhibited a stage-associated expression, with significantly (P<0.05) higher levels of ISG15 protein in muscle-invasive T2-T4 tumours, compared with normal urothelium. Although ISG15 is involved in the primary immune response, ISG15 expression did not correlate with bladder inflammation. However, immunohistochemical staining revealed expression of ISG15 protein in both cancer cells and stromal immune cells. Interestingly, a significant fraction of ISG15 protein was localised to the nuclei of tumour cells, whereas no nuclear ISG15 staining was observed in ISG15-positive stromal cells. Taken together, our findings identify ISG15 as a novel component of bladder cancer-associated gene expression.
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Citocinas/metabolismo , Perfilación de la Expresión Génica , Ubiquitinas/metabolismo , Neoplasias de la Vejiga Urinaria/metabolismo , Urotelio/metabolismo , Western Blotting , Núcleo Celular/metabolismo , Núcleo Celular/patología , Citocinas/genética , Humanos , Neoplasias de los Músculos/metabolismo , Neoplasias de los Músculos/patología , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos , Células del Estroma/metabolismo , Células del Estroma/patología , Ubiquitinas/genética , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
PURPOSE: To determine whether interferon (IFN) -alpha2, when given with or following chemotherapy, influences response rate, remission duration, and survival in newly diagnosed patients with follicular lymphoma. PATIENTS AND METHODS: Ten phase III studies evaluating the role of IFN-alpha2 in 1,922 newly diagnosed patients with follicular lymphoma were analyzed. Updated individual patient data were used to perform meta-analyses for response, survival, and remission duration. RESULTS: The addition of IFN-alpha2 to initial chemotherapy did not significantly influence response rate. An overall meta-analysis for survival showed a significant difference in favor of IFN-alpha2, but also showed significant heterogeneity between studies. Further analyses were carried out in order to explain this heterogeneity, and to define the circumstances in which IFN-alpha2 prolonged survival. The survival advantage was seen when IFN-alpha2 was given: (1) in conjunction with relatively intensive initial chemotherapy (2P = .00005), (2) at a dose >/= 5 million units (2P = .000002), (3) at a cumulative dose >/= 36 million units per month (2P = .000008), and (4) with chemotherapy rather than as maintenance therapy (P = .004). With regard to remission duration, there was also a significant difference in favor of IFN-alpha2, irrespective of the intensity of chemotherapy used, IFN dose, or whether IFN was given as a maintenance strategy or with chemotherapy. CONCLUSION: When given in the context of relatively intensive initial chemotherapy, and at a dose >/= 5 million units (>/= 36 x 10(6) units per month), IFN-alpha2 prolongs survival and remission duration in patients with follicular lymphoma.
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Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Interferón-alfa/uso terapéutico , Linfoma Folicular/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ensayos Clínicos Fase II como Asunto , Esquema de Medicación , Femenino , Humanos , Interferón alfa-2 , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Proteínas Recombinantes , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Melanoma cells are relatively resistant to Apo2L/TRAIL (TNF-related apoptosis-inducing ligand). We postulated that resistance might result from higher expression of inhibitors of apoptosis including Bcl-2, FLIP (FLICE-like inhibitory protein) or IAPs such as XIAP (X-linked inhibitor of apoptosis) or survivin. Compared to scrambled or mismatch controls, targeting individual inhibitors with siRNA (si-Bcl-2, si-XIAP, si-FLIP or si-Surv), followed by Apo2L/TRAIL resulted in marked increase in apoptosis in melanoma cells. Compared to Bcl-2 or FLIP, siRNAs against XIAP and survivin were most potent in sensitizing melanoma cells. A similar substantial increase in apoptosis was seen in renal carcinoma cells (SKRC-45, Caki-2), following the inhibition of either XIAP or survivin by siRNAs. Apo2L/TRAIL treatment in IAP-targeted cells resulted in cleavage of Bid, activation of caspase-9 and cleavage of PARP (poly ADP-ribose polymerase). Thus, Apo2L/TRAIL resistance can be overcome by interfering with expression of inhibitors of apoptosis regulating both extrinsic (death receptor) or intrinsic (mitochondrial) pathways of apoptosis in melanoma cells.
