RESUMEN
PURPOSE: To evaluate the safety, pharmacokinetics, and efficacy of a chimeric anti-epidermal growth factor receptor monoclonal antibody, cetuximab, in combination with radiation therapy (RT) in patients with advanced squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: We treated 16 patients in five successive treatment schedules. A standard dose escalation procedure was used; three patients entered onto the study at each dose level of cetuximab received conventional RT (70 Gy, 2 Gy/d), and the final three patients received hyperfractionated RT (76.8 Gy, 1.2 Gy bid). Cetuximab was delivered as a loading dose of 100 to 500 mg/m(2), followed by weekly infusions of 100 to 250 mg/m(2) for 7 to 8 weeks. Circulating levels of cetuximab during therapy were determined using a biomolecular interaction analysis core instrument. Human antichimeric antibody response was evaluated with a double-antigen radiometric assay. The recommended phase II/III dose was defined as the optimal cetuximab dose level based on the pharmacologic parameters and adverse events. RESULTS: The most commonly reported adverse events were fever, asthenia, transaminase elevation, nausea, and skin toxicities (grade 1 to 2 in most patients). Skin toxicity outside of the RT field was not strictly dose-dependent; however, grade 2 or higher events were observed in patients treated with higher dose regimens. There was one grade 4 allergic reaction. Most acute adverse effects were associated with RT (xerostomia, mucositis, and local skin toxicity). No antibodies against cetuximab were detected. All patients achieved an objective response (13 complete and two partial remissions). CONCLUSION: Cetuximab can be safely administered with RT. The recommended dose for phase II/III studies is a loading dose of 400 to 500 mg/m(2) and a maintenance weekly dose of 250 mg/m(2).
Asunto(s)
Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeza y Cuello/terapia , Radioterapia/métodos , Adulto , Anciano , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/uso terapéutico , Cetuximab , Terapia Combinada , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana EdadRESUMEN
PURPOSE: Epidermal growth factor receptor (EGFr) is overexpressed in a majority of head and neck squamous cell carcinomas, and this overexpression is associated with a poor prognosis. Therefore, EGFr has become the target of investigations aimed at disabling the receptor to determine whether this process leads to improved tumor kill with conventional treatment. MATERIALS AND METHODS: C225 is an anti-EGFr monoclonal antibody that inhibits receptor activity by blocking the ligand binding site. A panel of human head and neck squamous cell carcinoma cell lines was used to study the combination of C225 and radiation. RESULTS: It was determined that the combination of C225 (5 microgram/mL) delivered simultaneously with radiation (3 Gy) resulted in a greater decrement in cellular proliferation than either treatment alone. This reduction in proliferation correlated with reduced EGFr tyrosine phosphorylation and a reduction in phosphorylated signal transducer and activator of transcription-3 (STAT-3) protein (known to protect cells from apoptosis). Also, the decrement in proliferation correlated with increased apoptotic events, thereby indirectly linking C225/radiation-induced regulation of STAT-3 protein to apoptosis. CONCLUSION: This preclinical work serves as important support for the ongoing clinical investigation of C225 and radiotherapy for patients with head and neck carcinomas. The initial results of these clinical studies have been promising.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Carcinoma de Células Escamosas/terapia , Receptores ErbB/antagonistas & inhibidores , Neoplasias de Cabeza y Cuello/terapia , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/radioterapia , Ensayos Clínicos como Asunto , Terapia Combinada , Receptores ErbB/inmunología , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/patología , Humanos , Radiografía , Células Tumorales CultivadasRESUMEN
AmpliProbe System is a rapid, enzyme-labeled, non-isotopic probe system that has high sensitivity and flexibility. AmpliProbe System consists of two major components: target-specific "primary" probes and target-independent, enzyme-labeled, signal-generating "secondary" probes. The visualization of the complemental hybridization between the target DNA or RNA and probes is accomplished by an enzymatic chemiluminescent reaction. The AmpliProbe System format allows hybridization and signal visualization to be completed within five to seven hours. In this paper we present several successful applications of AmpliProbe in the detection of infectious disease pathogens and the detection of gene amplification and transcription elevation in the evaluation of oncogenes in cancer research.
Asunto(s)
Sondas de ADN , Virus de la Hepatitis B/aislamiento & purificación , Hepatitis B/diagnóstico , Neoplasias/genética , Northern Blotting , Southern Blotting , Células Cultivadas , ADN Viral/aislamiento & purificación , Amplificación de Genes , Hepatitis B/microbiología , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Neoplasias/diagnóstico , OncogenesRESUMEN
The conventional Hematology Wright's stain has been used in touch preparation from open lung biopsies to identify Pneumocystis carinii. A 100% positive correlation has been found using this rapid and readily available technique when compared to the conventional silver stain and permanent histologic sections.
