RESUMEN
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease. To improve the standard therapy with gemcitabine, we initiated a prospective randomised phase-II trial with gemcitabine (GEM) versus gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. The rational of adding sunitinib was its putative antiangiogenic mechanism of action. METHODS: A total of 106 eligible patients with locally advanced, unresectable or metastatic PDAC without previous system therapy were randomised to receive GEM at a dosage of 1.000mg/m(2) d1, 8, 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000mg/m(2) d1+8 and sunitinib 50mg p.o. d1-14, q21d. The primary end-point was progression free survival (PFS), secondary end-points were overall survival (OS), toxicity and overall response rate (ORR). RESULTS: The confirmatory analysis of PFS was based on the intend-to-treat (ITT) population (N=106). The median PFS was 13.3 weeks (95% confidence interval (95%-CI): 10.4-18.1 weeks) for GEM and 11.6 weeks for SUNGEM (95%-CI: 7.0-18.0 weeks; p=0.78 one-sided log-rank). The ORR was 6.1% (95%-CI: 0.7-20.2%) for GEM and for 7.1% (95%-CI: 0.9-23.5%) for SUNGEM (p=0.87). The median time to progression (TTP) was 14.0 weeks (95%-CI: 12.4-22.3 weeks) for GEM and 18.0 weeks (95%-CI: 11.3-19.3 weeks) for SUNGEM (p=0.60; two-sided log-rank). The median OS was 36.7 weeks (95%-CI: 20.6-49.0 weeks) for the GEM arm and 30.4 weeks (95%-CI: 18.1-37.6 weeks) for the SUNGEM (p=0.78, one-sided log-rank). In regard to toxicities, suspected SAEs were reported in 53.7% in the GEM arm and 71.2% in the SUNGEM arm. Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1% versus 27.8% in the GEM arm (p=0.045, two sided log-rank). CONCLUSIONS: The combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Indoles/uso terapéutico , Pirroles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Europa (Continente) , Femenino , Humanos , Indoles/administración & dosificación , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Pirroles/administración & dosificación , Sunitinib , Resultado del Tratamiento , GemcitabinaRESUMEN
Tivozanib is a potent selective tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. This Phase Ib study investigated the safety/tolerability, pharmacokinetics (PK), and activity of tivozanib with weekly paclitaxel in metastatic breast cancer (MBC). MBC patients with no prior VEGFR TKI treatment received daily oral tivozanib (3 weeks on, 1 week off) with weekly paclitaxel 90 mg/m(2). Standard 3 + 3 dose escalation was used; tivozanib cohorts (C) included C1 0.5 mg, C2 1.0 mg, and C3 1.5 mg. Assessments included Response Evaluation Criteria in Solid Tumors response, PK, and vascular function. Eighteen patients enrolled. Toxicities in >20 % of patients included fatigue, alopecia, nausea, diarrhea, peripheral sensory neuropathy, and hypertension. Grade 3/4 toxicities in >15 % of patients included fatigue and neutropenia. Maximum tolerated dose was tivozanib 1.5 mg with paclitaxel 90 mg/m(2). Four patients withdrew because of toxicity and one due to progressive disease. Thirteen patients were evaluable for response: four (30.8 %) had confirmed partial response; four had stable disease ≥6 months (30.8 %). PK data suggest no influence of paclitaxel on tivozanib concentrations. Tivozanib plus weekly paclitaxel was tolerable at all dose levels, supporting their combination at full dose. Activity in this small population was encouraging.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinolinas/administración & dosificación , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Paclitaxel/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/farmacocinética , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Quinolinas/efectos adversos , Quinolinas/farmacocinética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
The reactivation of the INK4-ARF locus, which is epigenetically repressed by Polycomb proteins in healthy cells, is a hallmark of senescence. One mechanism of reactivating Polycomb-silenced genes is mediated by the epigenetic factor ZRF1, which associates with ubiquitinated histone H2A. We show that cells undergoing senescence following oncogenic Ras expression have increased ZRF1 levels, and that this binds to the p15INK4b, ARF and p16INK4a promoters. Furthermore, ZRF1 depletion in oncogenic Ras-expressing cells restores proliferation by preventing Arf and p16Ink4a expression, consequently bypassing senescence. Thus, ZRF1 regulates the INK4-ARF locus during cellular proliferation and senescence, and alterations in ZRF1 may contribute to tumorigenesis.
