RESUMEN
OBJECTIVE: To identify reliable predictors of overall survival (OS), locoregional control (LC), and metastasis-free survival (MFS) after definitive concurrent chemo-radiotherapy (CCRT) for squamous cell carcinoma (SCC) of the pharynx (nasopharynx, oropharynx and hypopharynx), we examined 16 potential prognostic factors, including pre-treatment hemoglobin level and pre- and post-treatment [(18)F]fluorodeoxyglucose positron emission tomography CT (F-18 FDG-PET/CT) maximum standardized up-take values (SUVmax) of primary sites and lymph node (LN) regions. METHODS: We retrospectively reviewed records of 70 patients treated with definitive CCRT for pharyngeal cancer in our institution during July 2006-April 2012, with particular regard to 16 prognostic factors: age, sex, T stage, N stage, retropharyngeal LN (RPLN) involvement, existence of multiple primary cancer, treatment interruptions, overall treatment time, chemotherapy type, pre-treatment hemoglobin level, pre-treatment body mass index, enteral feeding period, and pre- and post-treatment F-18 FDG-PET/CT SUVmax of primary site and LN region. All patients in our cohort underwent pre- and post-treatment F-18 FDG-PET/CT. RESULTS: Multivariate analysis associated improved OS with pre-treatment hemoglobin level (≥12 g/dL; hazard ratio [HR] 3.902; 95 % confidence interval [CI] 1.244-12.236; P = 0.020) and post-treatment SUVmax (primary site) (SUVmax <5.00; HR 4.237; 95 % CI 1.072-16.747; P = 0.039). Improved LC was associated with pre-treatment hemoglobin level (≥12 g/dL; HR 2.983; 95 % CI 1.123-7.920; P = 0.028), and post treatment SUVmax (primary site) (SUVmax <5.00; HR 5.233; 95 % CI 1.582-17.309; P = 0.007). No variable was found to be significant for improved MFS. CONCLUSIONS: Significant predictors for outcome in pharyngeal SCC treated with definitive CCRT were pre-treatment baseline hemoglobin level and post-treatment F-18 FDG-PET/CT SUVmax for primary site. Patients who have hemoglobin level lower than 12 g/dL may tend to have dismal prognosis. Additional treatment should be considered in those who have higher SUVmax at primary site in post-treatment F-18 FDG-PET/CT finding.
Asunto(s)
Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias Faríngeas/tratamiento farmacológico , Neoplasias Faríngeas/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/sangre , Carcinoma de Células Escamosas/patología , Terapia Combinada , Femenino , Fluorodesoxiglucosa F18 , Estudios de Seguimiento , Hemoglobinas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Imagen Multimodal , Neoplasias Faríngeas/sangre , Neoplasias Faríngeas/patología , Faringe/efectos de los fármacos , Faringe/patología , Faringe/efectos de la radiación , Tomografía de Emisión de Positrones/métodos , Pronóstico , Radiofármacos , Estudios Retrospectivos , Análisis de Supervivencia , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
We experienced two cases of mucosa-associated lymphoid tissue (MALT) lymphoma arising at unusual locations and used F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) to evaluate their response to radiation therapy (RT). A 62-year-old male with proven prostatic MALT lymphoma and a 43-year-old woman with proven duodenal MALT lymphoma had diffuse FDG uptake in the lesion. Both cases were treated with RT; following FDG, PET/CT showed decreased FDG uptake in each lesion. Neither patient had evidence of recurrence at more than 18 months after RT. FDG PET/CT is useful for indicating the treatment site in MALT lymphoma and in evaluation of therapeutic response following RT.