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Apoptosis/fisiología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Glicoproteínas de Membrana/farmacología , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis , Proteína Proapoptótica que Interacciona Mediante Dominios BH3 , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Proteínas Portadoras/metabolismo , Caspasa 9 , Caspasas/metabolismo , Genes bcl-2/fisiología , Humanos , Proteínas Inhibidoras de la Apoptosis , Melanoma/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Neoplasias , ARN Interferente Pequeño/genética , Survivin , Ligando Inductor de Apoptosis Relacionado con TNF , Células Tumorales Cultivadas , Proteína Inhibidora de la Apoptosis Ligada a XRESUMEN
IFNs are a family of cytokines with pleiotropic biological effects mediated by scores of responsive genes. IFNs were the first human proteins to be effective in cancer therapy and were among the first recombinant DNA products to be used clinically. Both quality and quantity of life has been improved in response to IFNs in various malignancies. Despite its beneficial effects, unraveling the mechanisms of the anti-tumor effects of IFN has proven to be a complex task. IFNs may mediate anti-tumor effects either indirectly by modulating immunomodulatory and anti-angiogenic responses or by directly affecting proliferation or cellular differentiation of tumor cells. Both direct or indirect effects of IFNs result from induction of a subset of genes, called IFN stimulated genes (ISGs). In addition to the ISGs implicated in anti-viral, anti-angiogenic, immunomodulatory and cell cycle inhibitory effects, oligonucleotide microarray studies have identified ISGs with apoptotic functions. These include TNF-alpha related apoptosis inducing ligand (TRAIL/Apo2L), Fas/FasL, XIAP associated factor-1 (XAF-1), caspase-4, caspase-8, dsRNA activated protein kinase (PKR), 2'5'A oligoadenylate synthetase (OAS), death activating protein kinases (DAP kinase), phospholipid scramblase, galectin 9, IFN regulatory factors (IRFs), promyelocytic leukemia gene (PML) and regulators of IFN induced death (RIDs). In vitro IFN-alpha, IFN-beta and IFN-gamma induced apoptosis in multiple cell lines of varied histologies. This review will emphasize possible mechanisms and the role of ISGs involved in mediating apoptotic function of IFNs.
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Apoptosis/genética , Regulación de la Expresión Génica/genética , Interferones/genética , Animales , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Regulación de la Expresión Génica/inmunología , Humanos , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Transducción de Señal/genéticaAsunto(s)
Control de Medicamentos y Narcóticos/organización & administración , Economía Farmacéutica/organización & administración , Programas Nacionales de Salud/organización & administración , Canadá , Costos de los Medicamentos/legislación & jurisprudencia , Control de Medicamentos y Narcóticos/legislación & jurisprudencia , Economía Farmacéutica/legislación & jurisprudencia , Regulación Gubernamental , Humanos , Programas Nacionales de Salud/legislación & jurisprudencia , Evaluación de Necesidades , Formulación de PolíticasRESUMEN
BACKGROUND: To have a drug listed in a province's formulary, manufacturers must submit an application providing data required by the provincial rules and guidelines. The procedures for the scientific evaluation of drugs considered for listing for reimbursement in five provinces have been examined previously. OBJECTIVE: The present study investigates the clarity of the same five provinces' rules and guidelines about effectiveness and cost data that should be included in listing submissions from the perspective of the pharmaceutical company. METHODS: The manufacturers of five recently introduced drugs selected by the investigators received questionnaires asking about the departments within their companies that are responsible for the submission, the data required by each of the five provinces and the clarity of each province's requirements for submission. Each company was also asked similar questions about its own submission experience with its drug. Investigators visited each manufacturer to review the questionnaires and answer questions. RESULTS: The manufacturers perceived the rules and guidelines on effectiveness and economic data of several provinces as being neither clear nor consistent. Consequently, information that companies submit in their attempts at compliance with the rules and guidelines varies substantially. CONCLUSIONS: The manufacturers' perceptions of the information required by the provinces on effectiveness and cost information were inconsistent. Previous work indicated that the provinces make significant decisions about listings based on inadequate information resulting in a scientifically flawed system that contributes to considerable inequality in access to new drugs between provinces. The findings of the present work reinforce this conclusion.
