RESUMEN
AIM: To report on the multidisciplinary approach, focusing specifically on the role of the interventional radiologist (IR), used to support the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) and BATTLE-2 trials. MATERIALS AND METHODS: Patients who underwent percutaneous image-guided biopsy for the BATTLE and BATTLE-2 trials were reviewed. A radiology-based, three-point, lesion-scoring system was developed and used by two IRs. Lesions were given a score of 3 (most likely to yield sufficient material for biomarker analysis) if they met the following criteria: size >2 cm, solid mass, demonstrated imaging evidence of viability, and were technically easy to sample. Lesions not meeting all four criteria were scored 2 with the missing criteria noted as negative factors. Lesions considered to have risks that outweighed potential benefits receive a score of 1 and were not biopsied. Univariate and multivariate analyses were performed to evaluate the score's ability to predict successful yield for biomarker adequacy. RESULTS: A total of 555 biopsies were performed. The overall yield for analysis of the required biomarkers was 86.1% (478/555), and 84% (268/319) and 88.9% (210/236) for BATTLE and BATTLE-2, respectively (p=0.09). Lesions receiving a score of 3 were adequate for biomarker analysis in 89% of cases. Lesions receiving a score of 2 with more than two negative factors were adequate for molecular analysis in 69.2% (IR1, p=0.03) and 74% (IR2, p=0.04) of cases. The two IRs scored 78.4% of the lesions the same indicating moderate agreement (kappa=0.55; 95% confidence interval [CI]: 0.48, 0.61). CONCLUSIONS: IRs add value to clinical trial teams by optimising lesions selected for biopsy and biomarker analysis.
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Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Radiología Intervencionista/métodos , Anciano , Biopsia con Aguja Fina , Ensayos Clínicos como Asunto , Femenino , Humanos , Biopsia Guiada por Imagen , Pulmón/diagnóstico por imagen , Pulmón/patología , Masculino , Persona de Mediana Edad , Grupo de Atención al PacienteRESUMEN
We evaluated whether active osteoporosis care in patients experiencing their first distal radius fracture (DRF) reduces subsequent hip or spine fractures by comparing two cohorts. The incidence of subsequent fractures was significantly lower in the active care cohort than the other cohort in 4-year follow-up. PURPOSE: Studies show that osteoporosis care in patients with osteoporotic fracture reduces subsequent fractures, but the impact of such active care in patients with distal radius fracture (DRF) has not been well studied. We evaluated how much osteoporosis care in patients experiencing their first DRF can reduce subsequent hip or spine fractures at 4-year follow-up. METHODS: Active osteoporosis care by orthopedic surgeons for patients with DRF started from September 2009 at our institution, thus we had a unique opportunity to compare the two cohorts: pre-involvement (PreI) group (DRF before September 2009) and post-involvement (PostI) group (DRF from September 2009). We compared the two cohorts for subsequent hip or spine fracture incidence in the 4 years following DRF. RESULTS: Overall, 1057 patients with a DRF (85% women; mean age, 70 years) were studied, of whom 205 patients were in PreI group and 852 in PostI group. Subsequent fractures occurred in 27 patients (2.6%), with a mean interval of 29 months after DRF. The incidence was significantly lower in the PostI group than in the PreI group (1.9% vs. 5.4%, p = 0.004), especially in hip fractures (0.4% vs. 2.9%, p = 0.002). The relative risk reduction was 65% for all subsequent fractures and 86% for hip fractures. CONCLUSION: This study demonstrates that active osteoporosis care in patients with DRF significantly reduces subsequent fracture incidence even for the 4-year follow-up period. These findings add an evidence for the current proactive osteoporosis care programs such as fracture liaison services. LEVEL OF EVIDENCE: Therapeutic level III.
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Fracturas de Cadera , Osteoporosis , Fracturas Osteoporóticas , Fracturas del Radio , Fracturas de la Columna Vertebral , Anciano , Femenino , Fracturas de Cadera/epidemiología , Fracturas de Cadera/etiología , Fracturas de Cadera/prevención & control , Humanos , Estudios Longitudinales , Masculino , Osteoporosis/complicaciones , Osteoporosis/epidemiología , Osteoporosis/terapia , Fracturas Osteoporóticas/epidemiología , Fracturas Osteoporóticas/etiología , Fracturas Osteoporóticas/prevención & control , Fracturas del Radio/complicaciones , Factores de Riesgo , Fracturas de la Columna Vertebral/epidemiología , Fracturas de la Columna Vertebral/etiología , Fracturas de la Columna Vertebral/prevención & controlRESUMEN
BACKGROUND: The aim of this study is to investigate the prognostic role of phosphorylated AMP-activated protein kinase (pAMPK) in surgically resected non-small-cell lung cancer (NSCLC). METHODS: Immunohistochemical staining of pAMPK was carried out on tissue microarrays containing 463 samples obtained from patients with NSCLC and correlated with clinicopathological characteristics and survival. RESULTS: pAMPK expression levels were significantly higher in never smokers versus former smokers versus current smokers (P=0.045). A positive pAMPK expression was associated with increased overall survival (OS) and recurrence-free survival (RFS) (P=0.0009 and P=0.0007, respectively). OS and RFS were statistically superior in pAMPK-positive than in pAMPK-negative patients with adenocarcinoma (ADC; median OS: 5.6 and 4.2 years, respectively, P=0.0001; median RFS: 5.0 and 2.4 years, respectively, P=0.001), whereas they were similar in those patients with squamous cell carcinoma. Multivariate analysis confirmed that pAMPK positivity was associated with OS [hazard ratio (HR)=0.574, 95% confidence interval (CI) 0.418-0.789, P=0.0006) and RFS (HR=0.608, 95% CI 0.459-0.807, and P=0.0006), independent of clinical covariates. CONCLUSIONS: High pAMPK expression levels are associated with increased survival in patients with NSCLC, especially those with ADC. Our results support further evaluation of AMP-activated protein kinase as a potential prognostic and therapeutic target for lung cancer.
