RESUMEN
BACKGROUND: Bilateral Wilms tumours (BWTs) occur by germline mutation of various predisposing genes; one of which is WT1 whose abnormality was reported in 17-38% of BWTs in Caucasians, whereas no such studies have been conducted in East-Asians. Carriers with WT1 mutations are increasing because of improved survival. METHODS: Statuses of WT1 and IGF2 were examined in 45 BWTs from 31 patients with WT1 sequencing and SNP array-based genomic analyses. The penetrance rates were estimated in WT1-mutant familial Wilms tumours collected from the present and previous studies. RESULTS: We detected WT1 abnormalities in 25 (81%) of 31 patients and two families, which were included in the penetrance rate analysis of familial Wilms tumour. Of 35 BWTs from the 25 patients, 31 had small homozygous WT1 mutations and uniparental disomy of IGF2, while 4 had large 11p13 deletions with the retention of 11p heterozygosity. The penetrance rate was 100% if children inherited small WT1 mutations from their fathers, and 67% if inherited the mutations from their mothers, or inherited or had de novo 11p13 deletions irrespective of parental origin (P=0.057). CONCLUSIONS: The high incidence of WT1 abnormalities in Japanese BWTs sharply contrasts with the lower incidence in Caucasian counterparts, and the penetrance rates should be clarified for genetic counselling of survivors with WT1 mutations.
Asunto(s)
Mutación de Línea Germinal , Neoplasias Renales/genética , Proteínas WT1/genética , Tumor de Wilms/genética , Pueblo Asiatico/genética , Preescolar , Femenino , Heterocigoto , Homocigoto , Humanos , Incidencia , Lactante , Factor II del Crecimiento Similar a la Insulina/genética , Masculino , Penetrancia , Polimorfismo de Nucleótido SimpleRESUMEN
A 54 year-old Japanese female with cardiac insufficiency was found to have a left atrial mass and smaller masses on the mitral valve. Excisional surgery of the masses and mitral valve replacement were carried out. In spite of intensive post-operative radiation therapy, the patient died of intra-atrial recurrence and brain metastases after 8 months. Tumour cells were spindled to oval, were positive for vimentin, S100 protein and neurone specific enolase. Laminin and fibronectin were also demonstrated. Bone formation and myxoid areas were present. An ultrastructurally identifiable stromal component, possibly responsible for laminin and fibronectin staining, was also present. The merits of the two main diagnostic possibilities - a mesenchymal/fibroblastic sarcoma showing bone and aberrant S100 protein, and a malignant peripheral nerve sheath tumour with bone - were discussed. In practical terms, the tumour was given the diagnosis of unclassifiable sarcoma of the left atrium. Atrial sarcomas showing neural markers and bone formation are exceedingly rare, and this report adds a further exceptionally uncommon case to the literature.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Cardíacas/patología , Proteínas del Tejido Nervioso/metabolismo , Osificación Heterotópica/patología , Sarcoma/patología , Diagnóstico Diferencial , Resultado Fatal , Femenino , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Atrios Cardíacos/ultraestructura , Neoplasias Cardíacas/metabolismo , Neoplasias Cardíacas/ultraestructura , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Mixoma/metabolismo , Mixoma/patología , Mixoma/ultraestructura , Neoplasias de la Vaina del Nervio/metabolismo , Neoplasias de la Vaina del Nervio/patología , Neoplasias de la Vaina del Nervio/ultraestructura , Sarcoma/metabolismo , Sarcoma/ultraestructuraRESUMEN
A 45-year-old man was diagnosed as having acute lymphocytic leukemia (ALL) in February 1997. Complete remission was achieved by chemotherapy, and allogeneic BMT from his HLA-identical sister was performed on November 13, 1997. He developed acute GVHD (grade II), but quickly recovered after methyl-PSL pulse therapy. On June 5, 1998--day 202 after BMT--abdominal pain developed. X-ray and CT examinations showed pneumatosis intestinalis, pneumoperitoneum, pneumomediastinum and abdominal free air. We performed oxygen administration and methyl-PSL pulse therapy, and this quickly improved the symptoms. Corticosteroid and chronic GVHD were thought to be the causative factors of pneumatosis intestinalis in this case. Although pneumatosis intestinalis is relatively rare, it is one of the important potential complications that can occur after allogeneic BMT.
