RESUMEN
Determinants of interindividual variability in erlotinib pharmacokinetics (PK) and adverse events remain to be elucidated. This study with 50 Japanese non-small-cell lung cancer patients treated with oral erlotinib at a standard dose of 150 mg aimed to investigate whether genetic polymorphisms affect erlotinib PK and adverse events. Single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP1A1, CYP1A2, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT2B7, GSTM1, and GSTT1) or efflux transporters (ABCB1, and ABCG2) were analyzed as covariates in a population PK model. The ABCB1 1236C>T (rs1128503) polymorphism, not ABCB1*2 haplotype (1236TT-2677TT-3455TT, rs1128503 TT-rs2032582 TT-rs1045642 TT), was a significant covariate for the apparent clearance (CL/F), with the TT genotype showing a 29.4% decrease in CL/F as compared with the CC and the CT genotypes. A marginally higher incidence of adverse events (mainly skin rash) was observed in the TT genotype group; however, patients with high plasma erlotinib exposure did not always experience skin rash. None of the other SNPs affected PK or adverse events. The ABCB1 genotype is a potential predictor for erlotinib adverse events. Erlotinib might be used with careful monitoring of adverse events in patients with ABCB1 polymorphic variants.
Asunto(s)
Antineoplásicos/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Clorhidrato de Erlotinib/farmacocinética , Neoplasias Pulmonares/metabolismo , Modelos Biológicos , Polimorfismo de Nucleótido Simple , Transportadoras de Casetes de Unión a ATP/genética , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Sistema Enzimático del Citocromo P-450/genética , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Clorhidrato de Erlotinib/efectos adversos , Clorhidrato de Erlotinib/uso terapéutico , Femenino , Glucuronosiltransferasa/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Masculino , Estudios ProspectivosRESUMEN
Amrubicin is a novel synthetic 9-aminoanthracycline derivative and is converted enzymatically to its C-13 hydroxy metabolite, amrubicinol, whose cytotoxic activity is 10-100 times that of amrubicin. We aimed to determine the maximum tolerated dose (MTD) of amrubicin and to characterize the pharmacokinetics of amrubicin and amrubicinol in previously treated patients with refractory or relapsed lung cancer. The 15 patients were treated with amrubicin intravenously at doses of 30, 35, or 40 mg/m(2) on three consecutive days every 3 weeks for a total of 43 courses. Neutropenia was the major toxicity (grade 4, 67%). The MTD was 40 mg/m(2), with the specific dose-limiting toxicities being grade 4 neutropenia persisting for >4 days, febrile neutropenia, or grade 3 arrhythmia in the three patients treated at this dose. A patient with non-small-cell lung cancer showed a partial response, and ten individuals experienced a stable disease. The area under the plasma concentration versus time curve (AUC) for amrubicin and that for amrubicinol increased with amrubicin dose. The amrubicin AUC was significantly correlated with the amrubicinol AUC. The recommended phase II dose of amrubicin for patients with lung cancer refractory to standard chemotherapy is thus 35 mg/m(2) once a day for three consecutive days every 3 weeks.
Asunto(s)
Antraciclinas/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Anciano , Antraciclinas/administración & dosificación , Antraciclinas/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Área Bajo la Curva , Fibrilación Atrial/inducido químicamente , Fibrilación Atrial/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Células Pequeñas/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Disopiramida/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Disnea/inducido químicamente , Disnea/tratamiento farmacológico , Femenino , Semivida , Humanos , Hipoxia/inducido químicamente , Hipoxia/tratamiento farmacológico , Infusiones Intravenosas , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neutropenia/inducido químicamente , Neutropenia/terapia , Transfusión de Plaquetas , Neumonía/inducido químicamente , Neumonía/tratamiento farmacológico , Esteroides/uso terapéutico , Trombocitopenia/inducido químicamente , Trombocitopenia/terapiaRESUMEN
Aberrations of the tumor suppressor genes FHIT and p53 are frequently associated with a wide range of human cancers, including lung cancer. We studied the combined effects of FHIT and p53 proteins on tumor cell proliferation and apoptosis in human non-small cell lung carcinoma (NSCLC) cells in vitro and on tumor growth in animal models by adenoviral vector-mediated cotransfer of wild-type FHIT and p53 genes. We found that the coexpression of FHIT and p53 synergistically inhibited tumor cell proliferation in NSCLC cells in vitro and suppressed the growth of human tumor xenografts in nude mice. Furthermore, we found that this synergistic inhibition of tumor cell growth corresponded with the FHIT-mediated inactivation of MDM2, which thereby blocked the association of MDM2 with p53, thus stabilizing the p53 protein. Our results therefore reveal a novel molecular mechanism consisting of FHIT-mediated tumor suppression and the interaction of FHIT with other cellular components in the pathways regulating p53 activity. These findings show that combination treatment with synergistic tumor-suppressing gene therapy such as Ad-FHIT and Ad-p53 may be an effective therapeutic strategy for NSCLC and other cancers.