Asunto(s)
Senescencia Celular , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Proteínas de Unión al ADN/fisiología , Genes ras , Proteínas Oncogénicas/fisiología , Animales , Proteínas de Ciclo Celular/fisiología , Diferenciación Celular , Línea Celular , Proliferación Celular , Transformación Celular Neoplásica , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Proteínas de Unión al ADN/metabolismo , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Humanos , Ratones , Ratones Endogámicos C57BL , Chaperonas Moleculares , Proteínas de Unión al ARN , Tretinoina/farmacologíaRESUMEN
BACKGROUND: In a phase I dose-escalation study, regorafenib demonstrated tolerability and antitumour activity in solid tumour patients. The study was expanded to focus on patients with metastatic colorectal cancer (CRC). METHODS: Patients received oral regorafenib 60-220 mg daily (160 mg daily in the extension cohort) in cycles of 21 days on, 7 days off treatment. Assessments included toxicity, response, pharmacokinetics and pharmacodynamics. RESULTS: Thirty-eight patients with heavily pretreated CRC (median 4 prior lines of therapy, range 0-7) were enrolled in the dose-escalation and extension phases; 26 patients received regorafenib 160 mg daily. Median treatment duration was 53 days (range 7-280 days). The most common treatment-related toxicities included hand-foot skin reaction, fatigue, voice change and rash. Twenty-seven patients were evaluable for response: 1 achieved partial response and 19 had stable disease. Median progression-free survival was 107 days (95% CI, 66-161). At steady state, regorafenib and its active metabolites had similar systemic exposure. Pharmacodynamic assessment indicated decreased tumour perfusion in most patients. CONCLUSION: Regorafenib showed tolerability and antitumour activity in patients with metastatic CRC. This expanded-cohort phase I study provided the foundation for further clinical trials of regorafenib in this patient population.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Piridinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Neoplasias Colorrectales/mortalidad , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/farmacocinética , Piridinas/efectos adversos , Piridinas/farmacocinéticaRESUMEN
Polycomb group proteins have long been linked to the occurrence of different forms of cancer. Polycomb proteins form at least two distinct complexes, the Polycomb-repressive complexes 1 and 2 (PRC1 and PRC2). Some of the PRC complex subunits have been found to be overexpressed in a variety of different tumors. Epigenetic perturbations are likely to be the cause for transcriptional misregulation of tumor suppressor genes and of certain cell fates. It is especially critical for stem cells that their potential to self-renewal and to differentiate is tightly controlled and properly orchestrated. Misregulation of Polycomb protein levels often leads to either a block or unscheduled activation of developmental pathways, thereby enhancing the proliferation capability of a cell. The consequences of this misregulation have been linked to the establishment of cancer stem cells, which can produce tumors through a combination of increased self-renewal and the lack of complete cellular differentiation. Cancer stem cells are believed to persist within tumors and to elicit relapse and metastasis. In this review, we recapitulate the roles of Polycomb proteins in stem cell biology, and the impact their misregulation can have on cancer.
Asunto(s)
Células Madre Embrionarias/citología , Neoplasias/metabolismo , Proteínas Represoras/metabolismo , Animales , Proteínas Cromosómicas no Histona/metabolismo , Drosophila , Proteínas de Drosophila/metabolismo , Células Madre Embrionarias/metabolismo , Humanos , Neoplasias/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Proteínas del Grupo PolycombAsunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Neoplasias Hematológicas/tratamiento farmacológico , Antibióticos Antineoplásicos/metabolismo , Área Bajo la Curva , Ensayos Clínicos como Asunto , Doxorrubicina/análogos & derivados , Doxorrubicina/sangre , Doxorrubicina/química , Doxorrubicina/metabolismo , Monitoreo de Drogas , Semivida , Humanos , Infusiones Intravenosas , Leucocitos/citología , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Índice de Severidad de la EnfermedadAsunto(s)