Asunto(s)
Trasplante de Médula Ósea/efectos adversos , Neumatosis Cistoide Intestinal/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Enfermedad Crónica , Enfermedad Injerto contra Huésped/etiología , Humanos , Masculino , Metilprednisolona/efectos adversos , Persona de Mediana Edad , Trasplante HomólogoRESUMEN
BACKGROUND/AIM: EAT/mcl-1 (EAT), an immediate early gene, functions in a similar way to bcl-2 in neutralising Bax mediated cytotoxicity, suggesting that EAT is a blocker of cell death. The aim of this study was to determine the effect of overexpression of the human EAT gene on light induced retinal cell apoptosis. METHODS: EAT transgenic mice incorporating the EF-1alpha promoter were utilised, and expression of human EAT was detected by RT-PCR. Light damage was induced by raising mice under constant illumination. Two groups of animals, EAT transgenic mice (n=14) and littermates (n=13), were examined by ERG testing and histopathology at regular time points up to 20 weeks of constant light stimulation. Electrophysiological and histopathological findings were evaluated by established systems of arbitrary scoring as scores 0-2 and scores 0-3, respectively. RESULTS: The mean score (SD) of ERG response was significantly lower in EAT transgenic mice (0.79 (0.89)) than in littermates (1.69 (0.48)) (p<0.01). Although the differences between the two survival curves did not reach statistical significance (p=0.1156), the estimated incidence of electrophysiological retinal damage was higher in EAT mice (0.0495/mouse/week; 95% confidence interval (CI) 0.0347-0.0500) than in littermates (0. 0199/mouse/week; 95% CI 0.0035-0.0364). The mean scores (SD) for histopathological retinal degeneration were 2.31 (0.63) in littermates and 1.43 (1.22) in EAT transgenic mice (p=0.065). However, Kaplan-Meier curves for histopathological failure in two groups of mice showed that retinal photoreceptor cells were preserved significantly against constant light in the littermate compared with transgenic mice (p=0.0241). The estimated incidence of histopathological retinal damage was 0.0042/mouse/week in the littermates (95% CI 0-0.0120) and 0.0419/mouse/week in the EAT mice (95% CI 0.0286-0.0500). CONCLUSION: Retinal photoreceptor cell apoptosis under constant light stimulation is likely to be accelerated in transgenic retina overexpressing EAT.
Asunto(s)
Apoptosis/fisiología , Proteínas de Caenorhabditis elegans , Luz/efectos adversos , Proteínas de la Membrana/fisiología , Proteínas de Neoplasias/fisiología , Células Fotorreceptoras de Vertebrados/patología , Proteínas Proto-Oncogénicas c-bcl-2 , Activación Transcripcional/fisiología , Animales , Southern Blotting , Intervalos de Confianza , Electrorretinografía/métodos , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Células Fotorreceptoras de Vertebrados/efectos de la radiación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de SupervivenciaRESUMEN
A pilot study was performed to evaluate the feasibility and efficacy of irinotecan hydrochloride (CPT-11) plus carboplatin (CBDCA) for treatment of advanced or recurrent colorectal cancer. Fifteen patients with colorectal cancer (nonresectable, 1; noncurative resection, 5; recurrent disease, 9) were treated with CPT-11 (40-50 mg/m2) plus CBDCA (70-100 mg/m2) once a week for 2-3 weeks followed by a one-week rest. This treatment was repeated until disease progression or severe toxic effects were found. The total dose of CPT-11 ranged from 135 to 1,214 (median, 467) mg/m2 and that of CBDCA ranged from 267 to 2,022 (median, 933) mg/m2. Adverse effects included nausea (grade 2) in 2 (13.3%) diarrhea (grade 2) in 2 (13.3%), leukopenia (grade 3) in 2 (13.3%), thrombocytopenia (grade 1) in one (6.7%), and hair falling (grade 3) in one (6.7%). The response rate of 14 evaluable patients was 14.3% (CR, 1; PR,1; NC,7; PD,5). The median survival time of all patients was 405 days from the start of chemotherapy. The survival time of patients with CR, PR, and NC (n = 9) tended to be longer than that of those with PD (n = 5) (p = 0.06). The median time to disease progression was 105 days. These results suggest that this combination chemotherapy is feasible and effective in the treatment of advanced or recurrent colorectal cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Camptotecina/administración & dosificación , Carboplatino/administración & dosificación , Neoplasias Colorrectales/patología , Esquema de Medicación , Estudios de Factibilidad , Femenino , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Proyectos Piloto , Análisis de SupervivenciaRESUMEN
We report here two autopsy cases of carcinoma that metastasized to a thyroid follicular adenoma. The first was an 82-year-old man with sigmoid colon adenocarcinoma. Three years after a colectomy he died of multiple metastases. Autopsy revealed that the metastatic colonic carcinoma was located in a thyroid follicular adenoma. The second case was a 51-year-old man with primary lung adenocarcinoma. At the time of admission, he was inoperable because of multiple organ metastasis. He died 14 months after admission due to the carcinoma. Autopsy revealed a metastatic lung adenocarcinoma also located in a follicular adenoma, as in the first case. The phenomenon of tumor-to-tumor metastasis is rare. The mechanism is still unknown, and to our knowledge, only five cases of carcinoma metastatic to thyroid follicular adenoma have been documented in the literature.