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Proteínas Quinasas Activadas por AMP/biosíntesis , Biomarcadores de Tumor/análisis , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Fosforilación , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de Matrices TisularesRESUMEN
To better understand genetic alterations in oral premalignant lesions, we examined 84 oral leukoplakia samples from 37 patients who had been enrolled in a chemoprevention trial. The samples were analyzed for two microsatellite markers located at chromosomes 9p21 and 3p14. Loss of heterozygosity (LOH) at either or both loci was identified in 19 of the 37 (51%) patients. Of these 19 patients, seven (37%) have developed head and neck squamous cell carcinoma (HNSCC) while only one of 18 (6%) of patients without LOH developed HNSCC. Our data suggest that clonal genetic alterations are common in oral premalignant lesions; that multiple genetic alterations have already occurred in oral premalignant lesions, allowing at least a focal clonal expansion; and that losses of the 9p21 and 3p14 regions may be related to early processes of tumorigenesis in HNSCC. These genetic alterations in premalignant tissues may serve as markers for cancer risk assessment.
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Cromosomas Humanos Par 3 , Cromosomas Humanos Par 9 , ADN Satélite , Marcadores Genéticos , Leucoplasia Bucal/genética , Repeticiones de Microsatélite/genética , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Ensayos Clínicos como Asunto , Femenino , Frecuencia de los Genes , Heterocigoto , Humanos , Leucoplasia Bucal/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Valor Predictivo de las PruebasRESUMEN
ONYX-015 is an adenovirus with the E1B 55-kDa gene deleted, engineered to selectively replicate in and lyse p53-deficient cancer cells while sparing normal cells. Although ONYX-015 and chemotherapy have demonstrated anti-tumoral activity in patients with recurrent head and neck cancer, disease recurs rapidly with either therapy alone. We undertook a phase II trial of a combination of intratumoral ONYX-015 injection with cisplatin and 5-fluorouracil in patients with recurrent squamous cell cancer of the head and neck. There were substantial objective responses, including a high proportion of complete responses. By 6 months, none of the responding tumors had progressed, whereas all non-injected tumors treated with chemotherapy alone had progressed. The toxic effects that occurred were acceptable. Tumor biopsies obtained after treatment showed tumor-selective viral replication and necrosis induction.
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Adenovirus Humanos/genética , Cisplatino/uso terapéutico , Fluorouracilo/uso terapéutico , Terapia Genética/métodos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/terapia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/terapia , Adenovirus Humanos/fisiología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Femenino , Terapia Genética/efectos adversos , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Replicación ViralRESUMEN
A retroviral vector containing the wild-type p53 gene under control of a beta-actin promoter was produced to mediate transfer of wild-type p53 into human non-small cell lung cancers by direct injection. Nine patients whose conventional treatments failed were entered into the study. No clinically significant vector-related toxic effects were noted up to five months after treatment. In situ hybridization and DNA polymerase chain reaction showed vector-p53 sequences in posttreatment biopsies. Apoptosis (programmed cell death) was more frequent in posttreatment biopsies than in pretreatment biopsies. Tumor regression was noted in three patients, and tumor growth stabilized in three other patients.
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Carcinoma de Pulmón de Células no Pequeñas/terapia , Técnicas de Transferencia de Gen , Genes p53 , Terapia Genética , Neoplasias Pulmonares/terapia , Retroviridae/genética , Anciano , Secuencia de Bases , Carcinoma de Pulmón de Células no Pequeñas/patología , Cartilla de ADN , Terapia Genética/efectos adversos , Terapia Genética/métodos , Vectores Genéticos/efectos adversos , Vectores Genéticos/genética , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Datos de Secuencia MolecularRESUMEN
Chemoprevention is the use of pharmacologic or natural agents that inhibit the development of invasive cancer either by blocking the DNA damage that initiates carcinogenesis or by arresting or reversing the progression of premalignant cells in which such damage has already occurred. Recent advances in our understanding of the mechanisms of carcinogenesis have led to the synthesis of new drugs that can inhibit tumor development in experimental animals by selective action on specific molecular targets, such as the estrogen, androgen, and retinoid receptors or inducible cyclooxygenase. Several of these agents (including tamoxifen, 13-cis-retinoic acid, retinyl palmitate, and an acyclic retinoid) are clinically effective in preventing the development of cancer, particularly in patients who are at high risk for developing second primary tumors after surgical removal of the initial tumor.