Asunto(s)
Ácido Anhídrido Hidrolasas/biosíntesis , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Proteínas de Neoplasias/biosíntesis , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/biosíntesis , Ácido Anhídrido Hidrolasas/genética , Adenoviridae/genética , Animales , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , División Celular/genética , Línea Celular Tumoral , Femenino , Terapia Genética/métodos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Proteínas de Neoplasias/genética , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2 , Proteína p53 Supresora de Tumor/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Treating lung cancer cell lines using low-dose 5-aza-2'-deoxycytidine (DAC) caused an accumulation of procaspase-9 through mRNA upregulation, but the cells did not undergo apoptosis. However, when cells were treated with DAC and infected with a low dose of a recombinant wild-type p53 adenovirus vector (Ad-p53), a synergistic growth inhibitory effect was observed. Combination treatment induced Apaf-1 and procaspase-9 expression in which cytochrome c releases by Ad-p53 triggered the mitochondrial pathway of apoptosis. Selective blockage of caspase-9 activities by Z-LEHD-FMK completely attenuated DAC-induced enhancement of apoptosis mediated by Ad-p53 infection, and ectopic overexpression of procaspase-9 sensitized cells to Ad-p53-induced apoptosis in p53-null cells. In addition, DAC sensitized lung cancer cells to cisplatin and paclitaxel. Induction of the mitochondrial pathway of apoptosis using a slightly toxic dose of DAC may therefore be a strategy for treating lung cancer, and DAC treatment may have clinical implications when combined with chemotherapy or apoptosis-inducing gene therapy.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Apoptosis/fisiología , Azacitidina/análogos & derivados , Azacitidina/farmacología , Caspasas/genética , Regulación Enzimológica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/genética , Neoplasias Pulmonares/patología , Proteína p53 Supresora de Tumor/fisiología , Apoptosis/efectos de los fármacos , Caspasa 9 , Línea Celular Tumoral , Decitabina , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , HumanosRESUMEN
Gefitinib (Iressa, ZD1839) is an orally active inhibitor selective for the epidermal growth factor receptor tyrosine kinase and has shown promise in the treatment of non-small cell lung cancer (NSCLC). There has been no report to date of the effect of gefitinib treatment in patients with small-cell lung cancer (SCLC). Here we report a case of metastatic SCLC that was successfully treated with gefitinib. This case is the first reported of objective clinical response after gefitinib treatment in a patient with SCLC. Our report suggests that treatment with gefitinib is a novel option for a subset of patients with SCLC.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/uso terapéutico , Administración Oral , Anciano , Carcinoma de Células Pequeñas/patología , Femenino , Gefitinib , Humanos , Neoplasias Pulmonares/patología , Metástasis de la Neoplasia , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
We have found that mebendazole (MZ), a derivative of benzimidazole, induces a dose- and time-dependent apoptotic response in human lung cancer cell lines. In this study, MZ arrested cells at the G(2)-M phase before the onset of apoptosis, as detected by using fluorescence-activated cell sorter analysis. MZ treatment also resulted in mitochondrial cytochrome c release, followed by apoptotic cell death. Additionally, MZ appeared to be a potent inhibitor of tumor cell growth with little toxicity to normal WI38 and human umbilical vein endothelial cells. When administered p.o. to nu/nu mice, MZ strongly inhibited the growth of human tumor xenografts and significantly reduced the number and size of tumors in an experimental model of lung metastasis. In assessing angiogenesis, we found significantly reduced vessel densities in MZ-treated mice compared with those in control mice. These results suggest that MZ is effective in the treatment of cancer and other angiogenesis-dependent diseases.