Asunto(s)
Fluorodesoxiglucosa F18 , Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma de Células B de la Zona Marginal/radioterapia , Tomografía de Emisión de Positrones , Enfermedades Raras/diagnóstico , Enfermedades Raras/radioterapia , Tomografía Computarizada por Rayos X , Adulto , Femenino , Humanos , Linfoma de Células B de la Zona Marginal/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Enfermedades Raras/diagnóstico por imagen , Resultado del TratamientoRESUMEN
BACKGROUND: The hypoxic microenvironment is closely associated with the radiation resistance of tumor cells. Hypoxia induces several genes such as hypoxia-inducible factor (HIF-1) and vascular endothelial growth factor (VEGF) to promote tumor cell growth and survival. The up-regulated expression levels of HIF-1 and VEGF in tumor cells also correlate with their resistance to radiation, suggesting that these genes are potential therapeutic targets for strategies designed to enhance radiation effects. To further investigate this possibility, we investigated the effects of suppressing these genes upon the radiation sensitivity of cancer cells. We conducted these experiments using multicellular spheroids as a three-dimensional in vitro tumor model and RNA interference as the method of gene suppression. MATERIAL AND METHODS: SQ5 human lung carcinoma cells were treated with HIF-1/VEGF siRNA and/or radiation. Reversed transfection methods were employed for the spheroids. Gene expression was analyzed using quantitative RT-PCR and western blotting. Cell toxicity was qualified by colony formation assay. RESULTS: Compared with monolayer cells, spheroids showed up-regulated expression of HIF-1 and increased radiation resistance. Hypoxic conditions elevated the expression of HIF-1 and VEGF and enhanced the surviving fraction of spheroids after exposure to radiation. However, when the expression of HIF-1 and VEGF was down-regulated by transfection of targeting siRNA, this did not influence the cytotoxic effects of the radiation under either normoxic or hypoxic conditions. CONCLUSIONS: We have established a method to transfect siRNA into spheroid cells. Our current data indicate that the functions of HIF-1 or VEGF are independent of radiation sensitivity in spheroids under either normoxic or hypoxic conditions.
Asunto(s)
Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias Pulmonares/metabolismo , ARN Interferente Pequeño/administración & dosificación , Tolerancia a Radiación , Esferoides Celulares/efectos de la radiación , Factor A de Crecimiento Endotelial Vascular/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de la radiación , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , ARN Interferente Pequeño/genética , Supresión Genética/efectos de la radiación , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Sebaceous carcinoma is the rarest type of oral malignancies. We report a case of primary sebaceous carcinoma of the tongue. Systemic imaging studies revealed that the patient had a T2N2cM0 (International Union Against Cancer guidelines) primary lingual tumor. Histopathological examination revealed neoplastic sebocytic and basaloid cells, and Sudan III staining and electron microscopy revealed intracytoplasmic lipid droplets. The neoplastic cells stained positive for adipophilin; epithelial membrane antigen; epithelial antigen; and cytokeratins 7, 8, and 15, but negative for cytokeratins 5/6, 18, 19, and 20; the androgen receptor; and carcinoembryonic antigen. Superselective intraarterial chemotherapy was administered via the superficial temporal artery concurrent with daily radiotherapy. Multiple biopsies confirmed a complete response of the primary lesion. The patient then underwent neck dissection followed by pathological examination, which revealed lymph nodes metastases. After postoperative radiotherapy to the neck, distant metastases were identified in the mediastinal lymph nodes and the lung. The patient died 17 months after completing the initial course of chemoradiotherapy. Our case demonstrates that superselective intraarterial chemotherapy combined with concurrent radiotherapy can be effective in treating the primary lesion of patients with a sebaceous carcinoma of the tongue. However, an effective strategy to eradicate metastases has yet to be established.
Asunto(s)
Adenocarcinoma Sebáceo/patología , Neoplasias de la Lengua/patología , Adenocarcinoma Sebáceo/metabolismo , Adenocarcinoma Sebáceo/terapia , Anciano , Terapia Combinada , Humanos , Metástasis Linfática , Masculino , Neoplasias de la Lengua/metabolismo , Neoplasias de la Lengua/terapiaRESUMEN
Cell-free plasma DNA is elevated in cancer patients and decreases in response to effective treatments. Consequently, these nucleic acids have potential as new tumor markers. In our current study, we investigated whether the plasma DNA concentrations in patients with cancer are altered during the course of radiation therapy. To first determine the origin of cell-free plasma DNA, plasma samples from mice bearing transplanted human tumors were analyzed for human-specific and mouse-specific cell-free DNA. Human-specific DNA was detectable only in plasma from tumor-bearing mice. However, mouse-specific plasma DNA was significantly higher in tumor-bearing mice than in normal mice, suggesting that cell-free plasma DNA originated from both tumor and normal cells. We measured the total cell-free plasma DNA levels by quantitative polymerase chain reaction in 15 cancer patients undergoing radiation therapy and compared these values with healthy control subjects. The cancer patients showed higher pretreatment plasma DNA concentrations than the healthy controls. Eleven of these patients showed a transient increase of up to eightfold in their cell-free plasma DNA concentrations during the first or second week of radiation therapy, followed by decreasing concentrations toward the end of treatment. In two other cancer patients, the cell-free plasma DNA concentrations only decreased over the course of the treatment. The total cell-free plasma DNA levels in cancer patients thus show dynamic changes associated with the progression of radiation therapy. Additional prospective studies will be required to elucidate the potential clinical utility and biological implications of dynamic changes in cell-free plasma DNA during radiation therapy.