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Anticarcinógenos/uso terapéutico , Quimioprevención , Neoplasias/prevención & control , Lesiones Precancerosas/tratamiento farmacológico , Animales , Biomarcadores de Tumor/análisis , Ensayos Clínicos como Asunto , Quimioterapia Combinada , Humanos , Recurrencia Local de Neoplasia/prevención & control , Neoplasias/etiología , Neoplasias/patología , Neoplasias Primarias Secundarias/prevención & control , Factores de RiesgoRESUMEN
Retinoids, including retinol and retinoic acid derivatives, maintain the normal growth and differentiation of human bronchial epithelial (HBE) cells and are under investigation as agents for lung cancer prevention. In this study, we examined the biologic effects of retinoids on normal HBE cells and the molecular mechanisms of retinoid actions. At a dose of 10(-6) M, all-trans retinoic acid (t-RA) suppressed the proliferation of normal HBE cells, which accumulated in the G0 phase. No evidence of programmed cell death was observed. The class of retinoid nuclear receptor that mediated the growth arrest was explored. Normal HBE cell growth was suppressed by a retinoid that selectively activates retinoic acid receptors but not by one that activates retinoid X receptors. The E2F transcription factor has demonstrated a role in G0 entry through transcriptional suppression of genes that induce cell cycle progression. To investigate the role of E2F in retinoid signaling, transient transfection assays were performed using reporter plasmids containing E2F-binding sites. Findings from these experiments suggested that t-RA treatment converted E2F into a transcriptional suppressor. Supporting this possibility, t-RA inhibited the expression of the E2F target genes B-myb, cyclin A, and cyclin E. Further, t-RA increased the levels of nuclear E2F-4, p107, and p130 and enhanced the binding of E2F-4 to p107, which have been associated with the conversion of E2F into a transcriptional suppressor in other cells. These findings point to retinoic acid receptor- and E2F-dependent pathways as potential mediators of retinoid-induced growth arrest in normal HBE cells and have implications for the use of retinoids in clinical trials on the prevention of lung cancer.
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Bronquios/crecimiento & desarrollo , Bronquios/metabolismo , Proteínas Portadoras , Proteínas de Ciclo Celular , Células Epiteliales/metabolismo , Receptores de Ácido Retinoico/metabolismo , Factores de Transcripción/metabolismo , Tretinoina/metabolismo , Apoptosis , Northern Blotting , Western Blotting , Bronquios/citología , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Factores de Transcripción E2F , Factor de Transcripción E2F4 , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Genes Reporteros , Humanos , Plásmidos , Pruebas de Precipitina , Fase de Descanso del Ciclo Celular , Proteína 1 de Unión a Retinoblastoma , Receptores X Retinoide , Rodaminas/metabolismo , Transducción de Señal/genética , Factor de Transcripción DP1 , Factores de Transcripción/inmunología , Transcripción Genética , Transfección , Tretinoina/inmunología , Tretinoina/farmacologíaRESUMEN
Jun N-terminal kinases (JNKs) are serine-threonine kinases that play a critical role in the regulation of cell growth and differentiation. We previously observed that JNK activity is suppressed by all-trans-retinoic acid (t-RA), a ligand for retinoic acid nuclear receptors (RARs), in normal human bronchial epithelial cells, which are growth inhibited by t-RA. In this study, we investigated the mechanism by which t-RA inhibits JNK and the possibility that this signaling event is blocked in non-small cell lung cancer (NSCLC) cells. Virtually all NSCLC cell lines are resistant to the growth-inhibitory effects of t-RA, and a subset of them have a transcriptional defect specific to retinoid nuclear receptors. We found that in NSCLC cells expressing functional retinoid receptors, serum-induced JNK phosphorylation and activity were inhibited by t-RA in a bimodal pattern, transiently within 30 min and in a sustained fashion beginning at 12 h. Retinoid receptor transcriptional activation was required for the late, but not the early, suppression of JNK activity. t-RA inhibited serum-induced JNK activity by blocking mitogen-activated protein (MAP) kinase kinase 4-induced signaling events. This effect of t-RA was phosphatase dependent and involved an increase in the expression of the dual-specificity MAP kinase phosphatase 1 (MKP-1). t-RA did not activate MKP-1 expression or inhibit JNK activity in a NSCLC cell line with retinoid receptors that are refractory to ligand-induced transcriptional activation. These findings provide the first evidence that t-RA suppresses JNK activity by inhibiting JNK phosphorylation. Retinoid receptor transcriptional activation was necessary for the sustained inhibition of JNK activity by t-RA, and this signaling event was disrupted in NSCLC cells with retinoid receptors that are refractory to ligand-induced transcriptional activation.