Antineoplásicos/farmacocinética , Indazoles/farmacocinética , Neoplasias/metabolismo , Compuestos de Rutenio/farmacocinética , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Biomarcadores/sangre , Biomarcadores/química , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Aductos de ADN/sangre , Aductos de ADN/química , Relación Dosis-Respuesta a Droga , Semivida , Humanos , Indazoles/administración & dosificación , Indazoles/química , Indazoles/uso terapéutico , Infusiones Intravenosas , Leucocitos/química , Tasa de Depuración Metabólica , Neoplasias/tratamiento farmacológico , Compuestos Organometálicos , Compuestos de Rutenio/administración & dosificación , Compuestos de Rutenio/química , Compuestos de Rutenio/uso terapéutico , Albúmina Sérica/análisis , Albúmina Sérica/química , Albúmina Sérica/metabolismo , Transferrina/análisis , Transferrina/química , Transferrina/metabolismoAsunto(s)
Antineoplásicos/farmacocinética , Bencenosulfonatos/farmacocinética , Enfermedades Renales/terapia , Inhibidores de Proteínas Quinasas/farmacocinética , Piridinas/farmacocinética , Diálisis Renal , Antineoplásicos/metabolismo , Antineoplásicos/uso terapéutico , Bencenosulfonatos/metabolismo , Bencenosulfonatos/uso terapéutico , Recolección de Muestras de Sangre , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Humanos , Enfermedades Renales/sangre , Enfermedades Renales/fisiopatología , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/química , Piridinas/metabolismo , Piridinas/uso terapéutico , Sorafenib , Factores de TiempoRESUMEN
Sorafenib, an oral multikinase inhibitor, shows efficacy in renal cell and hepatocellular carcinoma (HCC) and is well tolerated when combined with doxorubicin in other solid tumours. Eighteen patients with inoperable HCC received doxorubicin 60 mg/m(2) IV for up to six 3-week cycles. Sorafenib 400mg bid was administered continuously starting day 4. Patients discontinuing doxorubicin were eligible for sorafenib monotherapy. The most frequent grade 3-4 drug-related adverse events were neutropaenia (61%), leukopaenia (45%) and diarrhoea (17%, grade 3). Seven of eight patients who completed six cycles of doxorubicin continued treatment with sorafenib for at least 3 months. Doxorubicin moderately increased AUC (21%) and C(max) (33%) when administered with sorafenib. The disease control rate for 16 evaluable patients was 69%. Sorafenib plus doxorubicin appears to be well tolerated and more effective in the treatment of HCC than doxorubicin alone. Follow-up with single-agent sorafenib in these patients also appears to be well tolerated.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencenosulfonatos/administración & dosificación , Bencenosulfonatos/efectos adversos , Bencenosulfonatos/sangre , Carcinoma Hepatocelular/sangre , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/sangre , Esquema de Medicación , Femenino , Humanos , Neoplasias Hepáticas/sangre , Masculino , Persona de Mediana Edad , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/sangre , Sorafenib , Resultado del TratamientoRESUMEN
BACKGROUND: Sorafenib (BAY 43-9006), a novel, oral multi-kinase inhibitor, blocks serine/threonine and receptor tyrosine kinases in the tumor and vasculature. Sorafenib demonstrated single-agent activity in Phase I studies, and was tolerated and inhibited tumor growth in combination with doxorubicin in preclinical studies. This Phase I dose-escalation study determined the safety, pharmacokinetics and efficacy of sorafenib plus doxorubicin. PATIENTS AND METHODS: Thirty-four patients with refractory, solid tumors received doxorubicin 60 mg/m(2) on Day 1 of 3-week cycles, and oral sorafenib from Day 4 of Cycle 1 at 100, 200 or 400 mg bid. RESULTS: Common drug-related adverse events were neutropenia (56%), hand-foot skin reaction (44%), stomatitis (32%), and diarrhea (32%). The maximum tolerated dose was not reached. One patient with pleural mesothelioma achieved a partial response (modified WHO criteria) and remained on therapy for 39.7 weeks. Fifteen patients (48%) achieved stable disease for >/=12 weeks. Doxorubicin exposure increased moderately with sorafenib 400 mg bid. The pharmacokinetics of sorafenib and doxorubicinol were not affected. CONCLUSION: Sorafenib 400 mg bid plus doxorubicin 60 mg/m(2) was well tolerated. The increased doxorubicin exposure with sorafenib 400 mg bid did not result in significantly increased toxicity; low patient numbers make the clinical significance of this unclear. These promising efficacy results justify further clinical investigation.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Bencenosulfonatos/administración & dosificación , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias/metabolismo , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/administración & dosificación , Terapia Recuperativa , SorafenibAsunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Neoplasias/metabolismo , Antibióticos Antineoplásicos/sangre , Preparaciones de Acción Retardada , Doxorrubicina/sangre , Humanos , Infusiones Intravenosas , LiposomasAsunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Colangiocarcinoma/tratamiento farmacológico , Doxorrubicina/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Piridinas/uso terapéutico , Adulto , Anciano , Antibacterianos , Antibióticos Antineoplásicos/efectos adversos , Antibióticos Antineoplásicos/farmacocinética , Área Bajo la Curva , Bencenosulfonatos/efectos adversos , Doxorrubicina/efectos adversos , Doxorrubicina/farmacocinética , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/efectos adversos , SorafenibRESUMEN