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Mebendazol/farmacología , Neovascularización Patológica/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/irrigación sanguínea , Carcinoma de Pulmón de Células no Pequeñas/patología , División Celular/efectos de los fármacos , Línea Celular/efectos de los fármacos , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Femenino , Fibroblastos/efectos de los fármacos , Fase G2/efectos de los fármacos , Humanos , Neoplasias Pulmonares/irrigación sanguínea , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos C3H , Ratones Desnudos , Quimera por Radiación , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/trasplante , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Microtubules have a critical role in cell division, and consequently various microtubule inhibitors have been developed as anticancer drugs. In this study, we assess mebendazole (MZ), a microtubule-disrupting anthelmintic that exhibits a potent antitumor property both in vitro and in vivo. Treatment of lung cancer cell lines with MZ caused mitotic arrest, followed by apoptotic cell death with the feature of caspase activation and cytochrome c release. MZ induces abnormal spindle formation in mitotic cancer cells and enhances the depolymerization of tubulin, but the efficacy of depolymerization by MZ is lower than that by nocodazole. Oral administration of MZ in mice elicited a strong antitumor effect in a s.c. model and reduced lung colonies in experimentally induced lung metastasis without any toxicity when compared with paclitaxel-treated mice. We speculate that tumor cells may be defective in one mitotic checkpoint function and sensitive to the spindle inhibitor MZ. Abnormal spindle formation may be the key factor determining whether a cell undergoes apoptosis, whereas strong microtubule inhibitors elicit toxicity even in normal cells.
Asunto(s)
Antinematodos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Mebendazol/farmacología , Huso Acromático/efectos de los fármacos , Tubulina (Proteína)/efectos de los fármacos , Administración Oral , Animales , Antineoplásicos Fitogénicos/farmacología , Biomarcadores de Tumor/metabolismo , Western Blotting , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Caspasas/metabolismo , Ciclo Celular/efectos de los fármacos , Grupo Citocromo c/metabolismo , Citometría de Flujo , Humanos , Etiquetado Corte-Fin in Situ , Neoplasias Pulmonares/enzimología , Ratones , Ratones Desnudos , Microscopía Fluorescente , Mitocondrias/efectos de los fármacos , Paclitaxel/farmacología , Tubulina (Proteína)/metabolismo , Células Tumorales CultivadasRESUMEN
AIMS: We analyzed the association of ABCB1 polymorphisms with erlotinib-induced toxicity and the pharmacokinetics in patients with non-small-cell lung cancer. MATERIALS & METHODS: After erlotinib 150 mg was administered to 50 patients, ABCB1 polymorphisms were analyzed via either TaqMan(®) assays or direct nucleotide sequencing. Plasma concentrations were measured by HPLC. RESULTS: The trough concentration at steady state in patients with the ABCB1 1236TT-2677TT-3435TT genotype was higher compared with others groups (p = 0.021) and patients carrying this genotype had a higher risk of developing higher grade 2 toxicity (p = 0.012). CONCLUSION: The present study suggested that the ABCB1 1236TT-2677TT-3435TT genotype was associated with higher plasma concentration and the risk of developing higher toxicity in patients treated with erlotinib.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Polimorfismo de Nucleótido Simple , Inhibidores de Proteínas Quinasas , Quinazolinas , Subfamilia B de Transportador de Casetes de Unión a ATP , Administración Oral , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib , Femenino , Humanos , Japón , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/efectos adversos , Quinazolinas/farmacocinética , Quinazolinas/uso terapéuticoRESUMEN
OBJECTIVES: To evaluate whether functional preservation after segmentectomy has a greater advantage of pulmonary functions than volume-reduction effects after lobectomy in patients with emphysema with clinical T1N0 non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Between January 2000 and December 2006, 47 cases of lobectomy and 71 cases of segmentectomy were performed in patients with stage I NSCLC using intraoperative sentinel node identification. The postoperative change of the forced expiratory volume in 1 second (deltaFEV(1)) 6 months after segmentectomy was compared with that of 6 months after lobectomy. The difference in the deltaFEV(1) between after segmentectomy and after lobectomy was evaluated according to the ratio of the estimated postoperative FEV(1) to the predicted normal value of FEV(1) (%ppoFEV(1)). RESULTS: In 50 patients with the preoperative