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Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Proteínas de Ciclo Celular , Proteínas Inmediatas-Precoces/metabolismo , MAP Quinasa Quinasa 4 , Quinasas de Proteína Quinasa Activadas por Mitógenos , Proteínas Quinasas Activadas por Mitógenos , Fosfoproteínas Fosfatasas , Proteínas Tirosina Fosfatasas/metabolismo , Tretinoina/metabolismo , Fosfatasa 1 de Especificidad Dual , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos , Proteína Fosfatasa 1 , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Receptores de Ácido Retinoico/metabolismo , Tretinoina/farmacología , Células Tumorales CultivadasRESUMEN
The survival rate is 40% for patients with advanced squamous cell carcinoma of the head and neck whose tumors are completely resected and 20% for those with unresectable tumors treated with radiotherapy alone. During the past 10 years, combined modality approaches have been developed in an effort to enhance locoregional disease control, reduce distant metastases, and preserve anatomic function. They include the following: (a) neoadjuvant chemotherapy followed by standard therapy with surgery and/or radiation, (b) adjuvant chemotherapy after surgery or radiotherapy with or without neoadjuvant chemotherapy, and (c) neoadjuvant chemotherapy concurrent with radiotherapy. Even early studies of cisplatin plus fluorouracil (5-FU) reported 50%-90% overall response rates, and this is the main drug combination used in clinical trials. In the Veterans Affairs Cooperative Study Program, 5-FU and cisplatin followed by radiotherapy achieved a 49% complete response rate and preservation of the larynx in 64% of the patients. These results supported the findings of other nonrandomized trials that sequential induction chemotherapy and radiotherapy results in laryngeal preservation without compromising overall survival. The Head and Neck Cancer Intergroup Trial compared adjuvant postoperative cisplatin plus 5-FU prior to radiotherapy with postoperative radiotherapy. Survival at 4 years was 44% with radiotherapy alone and 48% with chemotherapy and radiotherapy. Biochemical modulation of 5-FU with leucovorin and biologic response modifiers such as interferon has achieved complete response rates as high as 66%, but severe mucositis continues to be the dose-limiting toxic effect. Standard radiotherapy for advanced nasopharyngeal carcinoma--a unique type of head and neck cancer--resulted in 5-year survival of 10%-40%, but neoadjuvant chemotherapy plus radiotherapy has achieved overall complete response rates greater than 80% with median survival of 5 or more years. We conclude that curability of nasopharyngeal carcinoma with a combined modality approach appears to be an achievable goal, but adequate evaluation in large-scale randomized trials is hampered by low accrual to clinical trials. In summary, neoadjuvant therapy for squamous cell head and neck carcinoma results in complete response rates of 22%-66%, but addition of adjuvant therapy may be necessary for a survival advantage over standard therapy. Although concurrent chemoradiotherapy has produced increased survival, additional trials are needed to determine optimal dosages.
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Terapia Combinada , Neoplasias de Cabeza y Cuello/terapia , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Neoplasias Nasofaríngeas/terapia , PronósticoRESUMEN
BACKGROUND: Proliferating cell nuclear antigen (PCNA) is a 36-kd nuclear protein whose expression is associated with DNA synthesis and cell proliferation. Tumorigenesis in head and neck squamous cell carcinoma is proposed to be a multistep process; dysregulation of proliferation is a potential marker of this process. PURPOSE: PCNA dysregulation was analyzed in squamous cell carcinoma tissue samples containing premalignant lesions (hyperplasia and/or dysplasia) and in adjacent normal epithelium to better understand proliferative changes during head and neck tumor development. METHODS: Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded sections by using a monoclonal anti-PCNA antibody. PCNA expression was analyzed in 33 head and neck squamous cell carcinomas and in their adjacent premalignant lesions from different sites and compared with that in the control samples, which had never been exposed to first-hand tobacco smoke. PCNA expression was assessed by semiquantitative scoring (scale 0-3) in three epithelial layers (basal, parabasal, and superficial). The labeling index and the weighted mean index of PCNA expression were calculated. RESULTS: Normal epithelium adjacent to the tumor had much more proliferative activity than the controls: The weighted mean index of PCNA expression was four-fold higher in the basal layer and sixfold higher in the parabasal layer. PCNA expression increased as tissues progressed from adjacent normal epithelium to hyperplasia (P < .001), hyperplasia to dysplasia (P < .001), and dysplasia to squamous cell carcinoma (P = .065); the total increase in PCNA expression ranged from fourfold to 10-fold from adjacent normal epithelium to squamous cell carcinoma. PCNA expression was higher in the parabasal than in the basal layer at all premalignant stages (23 of 25 samples in adjacent normal epithelium, 12 of 13 in hyperplasia, and 17 of 22 in dysplasia). As the tissue progressed from normal through premalignant stages to squamous cell carcinomas, we observed not only incremental increases in the labeling index, but also incremental increases in PCNA expression per labeled cells. CONCLUSIONS: These results indicate that PCNA could be a useful biomarker for multistep carcinogenesis in head and neck cancer and may serve as an intermediate end point in chemopreventive trials.
