RESUMEN
Squamous cell carcinoma (SCC) cells refractory to initial chemotherapy frequently develop disease relapse and distant metastasis. We show here that tumor suppressor WW domain-containing oxidoreductase (WWOX) (also named FOR or WOX1) regulates the susceptibility of SCC to methotrexate (MTX) in vitro and cure of SCC in MTX therapy. MTX increased WWOX expression, accompanied by caspase activation and apoptosis, in MTX-sensitive SCC cell lines and tumor biopsies. Suppression by a dominant-negative or small interfering RNA targeting WWOX blocked MTX-mediated cell death in sensitive SCC-15 cells that highly expressed WWOX. In stark contrast, SCC-9 cells expressed minimum amount of WWOX protein and resisted MTX-induced apoptosis. Transiently overexpressed WWOX sensitized SCC-9 cells to apoptosis by MTX. MTX significantly downregulated autophagy-related Beclin-1, Atg12-Atg5 and LC3-II protein expression and autophagosome formation in the sensitive SCC-15, whereas autophagy remained robust in the resistant SCC-9. Mechanistically, WWOX physically interacted with mammalian target of rapamycin (mTOR), which potentiated MTX-increased phosphorylation of mTOR and its downstream substrate p70 S6 kinase, along with dramatic downregulation of the aforementioned proteins in autophagy, in SCC-15. When WWOX was knocked down in SCC-15, MTX-induced mTOR signaling and autophagy inhibition were blocked. Thus, WWOX renders SCC cells susceptible to MTX-induced apoptosis by dampening autophagy, and the failure in inducing WWOX expression leads to chemotherapeutic drug resistance.
Asunto(s)
Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Metotrexato/farmacología , Metotrexato/uso terapéutico , Oxidorreductasas/metabolismo , Neoplasias de la Lengua/tratamiento farmacológico , Proteínas Supresoras de Tumor/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/ultraestructura , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Humanos , Modelos Biológicos , Proteínas de Neoplasias/metabolismo , Fagosomas/efectos de los fármacos , Fagosomas/metabolismo , Fagosomas/ultraestructura , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias de la Lengua/metabolismo , Neoplasias de la Lengua/patología , Neoplasias de la Lengua/ultraestructura , Regulación hacia Arriba/efectos de los fármacos , Oxidorreductasa que Contiene Dominios WWRESUMEN
First-line treatment of metastatic colorectal cancer with combinations of cetuximab and irinotecan-based or oxaliplatin-based chemotherapy has shown promising efficacy. The clinical response to such treatment is generally assessed by tumor measurement through imaging. This study was performed to evaluate the correlation between serial changes in imaging results and carcinoembryonic antigen (CEA) levels. In 64 patients with metastatic colorectal cancer receiving cetuximab plus FOLFIRI or FOLFOX-4 chemotherapy we retrospectively analyzed the relationship between changes in serum CEA and changes in imaging results throughout the treatment course. Response in terms of serum CEA change was defined as a >/=50% drop in CEA level for more than 4 weeks. The sensitivity and specificity of serum CEA changes after targeted chemotherapy in relation to imaging results were 80.5% (33/41) and 73.9% (17/23), respectively, with a diagnostic accuracy of 78.1% (50/64). The progression-free survival time of responders assessed by serum CEA change was significantly longer than that of nonresponders (p=0.0091). Our results highlight the importance of serum CEA monitoring in assessing the response to targeted chemotherapy and in predicting the prognosis of patients with metastatic colorectal cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno Carcinoembrionario/sangre , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Cetuximab , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Humanos , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Estudios Retrospectivos , Resultado del TratamientoAsunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Carcinoma Verrugoso/tratamiento farmacológico , Neoplasias de los Labios/tratamiento farmacológico , Metotrexato/administración & dosificación , Anciano , Carcinoma Verrugoso/patología , Humanos , Infusiones Intraarteriales , Neoplasias de los Labios/patología , MasculinoRESUMEN
From 1978 to 1994, more than 2000 advanced cancers were treated by arterial infusion chemotherapy in the Department of Surgery, Kaohsiung Medical College Hospital. During these 16 years there are a lot of improvements in arterial therapy. The catheter changed from external catheter to implantable port catheter system. The infusion pump changed from spring driven pump to more accurate battery operated electric pump. But the principle of the higher the regional tumor drug exposure, the better the treatment result is the same. There are 3 main factors affecting the successful treatment, proper placement of the catheter, suitable selection of the drugs and adequate regional tumor blood supply. The first two factors can be improved by learning and experience. However, we can do little about the third one. The blood supply of the tumor had decided most of the outcome of the treatment. Those tumors over locations with very rich blood supply such as cancers of head, breast, external genitals and hands, always respond better to chemotherapy no matter the drugs were given regionally or systemically. Of course if the anticancer drug was administered by arterial route, very high concentration of anticancer drug can be delivered to the tumor region to induced rapid shrinkage of the tumor within a relative short time.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Infusiones Intraarteriales , Neoplasias/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/tratamiento farmacológico , Niño , Femenino , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Bombas de Infusión Implantables/efectos adversos , Infusiones Intraarteriales/efectos adversos , Neoplasias de los Labios/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/irrigación sanguínea , Neoplasias/patología , Cuidados Paliativos , Neoplasias del Pene/tratamiento farmacológicoRESUMEN
Independent and interactive effects related to the development of hepatocellular carcinoma were assessed using a community-based case-control study for hepatitis B virus, habitual alcohol drinking, cigarette smoking, peanut consumption and history of hepatocellular carcinoma among the immediate family. All 200 male newly diagnosed hepatocellular carcinoma patients were recruited consecutively through the period of study as the case group from two teaching medical centers in northern and southern Taiwan. Healthy community residents matched one-to-one with cases on age, sex, ethnic group and residential area were selected as the control group. The carrier status of HBsAg and HBeAg was determined by blind radioimmunoassays, and other risk factors were obtained through standardized interviews according to a structured questionnaire. Conditional logistic regression analysis showed a significant association between hepatocellular carcinoma and the carrier status of HBsAg and HBeAg with an odds ratio of 16.7 and 56.5, respectively, for carriers of HBsAg alone and for carriers of both HBsAg and HBeAg. There was a dose-response relationship between cigarette smoking and hepatocellular carcinoma with an odds ratio of 1.1, 1.5 and 2.6, respectively, for those who smoked 1 to 10, 11 to 20 and more than 20 cigarettes a day. A significant association with hepatocellular carcinoma was also observed for the habitual alcohol consumer with an odds ratio of 3.4. Those whose immediate family had a history of hepatocellular carcinoma were more likely to have the disease develop, with an odds ratio of 4.6. However, the frequency of peanut consumption was not significantly associated with hepatocellular carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)