FEV(1)% less than 70%, there was no difference in the deltaFEV(1) between the segmentectomy group (n = 30) and the lobectomy group (n = 20). In 36 patients with emphysema diagnosed by high-resolution chest computed tomography, a negative linear correlation between the %ppoFEV(1) and the deltaFEV(1) was found in the lobectomy subgroup (n = 16, r = 0.508, p = 0.0012), but not in the segmentectomy subgroup (n = 20). When patients with emphysema had the %ppoFEV(1) more than or equal to 70%, the deltaFEV(1) had a tendency to be smaller in the segmentectomy subgroups than in the lobectomy subgroups. CONCLUSION: Segmentectomy should be considered in patients with cT1N0 NSCLC with a normal (>80%) predicted postoperative FEV(1). In patients with a %ppoFEV(1) under 70%, segmentectomy offers no functional advantages over lobectomy.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/fisiopatología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/fisiopatología , Neoplasias Pulmonares/cirugía , Pulmón/fisiopatología , Enfisema Pulmonar/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Volumen Espiratorio Forzado , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Enfermedad Pulmonar Obstructiva Crónica/fisiopatologíaRESUMEN
STUDY OBJECTIVES: It has been reported that high levels of serum carcinoembryonic antigen (CEA) after surgery, or the presence of vascular invasion or both, are strong indicators of postoperative recurrence in patients with non-small cell lung cancer. The purpose of this study is to evaluate which kind of patients with p-stage I adenocarcinoma need adjuvant chemotherapy, using those predictors. PATIENTS AND METHODS: We studied 136 patients with curatively resected p-stage I adenocarcinoma during the 7-year period of January 1, 2000 to December 31, 2006. Receiver operating characteristics curves were constructed using postoperative CEA levels measured 2 months after surgery. Clinical variables were examined as possible predictors of disease recurrence by multivariate analysis using the Cox proportional-hazards model. RESULTS: The median time of follow-up after surgery was 28.3 months. Fifteen (11%) of 136 patients had postoperative recurrence (7 p-stage IA cases and 8 p-stage IB cases). The presence of vascular invasion (hazard ratio: 10.229, 95% confidence intervals: 2.811-37.223, p = 0.0004) and high postoperative CEA levels (hazard ratio: 1.650, 95% confidence intervals: 1.196-2.275, p = 0.0023) increased the risk of recurrence. There was no recurrence in patients who had both postoperative CEA levels less than or equal to 2.5 ng/ml and no vascular invasion. CONCLUSION: Combined evaluation of postoperative CEA levels and vascular invasion makes it possible to predict disease recurrence in the curatively resected p-stage I adenocarcinoma patients.
Asunto(s)
Adenocarcinoma/sangre , Antígeno Carcinoembrionario/sangre , Neoplasias Pulmonares/sangre , Recurrencia Local de Neoplasia/diagnóstico , Neovascularización Patológica/diagnóstico , Adenocarcinoma/irrigación sanguínea , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/irrigación sanguínea , Neoplasias Pulmonares/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Neumonectomía , Periodo Posoperatorio , Pronóstico , Curva ROC , Resultado del TratamientoRESUMEN
Amrubicin is a completely synthetic 9-aminoanthracycline agent for the treatment of lung cancer in Japan. The cytotoxicity of C-13 hydroxy metabolite, amrubicinol, is 10 to 100 times greater than that of amrubicin. The transporters responsible for the intracellular pharmacokinetics of amrubicin and amrubicinol remains unclear. This study was aimed to determine whether P-glycoprotein (P-gp) plays functional and preventive role in cellular accumulation and cytotoxicity of amrubicin and its active metabolite amrubicinol by in vitro transport and toxicity experiments. Cytotoxicity and intracellular accumulation of amrubicin and amrubicinol were evaluated by LLC-PK1 cells, MDR1 gene-transfected LLC-PK1 (L-MDR1) cells overexpressing P-gp, and human A549 lung adenocarcinoma cells. L-MDR1 cells showed 6- and 12-fold greater resistance to amrubicin and amrubicinol, respectively, than the parental LLC-PK1 cells. The intracellular accumulation of both drugs in L-MDR1 cells was significantly reduced compared to the LLC-PK1 cells. The basal-to-apical transepithelial transport of both drugs markedly exceeded, whereas the apical-to-basal transport of both drugs was significantly lower in L-MDR1 cells than LLC-PK1 cells. Cyclosporin A (CyA) restored the sensitivity, intracellular accumulation and transport activity for both drugs in L-MDR1 cells. In A549 cells, CyA significantly increased the intracellular accumulation and cytotoxicity of both drugs. These findings indicated that P-gp is responsible for cellular accumulation and cytotoxicity of both amrubicin and amrubicinol, therefore suggesting that the antitumor effect of amrubicin could be affected by the expression level of P-gp in lung cancer cells in chemotherapeutic treatments.