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Antígenos de Neoplasias/análisis , Biomarcadores de Tumor , Carcinoma de Células Escamosas/inmunología , Neoplasias de Cabeza y Cuello/inmunología , Proteínas Nucleares/análisis , Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/patología , Humanos , Inmunohistoquímica , Estadificación de Neoplasias , Antígeno Nuclear de Célula en ProliferaciónRESUMEN
BACKGROUND: Insulin-like growth factors (IGFs), in particular IGF-I and IGF-II, strongly stimulate the proliferation of a variety of cancer cells, including those from lung cancer. To examine the possible causal role of IGFs in lung cancer development, we compared plasma levels of IGF-I, IGF-II, and an IGF-binding protein (IGFBP-3) in patients with newly diagnosed lung cancer and in control subjects. METHODS: From an ongoing hospital-based, case-control study, we selected 204 consecutive patients with histologically confirmed, primary lung cancer and 218 control subjects who were matched to the case patients by age, sex, race, and smoking status. IGF-I, IGF-II, and IGFBP-3 plasma levels were measured by enzyme-linked immunosorbent assay and then divided into quartiles, based on their distribution in the control subjects. Associations between the IGF variables and lung cancer risk were estimated by use of odds ratios (ORs). Reported P values are two-sided. RESULTS: IGF and IGFBP-3 levels were positively correlated (all r>.27; all P<.001). High plasma levels of IGF-I were associated with an increased risk of lung cancer (OR = 2.06; 95% confidence interval [CI] = 1.19-3.56; P = .01), and this association was dose dependent in both univariate and multivariate analyses. Plasma IGFBP-3 showed no association with lung cancer risk unless adjusted for IGF-I level; when both of these variables were analyzed together, high plasma levels of IGFBP-3 were associated with reduced risk of lung cancer (OR = 0.48; 95% CI = 0.25-0.92; P = .03). IGF-II was not associated with lung cancer risk. CONCLUSIONS: Plasma levels of IGF-I are higher and plasma levels of IGFBP-3 are lower in patients with lung cancer than in control subjects. If these findings can be confirmed in prospective studies, measuring levels of IGF-I and IGFBP-3 in blood may prove useful in assessing lung cancer risk.
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Biomarcadores de Tumor/sangre , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor II del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Neoplasias Pulmonares/sangre , Análisis de Varianza , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Análisis por Apareamiento , Persona de Mediana Edad , Oportunidad Relativa , Riesgo , Factores de Riesgo , FumarRESUMEN
Head and neck cancer is a major worldwide health problem; it has been estimated that approximately 900,000 people were diagnosed with this disease in 1995. Patients are generally treated with surgery and/or radiation therapy. Treatment, especially of patients with early stage (I or II) head and neck squamous cell carcinoma, is often successful. A serious concern, however, is the fact that these patients subsequently develop second primary tumors at an annual rate of 4%-7%. Molecular analyses of premalignant and malignant tissues have produced strong evidence that clonal genetic alterations occur during the early stage of aerodigestive tract carcinogenesis. Although the roles of tobacco and diet in head and neck carcinogenesis have been the subjects of epidemiologic investigations for many years, it has only recently become possible to integrate information regarding genetic susceptibility factors into the development of comprehensive risk models for these cancers. The molecular and epidemiologic studies provide the foundation on which clinical trials can be designed to evaluate the role of retinoids and other compounds in the reversal of premalignancy and the prevention of second primary tumors (i.e., in chemoprevention). This translational approach has led to studies of the utility of intermediate end point markers, such as the nuclear retinoic acid receptors, in chemoprevention strategies. Given the rapid advances occurring in this area of research, it may soon be possible to use these biomarkers to identify patients who are most at risk for developing head and neck cancer and who are most likely to benefit from chemopreventive interventions.
