UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was undertaken to investigate cell death (particularly apoptosis) induced by etoposide, radiation, and both, and to examine p53 protein expression in relation to cell death. Nude mice transplanted with a human tumor (ependymoblastoma) were treated with etoposide (5-40 mg/kg) or 1-2 Gy X-ray irradiation or both. The tumor was excised at different points after treatment, and tumor tissue specimens were used to check for apoptosis and p53 protein expression by TUNEL, p53 protein staining, etc. Induction of p53-dependent apoptosis was observed in the etoposide treatment group, the X-ray irradiation group, and the combined (etoposide + X-ray irradiation) group. Etoposide 10 mg/kg was found to be approximately equivalent to 1 Gy X-ray irradiation in ability to induce apoptosis. When etoposide treatment was combined with X-ray irradiation at intervals of 3-6 hours, an approximately additive effect was observed.
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PMID:Experimental induction of apoptosis by a combination of etoposide and radiation treatment. 1076 50

Expression of Bcl-2 is important in determining cancer cell resistance to chemotherapy. However, it is not clear whether cell-cell interactions regulate Bcl-2 expression. Using rat breast carcinoma cells selected for loss of hormone responsiveness, we found that parental E-cadherin-expressing cells (E cells) were more sensitive to etoposide-induced apoptosis than hormone-non-responsive cells (F cells), which failed to express E-cadherin. Expression of beta-catenin and pp120 src substrate proteins, which associate with E-cadherin, was unaffected. To determine whether re-expression of E-cadherin in F cells would restore etoposide sensitivity, F cells were transfected with an expression vector coding for the mouse E-cadherin gene. Stable clonal isolates expressing E-cadherin (F. Cad) showed increased sensitivity to etoposide treatment compared with control clones (F.Neo). Expression of E-cadherin resulted in a redistribution of beta-catenin from the cytoskeletal/nuclear fraction to the cytoplasmic/membrane fraction of the cells. E-cadherin-expressing clones also showed reduced invasion through basement membrane. Etoposide-induced apoptosis was characterized by morphological changes (nuclear blebbing) and DNA fragmentation. Induction of CPP32-like caspase activity was also observed in F.Cad transfectants but not F.Neo cells. Unlike F cells, F.Cad transfectants were not able to express Bcl-2, but transient transfection of bcl-2 resulted in re-expression and resistance to etoposide treatment. Therefore, E-cadherin may negatively regulate Bcl-2 expression by altering the availability of nuclear beta-catenin. Loss of E-cadherin in invasive tumor cells may lead to increased Bcl-2 expression and resistance to chemotherapeutic drugs.
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PMID:Expression of E-cadherin reduces bcl-2 expression and increases sensitivity to etoposide-induced apoptosis. 1079 87

Topotecan (TPT) is a DNA-Topoisomerase I poison that exhibits antitumor activity. TPT, like other DNA-damaging agents, arrests or delays cell cycle progression during S- and G2-phase in a wide variety of tumor-derived cell lines. Particularly, the G2-arrest gives time for the cell to repair its DNA lesions prior to starting a new cell cycle. Based on these observations, we assessed the interaction between TPT and G2/M-active agents in p53-mutated cell lines of diverse origin in order to achieve cell toxicity. Two short-term sequential schedules were administered (TPT --> G2/M-active drug at the interval of greatest TPT-induced G2/M-phase cell arrest, and G2/M-active drug --> TPT), in three human tumor-derived cell lines with proven sensitivity to the following drugs: Bleomycin in HEp-2 (squamous larynx carcinoma); Docetaxel in SKBr-3 (breast adenocarcinoma); Etoposide in NCI-H23 (non-small-cell lung cancer). Our results show that: 1) Sequential TPT --> G2/M-active drugs are synergistic when administration overlapped the maximum percentage of TPT-induced G2/M-phase cell arrest interval in all three mutated p53 cell lines; 2) the reverse sequential schedule (G2/M-active drug --> TPT) was antagonistic, and being only additive for Etoposide --> TPT association. In conclusion, our findings further support the potential cytotoxic role of TPT in combination with other active drugs when the correct schedule of administration is applied. In addition, they provide a rationale for new applications in clinical trials using short-term sequential TPT --> G2/M-active drugs.
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PMID:Cytotoxic effects of topotecan combined with various active G2/M-phase anticancer drugs in human tumor-derived cell lines. 1085 93