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/fisiología , Antraciclinas/farmacología , Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Adenocarcinoma , Animales , Antraciclinas/farmacocinética , Antineoplásicos/farmacocinética , Transporte Biológico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Células LLC-PK1 , Neoplasias Pulmonares , Estructura Molecular , Porcinos , TransfecciónRESUMEN
Amrubicin, a synthetic 9-aminoanthracycline agent, was recently approved in Japan for treatment of small-cell lung cancer and non-small-cell lung cancer. Amrubicin is converted enzymatically to the C-13 hydroxy metabolite amrubicinol, which is active and possesses a cytotoxicity 10 to 100 times that of the parent drug. The purpose of this study was to characterize the pharmacokinetics of amrubicin and its active metabolite amrubicinol. Amrubicin was administered on days 1-3 in 16 patients with advanced lung cancer. The pharmacokinetics analysis of amrubicin and amrubicinol was performed by high-performance liquid chromatography. When 45 mg/m amrubicin was administered in a bolus injection once every 24 hours for 3 consecutive days, the areas under the curves (0 to 72 hours) for amrubicin and amrubicinol were 13,490 and 2585 ng . h/mL, respectively. The apparent total clearance (CLapp) of amrubicin was 15.4 L/h. The area-under-the-curve ratio of amrubicinol to amrubicin was 15.1 +/- 4.6% (mean +/- SD) at doses ranging from 30 to 45 mg/m. Interindividual variability in the enzymatic conversion of amrubicin to amrubicinol was small. In contrast, a large interindividual variability in the CLapp of amrubicin was observed (CV = 49.8%). The areas under the curves of amrubicin and amrubicinol seemed to be associated with the severity of hematologic toxicities. There is a possibility that monitoring of the plasma concentrations of amrubicin and amrubicinol may provide an efficient tool for establishing the optimal dosage of amrubicin in each patient.
Asunto(s)
Antraciclinas/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Células Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Anciano , Antraciclinas/efectos adversos , Antraciclinas/metabolismo , Antraciclinas/uso terapéutico , Área Bajo la Curva , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/patología , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Leucopenia/inducido químicamente , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Trombocitopenia/inducido químicamenteRESUMEN
The epidermal growth factor receptor (EGFR) variant type III (variously called EGFRvIII, de2-7 EGFR or deltaEGFR) has an in-frame deletion of the extracellular domain and is found in numerous types of human tumors. Since EGFRvIII has been reported to be tumor-specific and has oncogenic potential, it is being investigated as a potential therapeutic target. Because the cell-specific expression of EGFRvIII in lung has not been well documented, we examined the expression of EGFRvIII in 76 non-small cell lung cancers (NSCLCs) and 10 non-neoplastic lung tissues by immunohistochemistry using a new monoclonal antibody specific for this variant receptor. We found a higher incidence (30 of 76, 39%) of enhanced EGFRvIII expression in NSCLC than previously described. Interestingly, the presence of EGFRvIII was also observed in several normal tissue components of lung (e.g., normal bronchial epithelium). Given the high prevalence of EGFRvIII in NSCLC, a newly developed phospho-specific (activated) EGFR antibody was employed for immunohistochemical analysis that permitted visualization of activated EGFR and/or EGFRvIII in tumors. This study presents evidence, for the first time, that EGFRvIII expressed in human tumors is phosphorylated and hence activated. Our results suggest that the sustained activation of EGFRvIII is implicated in the pathogenesis of NSCLC and thus EGFRvIII is a potential therapeutic target in this challenging disease.