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Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/etiología , Neoplasias de Cabeza y Cuello/prevención & control , Retinoides/farmacología , Biomarcadores de Tumor/sangre , Dieta/efectos adversos , Predisposición Genética a la Enfermedad , Genotipo , Neoplasias de Cabeza y Cuello/sangre , Neoplasias de Cabeza y Cuello/epidemiología , Neoplasias de Cabeza y Cuello/genética , Humanos , Incidencia , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Primarias Secundarias/prevención & control , Valor Predictivo de las Pruebas , Ensayos Clínicos Controlados Aleatorios como Asunto , Retinoides/farmacocinética , Retinoides/uso terapéutico , Riesgo , Fumar/efectos adversos , Vitamina A/uso terapéutico , beta Caroteno/uso terapéuticoRESUMEN
BACKGROUND: The inhibitory effects of N-(4-hydroxyphenyl)retinamide (4HPR) on tumorigenesis and tumor growth may result from its ability to induce apoptosis (programmed cell death). Since antioxidants inhibit 4HPR-induced apoptosis, experiments were planned to determine whether the levels of reactive oxygen species increase in cells undergoing apoptosis after exposure to 4HPR. METHODS: Cells of the human cervical carcinoma cell line C33A and normal human cervical epithelial cells were treated with 4HPR and analyzed for survival, induction of apoptosis, generation of reactive oxygen species, and expression of the apoptosis-related proteins Bcl-2 and Bax. RESULTS: Treatment with 4HPR decreased C33A cell number by inducing apoptosis in a time- and dose-dependent fashion. DNA fragmentation typical of apoptosis was observed in cells exposed to 4HPR at concentrations of 3 microM or higher for 6-24 hours. The generation of reactive oxygen species was enhanced by 1.85-fold to 4.5-fold after a 1.5-hour treatment with 0.4-10 microM 4HPR. Pyrrolidine dithiocarbamate, an oxygen radical scavenger, suppressed the rate of generation of reactive oxygen species and inhibited 4HPR-induced apoptosis. 4HPR failed to modulate cellular levels of the Bcl-2 and Bax proteins. N-(4-Methoxyphenyl)retinamide, the major 4HPR metabolite, and several other retinoids that bind to nuclear retinoic acid receptors or retinoid X receptors failed to enhance the generation of reactive oxygen species and to induce apoptosis. 4HPR was much less effective in generating reactive oxygen species and in inducing apoptosis in normal human cervical epithelial cells than in C33A cervical carcinoma cells. CONCLUSIONS: Enhancement of the generation of reactive oxygen species may be involved in apoptotic pathway induction by 4HPR.
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Fenretinida/farmacología , Radicales Libres , Oxígeno/metabolismo , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/fisiopatología , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cuello del Útero/citología , Fragmentación del ADN/efectos de los fármacos , ADN de Neoplasias/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Epitelio/efectos de los fármacos , Femenino , Fenretinida/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas Proto-Oncogénicas/análisis , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Pirrolidinas/farmacología , Retinoides/farmacología , Tiocarbamatos/farmacología , Células Tumorales Cultivadas , Neoplasias del Cuello Uterino/química , Proteína X Asociada a bcl-2RESUMEN
BACKGROUND: We hypothesize that accumulation of genetic damage is dependent on an individual's intrinsic carcinogen sensitivity and on various humoral factors (e.g., insulin-like growth factors [IGFs]) that enhance proliferation, resistance to apoptotic cell death, and clonal outgrowth of genetically damaged cells. We tested this hypothesis by determining whether proliferation potential and genetic instability are associated with the risk of lung cancer. METHODS: In a study of 183 lung cancer patients and 227 matched control subjects, we examined the joint effects of latent genetic instability (measured as mutagen sensitivity) and elevated proliferation potential (assessed by measuring IGFs) in lung cancer risk. Levels of IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) in plasma were measured by use of immunoassay kits. Mutagen sensitivity was assessed by quantitating bleomycin- and benzo[a]pyrene diol epoxide (BPDE)-induced chromatid breaks in peripheral blood lymphocyte cultures. RESULTS: Although not statistically significant, the mean levels of IGF-I and the molar ratio of IGF-I/IGFBP-3 were higher in patients with advanced or poorly differentiated disease than in patients with early or well-differentiated disease. Variation in IGFs was not associated with any specific histologic type or tumor stage. High levels of IGF-I and enhanced mutagen sensitivity were individually associated with increased risk of lung cancer: odds ratio (OR) of 2.13 (95% confidence interval [CI] = 1.20-3.78) for IGF-I, 2.50 (95% CI = 1. 49-4.20) for bleomycin sensitivity, and 2.95 (95% CI = 1.72-5.06) for BPDE sensitivity. The OR was statistically significantly elevated to 8.88 for both higher IGF-I and bleomycin sensitivity (95% CI = 3.67-21.50) and to 13.53 for higher IGF-I and BPDE sensitivity combined (95% CI = 4.48-40.89). With all three risk factors considered together, the OR was 17.09 (95% CI = 4.16-70.27). High levels of IGFBP-3 alone were associated with reduced lung cancer risk: OR = 0.59 (95% CI = 0.33-1.05). CONCLUSIONS: Our data suggest that individuals with genetic instability and higher proliferation potential are at enhanced risk for lung cancer.