Asunto(s)
Adenocarcinoma/secundario , Adenoma/patología , Neoplasias del Colon/patología , Neoplasias Pulmonares/patología , Neoplasias Primarias Múltiples/patología , Neoplasias de la Tiroides/secundario , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The patient was a 58-year-old woman given curative treatment (pancreatectomy (body and tail) + intraoperative irradiation (25 Gy)) on the basis of a diagnosis of pancreatic carcinoma. Having a favorable postoperative course, she was discharged 24 days after surgery. A week after discharge, she was readmitted for a hemorrhagic gastric ulcer. She was later discharged again on conservative treatment, and followed up at the outpatient clinic, but nine months postoperatively, was readmitted complaining of loss of appetite and abdominal pain. Subsequent tests revealed stricture of the horizontal portion of the duodenum with distension oral to the stricture. Around the celiac artery, the paraaortic lymph nodes were swollen, and a diagnosis of stricture due to recurrent pancreatic carcinoma was made. On the day before bypass surgery was scheduled, the patient vomited blood, so the operation was postponed, conservative treatment such as blood transfusion was administered, and emergency angiography was performed simultaneously. The findings were an aortic pseudoaneurym 1 cm in diameter immediately below the origin of the superior mesenteric artery and between the left and right renal arteries, and a hemorrhage, caused by an aortoduodenal fistula, issuing from the horizontal portion of the duodenum. Hemostasis via a laparotomy was judged difficult, and so an indwelling stent-graft in the aorta was tried to stanch the blood, but without success. Another stent then had to be inserted within the first, thus stopping the flow, but the blood supply to the celiac artery, the superior mesenteric arteries and the renal arteries was impaired, and the patient died about six hours later. Postmortem examination revealed aortoduodenal fistula without recurrence of the carcinoma. The duodenal wall around the fistulous tract showed delayed radiation changes with deep ulceration. The intraoperative radiation may have played an important part in the formation of the fistula.
Asunto(s)
Enfermedades de la Aorta/etiología , Enfermedades Duodenales/etiología , Fístula Intestinal/etiología , Fístula Vascular/etiología , Enfermedades de la Aorta/diagnóstico , Enfermedades Duodenales/diagnóstico , Femenino , Humanos , Fístula Intestinal/diagnóstico , Persona de Mediana Edad , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/cirugía , Complicaciones Posoperatorias/etiología , Fístula Vascular/diagnósticoRESUMEN
Jumping translocations (JTs) are unbalanced chromosomal translocations in which an identical chromosomal region is translocated to the telomeric region of different chromosomes. JTs are rare in hematological malignancies where they are second translocations and may be an indicator of poor prognosis. We report a case of acute myeloid leukemia with t(16;21) and a JT in which the long arm of chromosome 1 distal to q21 is translocated to the terminal region of chromosome 10. The leukemic cells exhibit high expression of EAT/mcl1, an anti-apoptotic Bcl-2 related gene. Since EAT/mcl1 is mapped to 1q21 near the breakpoint in the JTs, high level expression of EAT/mcl1 may be associated with the poor prognosis of leukemia with JTs.