Asunto(s)
Biomarcadores de Tumor/sangre , ADN Circular/sangre , ADN de Neoplasias/sangre , Neoplasias/sangre , Neoplasias/radioterapia , Plasma/química , ARN Neoplásico/sangre , Anciano , Anciano de 80 o más Años , Animales , Estudios de Casos y Controles , ADN de Neoplasias/genética , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Neoplasias/mortalidad , Reacción en Cadena de la Polimerasa , ARN Neoplásico/genética , Tasa de Supervivencia , Resultado del Tratamiento , Células Tumorales CultivadasRESUMEN
This is the first study to demonstrate that the small-molecule Bcl-2 inhibitor HA14-1 renders human cervical cancer cells and their Bcl-2 overexpressing radioresistant counterparts, but not normal fibroblasts, more susceptible to heavy ions. Thus, Bcl-2 may be an attractive target for improving the efficacy of heavy-ion therapy.
Asunto(s)
Benzopiranos/farmacología , Iones Pesados , Nitrilos/farmacología , Fármacos Fotosensibilizantes/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Neoplasias del Cuello Uterino/radioterapia , Muerte Celular/efectos de la radiación , Supervivencia Celular/efectos de la radiación , Femenino , Fibroblastos/efectos de la radiación , Humanos , Tolerancia a Radiación , Radiación Ionizante , Células Tumorales Cultivadas , Neoplasias del Cuello Uterino/patologíaRESUMEN
PURPOSE: Loss of the cell-cycle regulatory protein p53 or overexpression of the antiapoptotic protein Bcl-2 is associated with resistance to radiation in several types of cancer cells. Flavopiridol, a synthetic flavone, inhibits the growth of malignant tumors cells in vitro and in vivo through multiple mechanisms. The purpose of the present study is to clarify whether flavopiridol enhances the cytotoxic effects of radiation in tumor cells that contain dysfunction p53 or that overexpress Bcl-2. METHODS AND MATERIALS: A human glioma cell line (A172/mp53) stably transfected with a plasmid containing mutated p53 and a human cervical cancer cell line (HeLa/bcl-2) transfected with a bcl-2 expression plasmid were used. Cells were incubated with flavopiridol for 24 h after radiation, and then cell viability was determined by a colony formation assay. Foci of phosphorylated histone H2AX were also evaluated as a sensitive indicator of DNA double-strand breaks. RESULTS: Compared with the parental wild-type cells, both transfected cell lines were more resistant to radiation. Post-treatment with flavopiridol increased the cytotoxic effects of radiation in both transfected cell lines, but not in their parental wild-type cell lines. Post-treatment with flavopiridol inhibited sublethal damage repair as well as the repair of DNA double-strand breaks in response to radiation. CONCLUSIONS: Flavopiridol enhanced the cytotoxic effect of radiation in radioresistant tumor cells that harbor p53 dysfunction or Bcl-2 overexpression. A combination treatment of flavopiridol with radiation has the potential to conquer the radioresistance of malignant tumors induced by the genetic alteration of p53 or bcl-2.
Asunto(s)
Antineoplásicos/farmacología , Flavonoides/farmacología , Piperidinas/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Tolerancia a Radiación/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/farmacología , Proteína p53 Supresora de Tumor/metabolismo , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Reparación del ADN/efectos de los fármacos , Reparación del ADN/efectos de la radiación , Femenino , Genes bcl-2 , Genes p53/genética , Glioma/metabolismo , Glioma/radioterapia , Células HeLa , Humanos , Tolerancia a Radiación/genética , Transfección , Ensayo de Tumor de Célula Madre , Proteína p53 Supresora de Tumor/genética , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/radioterapiaRESUMEN
Here, we investigated the cell killing effectiveness of heavy-ion radiation in Bcl-2 overexpressing radioresistant tumor cells. First, irradiated cells underwent primary colony formation. Radioresistance decreased with increasing linear energy transfer (LET), indicating that heavy ions may be a promising therapeutic modality for Bcl-2 overexpressing tumors. Second, cells in primary colonies were reseeded for secondary colony formation. The incidence of delayed reproductive death increased with LET irrespective of Bcl-2 overexpression, suggesting that Bcl-2 overexpression may not facilitate heavy ion-induced genomic instability.