Asunto(s)
Neoplasias Pulmonares/sangre , Linfocitos/efectos de los fármacos , Mutágenos/farmacología , Somatomedinas/metabolismo , 7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido/farmacología , Bleomicina/farmacología , Estudios de Casos y Controles , Aberraciones Cromosómicas/genética , Interpretación Estadística de Datos , Femenino , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor II del Crecimiento Similar a la Insulina/metabolismo , Neoplasias Pulmonares/genética , Linfocitos/metabolismo , Masculino , Pruebas de Mutagenicidad , Factores de RiesgoRESUMEN
BACKGROUND: Chemotherapeutic study of cervical squamous cell carcinoma has shown some positive results. Complete plus partial (overall) response rates of 15%-35% (complete response rate, less than 5%) were achieved with the use of a small number of cytotoxic single agents in patients with advanced disease. In addition, overall response rates of 60%-70% (complete response rates, 10%-20%) were achieved with cisplatin-based, multiagent regimens in patients with primary, locally advanced disease. However, the lack of clear evidence that existing chemotherapy can achieve a survival benefit, coupled with the worldwide annual deaths of hundreds of thousands of women from cervical cancer, indicates the urgent need for effective systemic therapy for this disease. PURPOSE: In view of the preclinical and clinical evidence that supports testing of the novel combination of 13-cis-retinoic acid (13-cRA) plus interferon-alpha (IFN-alpha) in cervical squamous cell carcinoma, we conducted a phase II study of this regimen in locally advanced disease. METHODS: Twenty-six patients with untreated, locally advanced squamous cell carcinoma of the cervix were treated daily for at least 2 months with oral 13-cRA (1 mg/kg) and subcutaneous recombinant human IFN alpha-2a (6 million units). In 21 patients (81%), the disease was stage II or higher. RESULTS: Thirteen patients (50%) experienced major responses (tumor regression greater than or equal to 50%) in association with resolution of symptoms; one achieved complete response, and 12 experienced partial response. Seven with partial response are improving further, four are being maintained in partial response, and one responder has relapsed during therapy. The response rate is 58% (11 of 19) in patients with stage IIB or higher disease and 66% (10 of 15) in patients with bulky disease (at least one dimension greater than or equal to 10 cm). Of the 13 non-responders, nine have stable disease and four have had disease progression during therapy. Toxicity was minimal. CONCLUSION: These preliminary results indicate that systemic 13-cRA plus IFN alpha-2a is a highly active, well-tolerated therapy for locally advanced cervical cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Adulto , Anciano , Evaluación de Medicamentos , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Isotretinoína/administración & dosificación , Persona de Mediana Edad , Proteínas Recombinantes , Inducción de RemisiónRESUMEN
BACKGROUND: Death-associated protein (DAP) kinase is a serine/threonine kinase that is important in ligand-induced programmed cell death and plays an important role in lung cancer metastasis in animal models. Hypermethylation of the promoter represses the expression of the DAP kinase gene. Our purpose was to determine whether the hypermethylation status of the DAP kinase promoter influences the prognosis of non-small-cell lung cancer (NSCLC). METHODS: We retrospectively studied 135 patients with pathologic stage I NSCLC who had undergone curative surgery. Methylation-specific polymerase chain reaction was used to determine the methylation status of the DAP kinase promoter in resected specimens from patients with primary NSCLC. Statistical analyses, all two-sided, were performed to determine the prognostic effect of methylation status on various clinical parameters. RESULTS: Hypermethylation of the DAP kinase promoter was found in 59 (44%) of the 135 tumors. Patients whose tumors exhibited such hypermethylation had a statistically significantly poorer probability of overall survival at 5 years after surgery than those without such hypermethylation (.46 versus.68; P: =.007). Moreover, the groups with and without hypermethylation of the DAP kinase promoter showed a striking difference in the probability of disease-specific survival; i.e., among people who died of lung cancer-related causes specifically, the probability of 5-year survival was.56 for those with such hypermethylation and.92 for those without it (P:<.001). Multivariate analysis indicated that hypermethylation of the DAP kinase promoter is the only independent predictor for disease-specific survival among clinical and histologic parameters tested. CONCLUSIONS: Hypermethylation of the DAP kinase promoter is a common abnormality in early-stage NSCLC. This abnormality is strongly associated with survival, suggesting that DAP kinase plays an important role in determining the biologic aggressiveness of early-stage NSCLC.
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Proteínas Quinasas Dependientes de Calcio-Calmodulina/genética , Carcinoma de Pulmón de Células no Pequeñas/enzimología , ADN de Neoplasias/metabolismo , Neoplasias Pulmonares/enzimología , Regiones Promotoras Genéticas , Adenocarcinoma/enzimología , Anciano , Proteínas Reguladoras de la Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Células Escamosas/enzimología , Proteínas Quinasas Asociadas a Muerte Celular , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Metilación , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Valor Predictivo de las Pruebas , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Only a fraction of cigarette smokers develop lung cancer, suggesting that people differ in their susceptibility to this disease. We investigated whether differences in DNA repair capacity (DRC) for repairing tobacco carcinogen-induced DNA damage are associated with differential susceptibility to lung cancer. METHODS: From August 1, 1995, through April 30, 1999, we conducted a hospital-based, case-control study of 316 newly diagnosed lung cancer patients and 316 cancer-free control subjects matched on age, sex, and smoking status. DRC was measured in cultured lymphocytes with the use of the host-cell reactivation assay with a reporter gene damaged by a known activated tobacco carcinogen, benzo[a]pyrene diol epoxide. Statistical tests were two-sided. RESULTS: Overall, lower DRC was observed in case patients than in control subjects (P:<.001) and was associated with a greater than twofold increased risk of lung cancer. Compared with the highest DRC quartile in the control subjects and after adjustment for age, sex, pack-years of smoking, family history of cancer, and other covariates, reduced DRC was associated with increased risk of lung cancer in a dose-dependent fashion (odds ratio [OR] = 1.8 with 95% confidence interval [CI] = 1.1-3.1, OR = 2.0 with 95% CI = 1.2-3.4, and OR = 4. 3 with 95% CI = 2.6-7.2 for the second, third, and fourth quartiles, respectively; P:(trend)<.001). Case patients who were younger at diagnosis (<60 years old), female, or lighter smokers or who reported a family history of cancer exhibited the lowest DRC and the highest lung cancer risk among their subgroups, suggesting that these subgroups may be especially susceptible to lung cancer. CONCLUSION: The results provide evidence that low DRC is associated with increased risk of lung cancer. The findings from this hospital-based, case-control study should be validated in prospective studies.