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Costos de los Medicamentos , Formularios Farmacéuticos como Asunto/normas , Reembolso de Seguro de Salud/normas , Canadá , Análisis Costo-Beneficio , Industria Farmacéutica , Reembolso de Seguro de Salud/legislación & jurisprudencia , Gobierno EstatalRESUMEN
BACKGROUND: Facing financial pressures, the provinces and territories have chosen to use "cost-effectiveness" for making decisions about drug listings. This study examines the scientific basis for the procedures used to determine cost-effectiveness in 5 Canadian provinces. METHODS: Questionnaires were mailed to key provincial informants asking about the respondent's expertise and role, the administrative and scientific basis for decision-making, organizational structures and other factors in the scientific evaluation and decision-making process, and the transparency of the process. There were also questions about the data required and received and their importance, the place of cost-effectiveness and other economic impact evaluations, the data sources for them, and the use of follow-up monitoring to evaluate the decisions made. RESULTS: Information required by the provinces for decision-making about cost-effectiveness is not available to them at the time of their decisions about listing new medications. The primary sources of data on both efficacy and cost-effectiveness are pharmaceutical companies. Efficacy information is generated in a scientifically rigorous manner, whereas the effectiveness and cost data are estimates potentially subject to biases and evaluated by judgement (expert opinion) alone. Moreover, there is no collaboration in the assessment process between provinces. The outcomes are large differences between provinces in the decisions made and, hence, in the pharmaceuticals accessible to residents. CONCLUSIONS: Current methods for making decisions about provincial drug listings are based on inadequate data, and the lack of consistency in the provinces' decisions suggest they may be scientifically flawed. We recommend establishing a single national scientific review committee, with re-evaluation of each drug's cost-effectiveness after a suitable period of monitored use.
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Análisis Costo-Beneficio/economía , Toma de Decisiones , Costos de los Medicamentos , Economía Farmacéutica , Reembolso de Seguro de Salud/economía , Canadá , Humanos , Encuestas y CuestionariosRESUMEN
The Eastern Cooperative Oncology Group (ECOG) performed a prospectively randomized study (E6484) evaluating the use of interferon alfa 2a (IFN-alpha2a) in patients with aggressive low-grade or with intermediate-grade non-Hodgkin's lymphoma (NHL) accruing close to 300 patients between 1985 and 1988. Patients were eligible for study if they had bulky or symptomatic low-grade lymphoma or defined intermediate-grade subtypes. Of 291 patients enrolled, 249 were eligible for analysis. All patients were randomized to receive a four-drug cytotoxic chemotherapy regimen including cyclophosphamide, doxorubicin, vincristine and prednisone in 4-week cycles with or without IFN-alpha2a in addition (COPA vs I-COPA). Treatment was given for up to 8-10 months. This report, at a time when the median follow-up among survivors has reached 12 years, updates the analysis of time to treatment failure (TTF), duration of disease-free survival (DFS), and overall survival. Patients randomized to receive IFN-alpha2a had a prolonged TTF (P= 0.008; median 2.4 vs 1.6 years). DFS for those patients who had complete responses was also longer if IFN-alpha2a had been given (P = 0.035; median 2.7 vs 1.8 years). There was a clinically but not a statistically significant prolongation of overall survival by IFN-alpha2a (P= 0.107; median 7.8 vs 5.7 years). There were fewer deaths over time due to lymphoma in patients receiving IFN-alpha2a (67 vs 80 deaths). A subset analysis, based on disease histology (low-grade, follicular, intermediate-grade), revealed a significant prolongation of TTF in patients receiving IFN-alpha2a with either low-grade (P = 0.002; median 2.4 vs 1.6 years) or follicular (P= 0.01; median 2.5 vs 1.7 years) NHL but not intermediate grade (P = 0.622; median 2.3 vs 1.6 years) NHL. This analysis, performed approximately 12 years after closure of the study to accrual, supports the addition of interferon alfa to an induction cytotoxic chemotherapy regimen including cyclophosphamide and doxorubicin in the treatment of follicular NHL.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Interferón-alfa/administración & dosificación , Linfoma no Hodgkin/tratamiento farmacológico , Humanos , Interferón alfa-2 , Linfoma no Hodgkin/mortalidad , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Recombinantes , Tasa de SupervivenciaRESUMEN
On the basis of in vitro inhibition of tumor cell growth, IFNs have been generally considered to be antiproliferative proteins. To probe further the potential mechanisms of the antitumor effects of IFNs, we have assessed apoptosis in response to IFN-alpha2 and IFN-beta in cell lines of varied histologies, with a focus on melanomas. Many of the cell lines tested underwent apoptosis in response to IFN-beta, as assessed both by Annexin V and terminal deoxynucleotidyl transferase-mediated nick end labeling staining. In general, IFN-beta had greater growth inhibitory and proapoptotic effects than IFN-alpha2 on all cell lines. The melanoma cell line WM9, sensitive to growth inhibition by IFNs, had a greater degree of apoptosis than A375 melanoma cells, which were largely resistant to antigrowth effects of IFNs. IFN-beta-induced apoptosis was dependent on activation of the caspase cascade with cleavage of caspases 3, 8, and 9 and of the caspase 3 substrate, poly(ADP-ribose) polymerase. Caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl keton or benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl keton, inhibited IFN-beta-induced apoptosis. Other changes associated with apoptosis, including the movement of cytochrome c from mitochondria to cytoplasm and DNA fragmentation, were also identified in response to IFN-beta. Apo2L ligand [tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)] was one of the early genes induced by IFN-beta in apoptosis-sensitive WM9 cells. Other sensitive melanoma cell lines had a similar IFN-beta-specific induction of TRAIL. Neutralizing antibody to TRAIL inhibited IFN-beta-induced apoptosis in WM9 cells. In resistant A375 cells, IFN-beta did not induce TRAIL/Apo2L expression. Thus, induction of TRAIL by IFNs in some tumor types may initiate the apoptotic cascade. This study offers another mechanism for the antitumor effects of IFNs.