Asunto(s)
Genes bcl-2 , Iones Pesados , Transferencia Lineal de Energía , Muerte Celular , Supervivencia Celular , Rayos gamma , Células HeLa , Humanos , Tolerancia a Radiación , Radiación IonizanteRESUMEN
BACKGROUND AND PURPOSE: Overexpression of Bcl-2 is frequent in human cancers and has been associated with radioresistance. Here we investigated the potential impact of heavy ions on Bcl-2 overexpressing tumors. MATERIALS AND METHODS: Bcl-2 cells (Bcl-2 overexpressing HeLa cells) and Neo cells (neomycin resistant gene-expressing HeLa cells) exposed to gamma-rays or heavy ions were assessed for the clonogenic survival, apoptosis and cell cycle distribution. RESULTS: Whereas Bcl-2 cells were more resistant to gamma-rays (0.2keV/microm) and helium ions (16.2keV/microm) than Neo cells, heavy ions (76.3-1610keV/microm) yielded similar survival regardless of Bcl-2 overexpression. Carbon ions (108keV/microm) decreased the difference in the apoptotic incidence between Bcl-2 and Neo cells, and prolonged G(2)/M arrest that occurred more extensively in Bcl-2 cells than in Neo cells. CONCLUSIONS: High-LET heavy ions overcome tumor radioresistance caused by Bcl-2 overexpression, which may be explained at least in part by the enhanced apoptotic response and prolonged G(2)/M arrest. Thus, heavy-ion therapy may be a promising modality for Bcl-2 overexpressing radioresistant tumors.
Asunto(s)
Iones Pesados , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Neoplasias del Cuello Uterino/radioterapia , Carbono , Muerte Celular/efectos de la radiación , Supervivencia Celular/efectos de la radiación , Femenino , Rayos gamma , Células HeLa/metabolismo , Células HeLa/efectos de la radiación , Humanos , Transferencia Lineal de Energía , Tolerancia a Radiación , Células Tumorales Cultivadas , Neoplasias del Cuello Uterino/patologíaRESUMEN
Receptor binding properties and antinociceptive activities of chimeric peptides linked by spacers were investigated. The peptides consisted of the micro-opioid receptor ligand dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH(2)) or its analog YRFB (Tyr-D-Arg-Phe-betaAla-NH(2)) linked to the ORL1 receptor ligand Ac-Arg-Tyr-Tyr-Arg-Ile-Lys-NH(2) (Ac-RYYRIK-NH(2)). All chimeric peptides were found to possess high receptor binding affinities for both micro-opioid and ORL1 receptors in mouse brain membranes although their binding affinities for both receptors in spinal membranes were significantly lower. Among them, chimeric peptide 2, which consists of dermorphin and Ac-RYYRIK-NH(2) connected by a long spacer, had the highest binding affinity towards both receptors. In the tail-flick test following intrathecal (i.t.) administration to mice, all chimeric peptides showed potent and dose-dependent antinociceptive activities with an ED(50) of 1.34-4.51 (pmol/mouse), nearly comparable to dermorphin alone (ED(50); 1.08 pmol/mouse). In contrast to their micro-opioid receptor binding profiles, intracerebroventricular (i.c.v.) administration of the chimeric peptides resulted in much less potent antinociceptive activity (ED(50) 5.55-100< pmol/mouse) than when administered i.t. (ED(50): 1.34-4.51 pmol/mouse). These results suggest the involvement of nociceptin-like agonistic effects of the Ac-RYYRIK pharmacophore in the peptides, and the regulation of mu-opioid receptor-mediated antinociception in brain. The present chimeric peptides may be useful as pharmacological tools for studies on micro-opioid receptor/ORL1 receptor heterodimers.