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Carcinógenos/efectos adversos , Aductos de ADN/genética , Reparación del ADN/genética , Neoplasias Pulmonares/etiología , Nicotiana/efectos adversos , Plantas Tóxicas , Fumar/efectos adversos , Factores de Edad , Anciano , Estudios de Casos y Controles , Línea Celular , Aductos de ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Modelos Logísticos , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/genética , Linfocitos , Masculino , Persona de Mediana Edad , Plásmidos , Factores Sexuales , Texas/epidemiología , TransfecciónRESUMEN
BACKGROUND: Interindividual differences in the structure and expression of the dopamine receptor genes affect dopamine availability and may be the genetic basis for variation in vulnerability to tobacco smoking. In this study, prevalences of polymorphisms in the TaqIA allele (A1 and A2) and the TaqIB allele (B1 and B2) of the D2 dopamine receptor gene in 157 lung cancer case patients and 126 control subjects were determined to assess whether individuals homozygous or heterozygous for the less common A1 and B1 alleles are more vulnerable to nicotine addiction. METHODS: Case and control subjects were accrued from an ongoing epidemiologic study. Blood samples were collected from them and subjected to molecular genetic analyses. Subjects were interviewed to obtain relevant information. Current and former smokers were administered a questionnaire to quantify their addiction to nicotine. RESULTS: The combined B1B2 genotypes appeared to be more prevalent in ever smokers than in never smokers among case patients (30.3% versus 13.3%; two-sided P = .233) and among control subjects (30.9% and 0%; two-sided P = .02); statistically significant differences were not observed among those with A1 genotypes. Statistically significant correlations between the presence of the A1 and B1 alleles were observed (r = .73 for case subjects and r = .76 for control subjects; two-sided P<.001). Individuals with rarer genotypes reported having been substantially younger at the time of smoking initiation (statistically significant for both A1 and B1) and having attempted to quit smoking fewer times (statistically significant for only A1). CONCLUSION: Variant alleles of the D2 dopamine receptor gene may play a role in determining nicotine addiction, although the associations between the at-risk genotypes and measures of nicotine addiction were not entirely consistent.
Asunto(s)
Neoplasias Pulmonares/etiología , Receptores de Dopamina D2/genética , Fumar/efectos adversos , Tabaquismo/complicaciones , Anciano , Alelos , Estudios de Casos y Controles , Cartilla de ADN , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Cese del Hábito de Fumar , Tabaquismo/genéticaRESUMEN
BACKGROUND: Lung cancer originates in a diffusely damaged bronchial epithelium as a result of sequential and cumulative genetic alterations. We investigated the feasibility of in vivo gene replacement in endobronchial precancerous and cancerous cells by a regionally administered nonviral delivery system. METHODS: After evaluating the in vitro transfection efficiency and cytotoxicity of a variety of cationic liposome-p53 formulations, a specific formulation, DP3-p53, was selected for further in vitro and in vivo evaluation. The ability of DP3-p53 to introduce the p53 gene in the normal bronchial epithelium was studied in transgenic mice that lack the p53 gene. The therapeutic effect of DP3-p53 administered intratracheally was studied in two nude mouse models of endobronchial human lung cancer by use of H358 (p53-null) and H322 (p53-mutant) cells. RESULTS: DP3-p53 was able to effectively introduce and express the p53 gene and induce G1 arrest and apoptosis in H358 cells in vitro and to introduce and transcribe the p53 gene in the bronchial epithelium of transgenic mice that lack the p53 gene in vivo. In therapeutic experiments using groups of four or five mice each, administration of five intratracheal doses of DP3-p53 (2 microg or 8 microg DNA per dose) on days 4, 8, 12, 16, and 20 after intratracheal tumor inoculation significantly inhibited lung tumor formation and prolonged by approximately twofold the survival of mice bearing H358 or H322 endobronchial tumor cells in contrast to the survival among untreated mice and mice treated with the DP3-empty vector (P = .007 [two-sided logrank test] for mice bearing H358 cells and P = .008 [two-sided logrank test] for those bearing H322 cells). CONCLUSIONS/IMPLICATIONS: Liposome-based p53 delivery through the airways is a potentially effective strategy for the treatment of early endobronchial cancer. These results have important implications for the gene therapy and prevention of human lung cancer.