Asunto(s)
Apoptosis/genética , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 21/genética , Cromosomas/genética , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda/genética , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas c-bcl-2 , Translocación Genética , Adolescente , Secuencia de Aminoácidos , Secuencia de Bases , Cromosomas/ultraestructura , Cromosomas Humanos Par 1/ultraestructura , Cromosomas Humanos Par 16/ultraestructura , Cromosomas Humanos Par 21/ultraestructura , ADN de Neoplasias/genética , Humanos , Cariotipificación , Leucemia Mieloide Aguda/patología , Masculino , Datos de Secuencia Molecular , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteínas de Neoplasias/biosíntesis , Pronóstico , Telómero/genética , Telómero/ultraestructuraRESUMEN
We report a case of lipodystrophia centrifugalis abdominalis infantilis (LCAI) showing apoptosis during the lipoatrophic process by immunohistochemical staining. A 3-year-old boy was seen with a 3-month history of a centrifugally spreading depressed eruption without pain and pruritus on his abdomen. He had fever, diarrhea and vomiting for a week at the beginning of his eruption. Physical examination revealed a palm-sized well-demarcated atrophic plaque on his lower abdomen and left inguinal fold. His plaque showed fine erythema peripherally. A skin biopsy specimen showed remarkably decreased subcutaneous fatty tissue. Inflammatory cell infiltration including lymphocytes and histiocytes was noted in the degenerating fatty tissue. In the degenerating subcutaneous fatty tissue, positive staining for HLA-DR, Fas, bcl-2, p53 and transferase-mediated uridine nick end labeling in mononuclear cells were observed. He was diagnosed as having LCAI. The present case showed the possible involvement of apoptosis in the fatty tissue degeneration in LCAI.
Asunto(s)
Lipodistrofia/patología , Abdomen , Tejido Adiposo/patología , Apoptosis , Antígenos CD4/análisis , Antígenos CD8/análisis , Preescolar , Antígenos HLA-DR/análisis , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Lipodistrofia/metabolismo , Masculino , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Piel/química , Piel/patología , Proteína p53 Supresora de Tumor/análisis , Receptor fas/análisisRESUMEN
EAT/mcl-1 (EAT), a bcl-2-related immediate early gene, is up-regulated at an early stage of differentiation of human embryonal carcinoma cells. Recent studies have revealed that EAT inhibits apoptosis both in vitro and in vivo. In the present study, we demonstrated that the EAT gene was up-regulated in the early stage of rat myocardial infarction. This pattern of up-regulation was apparently different from that of another immediate early gene, c-fos. EAT, an anti-apoptotic molecule, was strongly up-regulated in the non-ischemic region. In contrast, the expression of c-fos was induced in both ischemic and non-ischemic regions, and was higher in the ischemic region. Apoptosis of cardiomyocytes is currently thought to significantly contribute to acute myocardial infarction. We detected cardiomyocyte apoptosis by gel electrophoresis of genomic DNA and in situ nick end labeling in the ischemic region, but not in the non-ischemic region. As an inhibitor of apoptosis, EAT may play a role in the protection of cardiomyocytes in the early stage of acute myocardial infarction.
Asunto(s)
Apoptosis/genética , Infarto del Miocardio/genética , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas c-bcl-2 , Animales , Modelos Animales de Enfermedad , Etiquetado Corte-Fin in Situ , Masculino , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Proteínas de Neoplasias/biosíntesis , ARN Mensajero/biosíntesis , Ratas , Ratas Wistar , Regulación hacia ArribaRESUMEN
Five cases of primitive, small, round-cell tumor that are a type of hitherto unclassified neurogenic sarcoma are described. The tumors were located deep within the soft tissue of the trunks and limbs without association with major nerves. The histologic features consisted mainly of uniform, small, round, tumor cells with scanty cytoplasm. Foci of uniform, short, spindle-shaped tumor cells arranged in whorl-like patterns were observed in some areas. Although the immunoreactivity for the neural markers, Leu-7 and MIC-2, was not marked, cell processes and fragmentous basal laminae, which are ultrastructural neural features, were found in both spindle-shaped and round tumor cells. In four cases, EWS chimeric transcripts were analyzed by reverse-transcription polymerase chain reaction. EWS chimeric mRNA (EWS-FLI-1, EWS-ERG, EWS-E1AF, EWS-ETV1, EWS-FEV) was not detected in any cases. The tumors were not consistent with peripheral primitive neuroectodermal tumor. We propose them as a small round-cell type of MPNST that might differentiate toward the immature neural cells.