The complex of neurological symptoms, which occur in the course of neoplasms of the internal organs and caused by the distant effect of the neoplasm on the nervous system, excluding other factors which could be responsible for changes in the nervous system, is called the paraneoplastic syndrome (PS). Pathogenesis of PS has not been clearly explained so far. Besides toxic, metabolic and infectious causes, the autoimmunologic one is taken into consideration. Paraneoplastic syndrome is mostly evoked by the oat cell carcinoma, subsequently by the breast, ovary and rarely by gastric carcinoma. The aim of the work was to determine: 1) the changes in the electroneurographic as well as visual and auditory evoked potentials examinations in the course of gastric carcinomas, 2) the influence of the treatment applied in gastric carcinomas on changes in visual and auditory evoked potentials and electroneurographic examinations. The examined group included 33 patients with diagnosed gastric carcinoma and having no clinical symptoms of lesion of the central and peripheral nervous systems. The results were compared to the control group, which consisted of healthy volunteers and patients after ventricular resection because of the chronic peptic ulcer disease. Clinical, neurographic as well as visual and auditory evoked potentials examinations were carried out three times. I.--just after the diagnosis of the neoplastic disease, II.--after end of treatment, III.--after 18 months (on average) since the end of the therapy. All patients had operative treatment. A part of them had supplementary chemotherapy--EEP cycle (Etoposide, Epirubicin, Cisplatin) or 5-fluorouracil. On the basis of the performed examinations of patients with gastric carcinoma, without clinical symptoms of lesions of the nervous system, primary axonal sensory-motoric neuropathic changes were observed in 36%. Changes in visual and auditory evoked potentials were found only in patients over 65 years old in over 50%. In patients after chemotherapy they were observed in visual and auditory evoked potentials and electroneurographic examinations, which could be caused by neurotoxic side-effect of the cytostatics applied.
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PMID:[Evaluation of nervous system disorders during the course of gastric carcinoma on the basis of clinical electrophysiologic analysis]. 1090 89

Etoposide (VP-16) a topoisomerase II inhibitor induces apoptosis of tumor cells. The present study was designed to elucidate the mechanisms of etoposide-induced apoptosis in C6 glioma cells. Etoposide induced increased formation of ceramide from sphingomyelin and release of mitochondrial cytochrome c followed by activation of caspase-9 and caspase-3, but not caspase-1. In addition, exposure of cells to etoposide resulted in decreased expression of Bcl-2 with reciprocal increase in Bax protein. z-VAD.FMK, a broad spectrum caspase inhibitor, failed to suppress the etoposide-induced ceramide formation and change of the Bax/Bcl-2 ratio, although it did inhibit etoposide-induced death of C6 cells. Reduced glutathione or N-acetylcysteine, which could reduce ceramide formation by inhibiting sphingomyelinase activity, prevented C6 cells from etoposide-induced apoptosis through blockage of caspase-3 activation and change of the Bax/Bcl-2 ratio. In contrast, the increase in ceramide level by an inhibitor of ceramide glucosyltransferase-1, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol caused elevation of the Bax/Bcl-2 ratio and potentiation of caspase-3 activation, thereby resulting in enhancement of etoposide-induced apoptosis. Furthermore, cell-permeable exogenous ceramides (C2- and C6-ceramide) induced downregulation of Bcl-2, leading to an increase in the Bax/Bcl-2 ratio and subsequent activation of caspases-9 and -3. Taken together, these results suggest that ceramide may function as a mediator of etoposide-induced apoptosis of C6 glioma cells, which induces increase in the Bax/Bcl-2 ratio followed by release of cytochrome c leading to caspases-9 and -3 activation.
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PMID:Ordering of ceramide formation, caspase activation, and Bax/Bcl-2 expression during etoposide-induced apoptosis in C6 glioma cells. 1104 71

Etoposide, a clinically useful anticancer drug, is a potent inhibitor of topoisomerase II. The DNA strand breaks caused by this epipodophyllotoxin lead to apoptotic death of tumor cells. Flow cytometry was used to investigate the relationship between the effects of the drug on the cell cycle of human leukemia HL-60 cells and the variations of the mitochondrial transmembrane potential (DeltaPsi(mt)). Three cationic fluorescent probes, DiOC(6), JC-1, and TMRM, were used to measure drug-induced changes of DeltaPsi(mt). In all three cases, we found that the arrest in the G2/M phase of the cells treated with 0.5 microM etoposide is associated with an increase in the potential of mitochondrial membranes whereas treatment with a tenfold higher drug concentration trigger massive apoptosis and a collapse of DeltaPsi(mt). DNA fragmentation (TUNEL assay) and externalization of phosphatidylserine residues in the outer leaflet of the plasma membrane (annexin V binding) were measured to characterize the apoptotic cell population.
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PMID:Relationship between cell cycle changes and variations of the mitochondrial membrane potential induced by etoposide. 1115 26