Asunto(s)
Apoptosis , Interferón-alfa/biosíntesis , Interferón beta/biosíntesis , Melanoma/metabolismo , Melanoma/patología , Glicoproteínas de Membrana/biosíntesis , Factor de Necrosis Tumoral alfa/biosíntesis , Anexina A5/metabolismo , Proteínas Reguladoras de la Apoptosis , Caspasa 3 , Caspasa 8 , Caspasa 9 , Caspasas/metabolismo , División Celular , Grupo Citocromo c/metabolismo , Citoplasma/metabolismo , Relación Dosis-Respuesta a Droga , Activación Enzimática , Inhibidores Enzimáticos/metabolismo , Humanos , Immunoblotting , Etiquetado Corte-Fin in Situ , Mitocondrias/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ribonucleasas/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
The only consistent factor influencing prognosis of primary melanoma in pregnancy has been the stage of disease at diagnosis, not the pregnancy. However, several studies suggest that pregnant women may have melanoma diagnosed at a later stage of disease. Thus, suspicious changes in nevi during pregnancy warrant prompt biopsy-not observation or deferral to the postpartum period. No hormonal factors in pregnancy that clearly influence melanoma development have been identified; there is no increased risk of recurrent disease with subsequent pregnancy. Thus, the decision for further childbearing should be a prognostic and personal one. Placental and/or fetal metastasis are limited to patients with hematogenous dissemination. Except possibly for this reason in women with distant metastases, there are no medical data to justify therapeutic abortion. Recommendations to the pregnant woman or the woman of reproductive age should not differ from that of other patients with melanoma.
Asunto(s)
Melanoma , Complicaciones Neoplásicas del Embarazo , Femenino , Humanos , Melanoma/diagnóstico , Melanoma/secundario , Embarazo , Complicaciones Neoplásicas del Embarazo/diagnóstico , Complicaciones Neoplásicas del Embarazo/fisiopatología , Resultado del Embarazo , PronósticoRESUMEN
The authors present an unusual case that has been seldom reported in the literature. The clinical rhabdomyolysis syndrome, resulting from muscle disintegration, can be the result of numerous etiologic events and have serious sequelae. The pedal manifestations result from muscular and neurologic insult. The patient in this reported case survived rhabdomyolysis despite renal and hepatic failure requiring diuresis and hemodialysis. The only permanent long-term sequelae the patient suffered was flexible hammertoe deformities and parasthesias of all lesser digits of both feet. The follow-up is over 8 years.
Asunto(s)
Deformidades Adquiridas del Pie/etiología , Parestesia/etiología , Rabdomiólisis/complicaciones , Adulto , Femenino , Deformidades del Pie , Deformidades Adquiridas del Pie/patología , Humanos , Dedos del Pie/patologíaRESUMEN
IFNs were the first new therapeutic products resulting from recombinant DNA technology. IFNs were also the first human proteins effective in cancer treatment. There is however much to be discovered which will lead to new clinical applications. Areas which represent major research challenges for full understanding and application of the IFN system are: (i) the diversity of the IFN family; (ii) the role of induction; (iii) molecular mechanism of action; (iv) cellular modulatory effects; (v) advantages of combinations, and (vi) identification of new therapeutic indications. This review will emphasize the diversity of the IFN family and chemical modifications which will result in second-generation IFNs. Pre-clinical and clinical findings form the basis for new therapeutic directions in chronic myelogenous leukemia, lymphomas, myelomas, melanoma, urologic malignancies, primary brain tumors, and ovarian carcinoma.