Asunto(s)
Neurofibrosarcoma/patología , Neoplasias del Sistema Nervioso Periférico/patología , Sarcoma de Células Pequeñas/patología , Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Masculino , Microscopía Electrónica , Neurofibrosarcoma/diagnóstico , Neurofibrosarcoma/genética , Neoplasias del Sistema Nervioso Periférico/diagnóstico , Neoplasias del Sistema Nervioso Periférico/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sarcoma de Células Pequeñas/diagnóstico , Sarcoma de Células Pequeñas/genéticaRESUMEN
We have cloned a murine homologue of the human Mcl1/EAT gene, a Bcl-2 related gene. Sequence analysis revealed that murine Mcl1/EAT (mMcl1/EAT) has three Bcl-2 homology domains, two PEST sequences, and immediate response boxes (IRB). The presence of IRB indicates that mMcl1/EAT is an immediate-early gene. mMcl1/EAT increases dramatically with exposure to retinoic acid in murine embryonal carcinoma cell lines (F9 and PCC3) as well as embryonic stem cells, both of which are models of early embryogenesis.
Asunto(s)
Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Regulación hacia Arriba , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Diferenciación Celular , Línea Celular , ADN Complementario , Humanos , Ratones , Datos de Secuencia Molecular , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Homología de Secuencia de Aminoácido , Células Madre , Células Tumorales CultivadasRESUMEN
We report a 54-year-old Japanese man who was diagnosed as progressive multifocal leukoencephalopathy (PML). He had been maintained on regular hemodialysis for 10 years. He was admitted to our hospital with chief complaints of visual disturbance and disorientation. On neurological examination, he was somnolent, and showed mild weakness in the right upper and lower limbs. Deep tendon reflexes were brisk on the right upper and bilateral lower limbs. Sensory examination revealed no abnormal findings. The cerebrospinal fluid (CSF) showed five mononuclear cells/mm3, protein 39 mg/dl and glucose 38 mg/dl. Brain MRI revealed multiple hyperintense lesions in T2-images, which were confined to the white matter of bilateral occipital and the left frontal lobes without an enhancement after gadolinium administration. Using polymerase chain reaction, we amplified the JCV regulatory region from the CSF of the patient. The amplified product contained a rearranged regulatory region that could have been generated from the archetype by deletion and amplification. PML was diagnosed on the basis of these findings. The patient died 7 months after onset of the symptoms. The diagnosis of PML was confirmed by the postmortem findings. The present case indicates that PCR of JCV from CSF is very useful for definitive diagnosis of PML.
Asunto(s)
ADN Viral/líquido cefalorraquídeo , Virus JC/genética , Leucoencefalopatía Multifocal Progresiva/diagnóstico , Encéfalo/patología , Humanos , Virus JC/aislamiento & purificación , Leucoencefalopatía Multifocal Progresiva/virología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Reacción en Cadena de la PolimerasaRESUMEN
The expression of p53 and PCNA on deparaffinized sections of tumor was assessed in relation to the International Index and response to chemotherapy. Thirty-five non-Hodgkin's lymphoma (NHL) patients were divided into three groups: aggressive NHL, mantle cell lymphoma (MCL), and low-grade NHL. None of the expressions correlated with the International Index or early response to chemotherapy in any group. In low-grade NHL, none of the patients expressed p53. Only one of three patients with overexpression of p53 showed conformational change and alteration of sequence in exon 7 by PCR-SSCP and DNA sequencing. The results showed that p53 and PCNA staining were not useful for predicting early response to chemotherapy, and that their expressions had no correlation with the International Index.