A primary goal of the histopathologic evaluation of the gastric resection specimen is the determination of prognostically relevant factors, but it is not known whether, following neoadjuvant therapy, these factors have the same influence on prognosis. The goal of this study was to investigate prognostically relevant macroscopic and microscopic findings after neoadjuvant chemotherapy. The resection specimens of 36 patients with locally advanced gastric carcinoma who had been treated with Etoposide, Adriamycin and Cisplatin were investigated with respect to tumor size, Lauren type, ypTNM, UICC R-status, lymphangiosis, and degree of regression. On the basis of these factors, a prognosis score was developed that included both the degree of regression (grade 1-3), staging parameters (UICC T-category, R-status), tumor size and lymphatic vessel invasion. All of the parameters were weighted according to a score (1 point--best, 3 points--worst). The points were added for each individual case and the cases were divided into three prognosis groups, Group A: 5-7 points (n = 5), Group B: 8-10 points (n = 15), and Group C: > or = 11 points (n = 16). When compared with survival by the Kaplan-Meier method, these three prognosis groups showed highly significant differences (p < 0.0001). These results demonstrate that it is possible to accurately predict survival using resection specimens following neoadjuvant chemotherapy, which could lead to the identification of subgroups for which additional, further adjuvant therapy might be useful.
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PMID:[Morphologic response evaluation of neoadjuvant chemotherapy of gastric carcinoma]. 1121 37

The purpose of this study was to examine the antitumor activity, toxic effects, and plasma pharmacokinetics of fractionated doses of oral etoposide aiming at the achievement of prolonged safe and active plasma drug levels in patients with AIDS-related Kaposi sarcoma (KS). This was designed as a phase II trial in which consecutive patients with progressing AIDS-KS after at least 3 months of active antiretroviral therapy received oral etoposide at the dose of 20 mg/m2 every 8 hours daily for 7 days every 21 days, with the study of its plasma pharmacokinetics. Eligible patients were 18 to 60 years old, with a histopathologically confirmed diagnosis of AIDS-related KS, human immunodeficiency virus-positive test, progressing after at least 3 months of active antiretroviral therapy, World Health Organization (WHO) performance status 0 to 3, New York University staging IIA or greater, no active infection except oral candidiasis, normal bone marrow, liver, and renal function, and who signed an informed consent. Objective tumor responses were evaluated after at least one full treatment course according to a modified WHO criteria, and toxicity was evaluated weekly and graded using the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) criteria. For the pharmacokinetic study, plasma was obtained from patients during the first drug administration immediately before and at various time points thereafter. Etoposide was measured after extraction from plasma by a standard high-performance liquid chromatography. Twenty-one patients were accrued for the study, and 18 of them met the eligibility criteria. They were all men, with median age of 36 years old (range: 25-50 years), median WHO performance status 0 (range: 0-3) median CD4+ count (cells/mm3) 67 (range: 8-443), prior AIDS diagnosis in 10 of 18 cases, NYU staging IIA (1 patient), IIB (1), IIIA (7), IIIB (1), IVA (4), and IVB (4) sites of disease: mucocutaneous only (5), mucocutaneous/lymph nodes (5), mucocutaneous/lung (5) and mucocutaneous/lymph nodes/lung (2); and prior cytotoxic treatment in two patients. Seventy-two percent of cases presented some form of toxic effect (NCI-CTC). Leukopenia was documented in 50% of cases, anemia occurred in 61%, whereas thrombocytopenia was documented in 17% of the patients. The main nonhematologic toxicities were nausea and vomiting in 17% of cases and alopecia in 44%. The overall objective response rate was 83%, with 2 complete remissions documented (11%). The median duration of responses was 12 weeks (range: 3-45 weeks). The median t1/2 of etoposide in plasma was 4.11 hours (range: 1.95-9.64), area under the curve was 13.51 microg/h/ml (range: 7.12-24.42), Cmax was 2.17 microg/ml (1.40-4.41), tmax (1.00-2.00), mean residence time 4.62 hours (range: 3.75-5.20 hours), CIt (total clearance) 3.13 l/m2/h (range: 1.49-5.20 l/m2/h), Vd 13.08 l/m2 (range: 6.23-19.65 l/m2), and the median etoposide plasma concentration time greater than 1 microg/ml was 3.69 hours (range: 1.00-6.80 hours). The use of fractionated oral daily doses of etoposide produced significant antitumor activity with manageable clinical toxicity in the individuals with AIDS-KS included in this trial. This more favorable therapeutic index of etoposide could be due to the achievement of more sustained plasma levels of the drug within safe but active concentrations.
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PMID:Fractionated doses of oral etoposide in the treatment of patients with aids-related kaposi sarcoma: a clinical and pharmacologic study to improve therapeutic index. 1131 95