BACKGROUND: The aim of this study was to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of the camptothecin glycoconjugate BAY 38-3441, administered as an infusion for 30 min on two separate schedules every 3 weeks. PATIENTS AND METHODS: A total of 81 patients with advanced solid tumors were treated with BAY 38-3441 either at doses of 20, 40, 67, 100, 140, 210, 315, 470 and 600 mg/m2/day for 1 day every 3 weeks (single-dose schedule), or at doses of 126, 189, 246, 320 and 416 mg/m2/day once daily for three consecutive days every 3 weeks (3-day schedule). Plasma sampling was performed to characterize the pharmacokinetics of BAY 38-3441 and camptothecin with these schedules. RESULTS: DLTs included renal toxicity, granulocytopenia and thrombocytopenia on the single-day schedule at doses > or = 470 mg/m2/day, and diarrhea and thrombocytopenia on the 3-day schedule at doses > or = 320 mg/m2/day. Other non-DLTs were gastrointestinal, dermatological and hematological. Pharmacokinetics of BAY 38-3441 and camptothecin appear to be dose-dependent, but not linear. CONCLUSIONS: Renal toxicity was dose-limiting for BAY 38-3441 using 30-min infusions on the single-dose schedule. Dose escalation to 470 mg/m2/day is feasible using a 2-h infusion. However, because of the superior safety profile, we recommend the 3-day schedule for BAY 38-3441 at a dose of 320 mg/m2/day as 30-min infusions for further phase II studies.
Asunto(s)
Camptotecina/análogos & derivados , Camptotecina/efectos adversos , Camptotecina/farmacocinética , Dipéptidos/efectos adversos , Dipéptidos/farmacocinética , Camptotecina/administración & dosificación , Dipéptidos/administración & dosificación , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/tratamiento farmacológicoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencenosulfonatos/farmacología , Bencenosulfonatos/farmacocinética , Neoplasias/tratamiento farmacológico , Piridinas/farmacología , Piridinas/farmacocinética , Administración Oral , Área Bajo la Curva , Aspartato Aminotransferasas/farmacología , Bencenosulfonatos/administración & dosificación , Doxorrubicina/administración & dosificación , Humanos , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/administración & dosificación , Sorafenib , Resultado del TratamientoAsunto(s)
Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/efectos adversos , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Epirrubicina/administración & dosificación , Epirrubicina/efectos adversos , Epirrubicina/farmacocinética , Femenino , Humanos , Infusiones Intravenosas , Hígado/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Estudios ProspectivosAsunto(s)
Bencenosulfonatos/farmacología , Inhibidores Enzimáticos/farmacología , Proteínas Proto-Oncogénicas c-raf/antagonistas & inhibidores , Piridinas/farmacología , Bencenosulfonatos/efectos adversos , Bencenosulfonatos/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Humanos , Dosis Máxima Tolerada , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neoplasias/metabolismo , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Fosforilación , Proteínas Proto-Oncogénicas c-raf/metabolismo , Piridinas/efectos adversos , Piridinas/farmacocinética , SorafenibRESUMEN
The OLE pathway of yeast regulates the level of the ER-bound enzyme Delta9-fatty acid desaturase OLE1, thereby controlling membrane fluidity. A central component of this regulon is the transcription factor SPT23, a homolog of mammalian NF-kappaB. SPT23 is synthesized as an inactive, ER membrane-anchored precursor that is activated by regulated ubiquitin/proteasome-dependent processing (RUP). We now show that SPT23 dimerizes prior to processing and that the processed molecule, p90, retains its ubiquitin modification and initially remains tethered to its unprocessed, membrane-bound SPT23 partner. Subsequently, p90 is liberated from its partner for nuclear targeting by the activity of the chaperone-like CDC48(UFD1/NPL4) complex. Remarkably, this enzyme binds preferentially ubiquitinated substrates, suggesting that CDC48(UFD1/NPL4) is qualified to selectively remove ubiquitin conjugates from protein complexes.