Asunto(s)
Analgésicos/farmacología , Antagonistas de Narcóticos , Péptidos Opioides/farmacología , Péptidos/farmacología , Receptores Opioides mu/agonistas , Analgésicos/metabolismo , Animales , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Péptidos Opioides/administración & dosificación , Péptidos Opioides/metabolismo , Péptidos/metabolismo , Receptores Opioides/metabolismo , Receptores Opioides mu/metabolismo , Médula Espinal/metabolismo , Receptor de NociceptinaRESUMEN
PURPOSE: Bcl-2, an inhibitor of apoptosis frequently shows elevated expression in human tumors, thus resulting in resistance to radiation therapy. Therefore, inhibiting Bcl-2 function may enhance the radiosensitivity of tumor cells. Tetrocarcin A (TC-A) and bcl-2 antisense oligonucleotides exhibit antitumor activity by inhibiting Bcl-2 function and transcription, respectively. We investigated whether these antitumor agents would enhance the cytotoxic effects of radiation in tumor cells overexpressing Bcl-2. METHODS AND MATERIALS: We used HeLa/bcl-2 cells, a stable Bcl-2-expressing cell line derived from wild-type HeLa (HeLa/wt) cells. Cells were incubated with TC-A and bcl-2 antisense oligonucleotides for 24 h after irradiation, and cell viability was then determined. Apoptotic cells were quantified by flow cytometric assay. RESULTS: The HeLa/bcl-2 cells were more resistant to radiation than HeLa/wt cells. At concentrations that are not inherently cytotoxic, both TC-A and bcl-2 antisense oligonucleotides increased the cytotoxic effects of radiation in HeLa/bcl-2 cells, but not in HeLa/wt cells. However, in HeLa/bcl-2 cells, additional treatment with TC-A in combination with radiation did not significantly increase apoptosis. CONCLUSIONS: The present results suggest that TC-A and bcl-2 antisense oligonucleotides reduce radioresistance of tumor cells overexpressing Bcl-2. Therefore, a combination of radiotherapy and Bcl-2 inhibitors may prove to be a useful therapeutic approach for treating tumors that overexpress Bcl-2.
Asunto(s)
Aminoglicósidos/farmacología , Apoptosis , Oligonucleótidos Antisentido/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Tolerancia a Radiación/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/farmacología , Análisis de Varianza , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Células HeLa/efectos de los fármacos , Células HeLa/metabolismo , Células HeLa/efectos de la radiación , Humanos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Mensajero/antagonistas & inhibidores , Ensayo de Tumor de Célula MadreRESUMEN
Despite considerable research into the etiology of neuroblastoma, the molecular basis of this disease has remained elusive. In contrast to the absence of expression of the known tumor suppressor CDKN2A (also known as p16 and INK4A) in a wide variety of tumor types we have found in previous studies that CDKN2A protein is paradoxically highly expressed in many advanced stage neuroblastomas and unrelated to RB1 status. In the present study, we sought to identify the mechanistic relationships that might influence CDKN2A expression and negate its influence on tumor cell proliferation. In this regard, we examined the role of the tumor-suppressor gene CDKN1B (also known as p27 and Kip1) and the oncogene ID2 in relationship to CDKN2A expression, MYCN amplification, and neuroblastoma pathogenesis in 17 neuroblastoma cell lines and 129 samples of primary tumors of all stages. All neuroblastoma cell lines expressed the ID2 transcript and protein. However, although the majority of primary neuroblastomas also expressed the ID2 transcript, expression of the ID2 protein was undetectable or only barely detectable, regardless of transcript expression. In both cell lines and primary tumors, ID2 expression was independent of both CDKN2A and MYCN expression. In primary neuroblastomas, CDKN1B protein was expressed in significantly fewer advanced-stage neuroblastomas than early-stage neuroblastomas, but its expression had no relationship with CDKN2A expression or MYCN amplification. We concluded that the paradoxical expression of CDKN2A in neuroblastoma cannot be explained by inactivation of the tumor-suppressor gene CDKN1B or overexpression of the oncogene ID2. We further concluded that ID2 is not a target of MYCN regulation nor is it a prognostic factor for neuroblastoma. Finally, the loss of CDKN1B in advanced-stage neuroblastoma suggests this protein may play a role in the neuroblastoma disease process.