Gastric cancer usually shows poor sensitivity to chemotherapy, and the presence of lymph node metastases is associated with extremely poor prognosis, especially when the number of such nodes is more than 10. We report here a case of advanced gastric cancer with histopathologically confirmed metastases in 15 regional lymph nodes, in which the recurrent tumor was sensitive to combination chemotherapy. Distal gastrectomy with lymphadenectomy was performed for the primary tumor. A hard (recurrent) tumor was detected in the upper abdomen 5 months postoperatively. Abdominal CT revealed two tumors measuring 3.5 x 1.8 and 3.3 x 2 cm in diameter at the front of the pancreatic head, which suggested recurrence. Etoposide, adriamycin and cisplatin (EAP) chemotherapy (20 mg/kg adriamycin, 100 mg/kg etoposide and 50 mg/kg cisplatin (CDDP)) was administered every 6 weeks. The tumors regressed and became undetectable on CT after four cycles. At that stage, CDDP was replaced with 400 mg/kg carboplatin, which was administered every 1 or 2 months. The patient had no recurrence 8 years after surgery. For treatment of advanced gastric cancer with multiple lymph node metastases, a wide resection of the tumor should be performed followed by treatment of the residual tumor cells with a suitable combination chemotherapy taking into consideration the characteristics of the tumor and the condition of the host. We present a patient with gastric cancer and histopathologically confirmed metastases in 15 regional lymph nodes, who was successfully treated by surgery followed by EAP adjuvant chemotherapy. The patient remains alive and well at 8 years after surgery.
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PMID:Advanced gastric cancer with multiple lymph node metastasis successfully treated with etoposide, adriamycin and cisplatin. 1135 May 60

Recently, it has been demonstrated that Etoposide, a topoisomerase II inhibitor, can induce apoptosis in MDM2-overexpressing tumor cells by inhibition of MDM2 synthesis. We have previously shown that E2F-1 overexpression induces apoptosis of MDM2-overexpressing sarcoma cells, which is related to the inhibition of MDM2 expression. Therefore, the present study was designed to investigate the in vitro and in vivo effect of combined treatment of adenovirus-mediated E2F-1 and topoisomerase II inhibitors on the growth inhibition and apoptosis in human sarcoma cells. Two human sarcoma cell lines, OsACL and U2OS, were treated with topoisomerase II inhibitors (Etoposide and Adriamycin), alone or in combination with adenoviral vectors expressing beta-galactosidase (Ad-LacZ) or E2F-1 (Ad-E2F-1). E2F-1 expression was confirmed by Western blot analysis. Ad-E2F-1 gene transfer at a low dose (multiplicity of infection, 2) markedly increased the sensitivity of human sarcoma cells to topoisomerase II inhibitor treatment. This cooperative effect of E2F-1 and topoisomerase II inhibitors was less marked in SAOS-2 cells (p53 and pRb null). Topoisomerase II inhibitors also cooperated with E2F-1 overexpression to enhance tumor cell killing in an in vivo model using xenografts in nude mice. When combined with Adriamycin or Etoposide, E2F-1 adenovirus therapy resulted in approximately 95% and 85% decrease in tumor size, respectively, compared to controls (P<.05). These results suggest a new chemosensitization strategy that is effective in MDM2-overexpressing tumors and may have clinical utility.
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PMID:Additive effect of adenovirus-mediated E2F-1 gene transfer and topoisomerase II inhibitors on apoptosis in human osteosarcoma cells. 1139 76

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