Asunto(s)
Neumonía por Pneumocystis/diagnóstico , Humanos , Coloración y Etiquetado , Factores de TiempoRESUMEN
Thymus-reticular epithelial cells (TE-cells) were grown in a cell culture devoid of any lymphocytic elements. These cells were able to induce T-cell differentiation in spleen cells from T-dificient mice as expressed by con-A responsiveness and GvH reactivity. It was also shown that xenogeneic rat TE cells were as effective in the induction of T-cell differentiation in vitro as syngeneic TE cells. This system is therefore ideal for the study of T-cell development.
Asunto(s)
Diferenciación Celular , Células Epiteliales , Epitelio/inmunología , Linfocitos T/inmunología , Timo/citología , Animales , Células Cultivadas , Concanavalina A , ADN/biosíntesis , Epitelio/ultraestructura , Femenino , Reacción Injerto-Huésped , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Microscopía Electrónica , Quimera por Radiación , Ratas , Ratas Endogámicas Lew , Especificidad de la Especie , Bazo/citología , Linfocitos T/trasplante , Timectomía , Timidina/metabolismo , Timo/inmunología , Trasplante Homólogo , TritioAsunto(s)
Activación de Linfocitos , Prueba de Cultivo Mixto de Linfocitos , Linfocitos T/inmunología , Animales , Resistencia a Medicamentos , Hidrocortisona/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Mitomicinas/farmacología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Timidina/metabolismoRESUMEN
Recent technological advances, together with the discovery of the important role many growth factors play in modulating cell proliferation and differentiation, have led to the development of novel therapeutic agents for the treatment of cancer. In particular, advances in hybridoma technology and molecular engineering have permitted the development of humanized or chimeric monoclonal antibodies capable of interfering with growth factor signaling pathways. One promising target of interest is the epidermal growth factor receptor (EGFr), which is activated by the ligands EGF and TGF-alpha. This ligand receptor interaction plays a crucial role in the growth and survival of many human cancers. A chimeric (human/mouse) monoclonal antibody p6tuximab (IMC-C225) targets the EGFr and has potential clinical value as an anticancer agent.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Receptores ErbB/inmunología , Neoplasias/tratamiento farmacológico , Animales , Anticuerpos Monoclonales Humanizados , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cetuximab , Ensayos Clínicos como Asunto , Factor de Crecimiento Epidérmico/fisiología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/fisiología , Humanos , Ratones , Neoplasias/patología , Ingeniería de Proteínas , Proteínas Recombinantes de Fusión/uso terapéutico , Transducción de Señal , Factor de Crecimiento Transformador alfa/fisiologíaRESUMEN
BACKGROUND: Pancreatic carcinoma is associated with a poor prognosis, and treatment options for patients with this disease are limited. The epidermal growth factor (EGF) receptor and its ligands are overexpressed in human pancreatic carcinoma and may contribute to the pathophysiology of these tumors. METHODS: The anti-EGF receptor monoclonal antibody IMC-C225 was used to determine the effects of EGF receptor blockade on the growth of human pancreatic carcinoma BxPC-3 cells in vitro. Athymic mice bearing established (200 mm(3)) subcutaneous BxPC-3 xenografts were treated with IMC-C225 (17 or 33 mg/kg every 3 days) alone or in combination with 5-fluorouracil (17 mg/kg twice weekly). RESULTS: IMC-C225 inhibited exogenous ligand-stimulated tyrosine phosphorylation of the EGF receptor on BxPC-3 tumor cells. Treatment of BxPC-3 cells with IMC-C225 inhibited DNA synthesis (23.8%) and colony formation in soft agar (45.6%). IMC-C225 treatment significantly suppressed the growth of BxPC-3 tumors compared with treatment with vehicle alone (P = 0.003). Combination therapy with IMC-C225 and the chemotherapeutic agent 5-fluorouracil enhanced the antitumor effects compared with either agent alone and resulted in regression of pancreatic tumors in several animals. Histologic examination of pancreatic tumors from mice treated with IMC-C225 showed extensive tumor necrosis that coincided with a substantial decrease in tumor cell proliferation and an increase in tumor cell apoptosis. CONCLUSIONS: These data suggest that IMC-C225 affects the growth of pancreatic tumors by inhibiting EGF receptor-dependent proliferation and survival, and demonstrates the potential for therapeutic application of IMC-C225 antibody in the treatment of human pancreatic carcinoma.