Asunto(s)
Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/metabolismo , Antígeno Nuclear de Célula en Proliferación/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunohistoquímica , Cooperación Internacional , Ganglios Linfáticos/patología , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Modelos Teóricos , Mutación/genética , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Pronóstico , Proteína p53 Supresora de Tumor/genéticaRESUMEN
We present a case of portal-systemic encephalopathy due to intrahepatic multiple portal-hepatic venous shunts. A 71-year-old woman was admitted to our hospital because of recurrent episodes of disturbed consciousness. She showed no clinical signs of portal hypertension. Liver function was normal, except for an indocyanine green retention rate of 34% at 15 min and blood ammonia level of 282 microg/dL. Portal venography revealed dilatation of the portal vein and multiple portal-hepatic venous shunts, and a liver biopsy specimen revealed almost normal liver. Further clinical examination revealed a huge pelvic tumour. At laparotomy, two dilated veins were seen to arise from the pelvic tumour with blood flow into the mesentery. The tumour was resected successfully and a histological diagnosis of leiomyoma was made. The blood ammonia concentration decreased to the normal range postoperatively. A follow-up portal venogram demonstrated decreased portal vein dilatation and minor portal-hepatic venous shunts, considered to be congenital in origin. It is concluded that hepatic encephalopathy was produced in this patient due to an excess portal blood flow from the huge pelvic leiomyoma via the mesentery, with portosystemic shunting through pre-existent (probably congenital) intrahepatic anastomoses.
Asunto(s)
Encefalopatía Hepática/etiología , Venas Hepáticas/anomalías , Leiomioma/complicaciones , Neoplasias Pélvicas/complicaciones , Vena Porta/anomalías , Anciano , Femenino , HumanosRESUMEN
EAT/mcl-1 showed increased expression during the differentiation of a multipotent human embryonic carcinoma cell line, NCR-G3, and of myeloblastic cells "ML-1," and has sequence similarity to Bcl-2. In this present study, we determined whether the apoptotic cell death induced by chemotherapeutic agents could be inhibited by EAT/mcl-1, as has been found with Bcl-2. Cells transfected with EAT/mcl-1 showed higher resistance to cis-diammine dichloroplatinum (II) (CDDP) and carboplatin compared with the parental line (10)1 and neomycin-resistance gene-transfected clone, (10)1/neo. There was, however, no difference in sensitivity to etoposide, N,N-bis-(2-chloroethyl)-N'-(3-hydroxypropyl) phosphordiamidic acid cyclic ester monohydrate, adriamycin or other chemotherapeutic agents tested. DNA fragmentation of the parental cells following treatment with CDDP and carboplatin was observed in a concentration-dependent manner. In contrast, cells transfected with EAT/mcl-1 did not show DNA fragmentation following treatment with the same concentration of these drugs. EAT/mcl-1 was capable of delaying the onset of p53-independent apoptosis, although it could not inhibit apoptosis completely. Since CDDP and carboplatin damage DNA and then activate c-abl and the JNK/SAPK pathway, EAT/mcl-1 may inhibit p53-independent apoptosis through a c-abl/JNK (SAPK)-dependent mechanism. EAT/mcl-1 has functional homology to Bcl-2 in that it can enhance cell viability under conditions which otherwise cause apoptosis and increase resistance to chemotherapeutic agents.
Asunto(s)
Apoptosis/efectos de los fármacos , Cisplatino/antagonistas & inhibidores , Genes bcl-2 , Familia de Multigenes , Proteínas de Neoplasias/fisiología , Proteínas Proto-Oncogénicas c-bcl-2 , Animales , Antineoplásicos/farmacología , Cisplatino/farmacología , Fragmentación del ADN , Fibroblastos/efectos de los fármacos , Ratones , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteínas Recombinantes de Fusión/fisiología , Transducción de Señal/efectos de los fármacos , Transfección , Proteína p53 Supresora de Tumor/fisiologíaRESUMEN
We report two leukemia patients with double minutes (DMs) chromosomes. Both patients were diagnosed as having acute myelocytic leukemia (AML) FAB M2. Cytogenetic analysis showed normal chromosome karyotype with 1-53 DMs chromosomes in the first patient, and complex chromosome aberrations including deletion of chromosome 8 at 8q24 region and 1-84 DMs chromosomes in the second patient who had a history of extensive radiotherapy for laryngeal cancer 8 years prior to the development of leukemia. Analysis of DNA from the two patients revealed that oncogene of c-myc was amplified about 5 to 10 folds in the leukemic cells. The other fourteen oncogene of c-myc was c-myb, c-abl and N-myc, showed no increases of gene content. Furthermore, a transforming gene, N-ras was detected in the first patient by in vivo selection assay method. This is the second report on AML patients with c-myc gene amplification and DMs chromosomes.