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51.
Apoptosis is the major form of cell death associated with the action of chemotherapeutic agents on tumor cells, and therefore the expression of genes that interfere with apoptosis can have important consequences for the efficacy of therapeutic approaches. Here we show that K562, a chronic myelogenous leukemia (CML) cell line expressing the BCR-ABL fusion protein, are resistant to the induction of apoptosis by a number of agents and conditions. Antisense oligodeoxynucleotides corresponding to the translation start of bcr downregulate bcr-abl protein in these cells and render them susceptible to induction of apoptosis by chemotherapeutic agents or serum deprivation. Expression of a temperature sensitive v-Abl protein reverses the effects of the antisense oligonucleotides, such that the cells remain resistant to apoptosis at the permissive temperature. These data indicate that bcr- abl acts as an anti-apoptosis gene in CML cells and suggests that the effect is dependent on the abl kinase activity in this chimeric protein. Inhibition of bcr-abl to render CML cells susceptible to apoptosis can be combined with therapeutic drugs and/or treatment capable of inducing apoptosis to provide an effective strategy for elimination of these cells. 相似文献
52.
Kathrine R?e Lars TG Mikalsen Albert J van der Kogel Johan Bussink Heidi Lyng Anne H Ree Laure Marignol Dag R Olsen 《Radiation oncology (London, England)》2012,7(1):1-13
Background
The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is activated in tumor cells and promotes tumor cell survival after radiation-induced DNA damage. Because the pathway may not be completely inhibited after blockade of PI3K itself, due to feedback through mammalian target of rapamycin (mTOR), more effective inhibition might be expected by targeting both PI3K and mTOR inhibition.Materials and methods
We investigated the effect of two dual PI3K/mTOR (both mTORC1 and mTORC2) inhibitors, NVP-BEZ235 and NVP-BGT226, on SQ20B laryngeal and FaDu hypopharyngeal cancer cells characterised by EGFR overexpression, on T24 bladder tumor cell lines with H-Ras mutation and on endothelial cells. Analysis of target protein phosphorylation, clonogenic survival, number of residual ??H2AX foci, cell cycle and apoptosis after radiation was performed in both tumor and endothelial cells. In vitro angiogenesis assays were conducted as well.Results
Both compounds effectively inhibited phosphorylation of Akt, mTOR and S6 target proteins and reduced clonogenic survival in irradiated tumor cells. Persistence of DNA damage, as evidenced by increased number of ??H2AX foci, was detected after irradiation in the presence of PI3K/mTOR inhibition, together with enhanced G2 cell cycle delay. Treatment with one of the inhibitors, NVP-BEZ235, also resulted in decreased clonogenicity after irradiation of tumor cells under hypoxic conditions. In addition, NVP-BEZ235 blocked VEGF- and IR-induced Akt phosphorylation and increased radiation killing in human umbilical venous endothelial cells (HUVEC) and human dermal microvascular dermal cells (HDMVC). NVP-BEZ235 inhibited VEGF-induced cell migration and capillary tube formation in vitro and enhanced the antivascular effect of irradiation. Treatment with NVP-BEZ235 moderately increased apoptosis in SQ20B and HUVEC cells but not in FaDu cells, and increased necrosis in both tumor and endothelial all cells tumor.Conclusions
The results of this study demonstrate that PI3K/mTOR inhibitors can enhance radiation-induced killing in tumor and endothelial cells and may be of benefit when combined with radiotherapy. 相似文献53.
Argyriou AA Antonacopoulou A Iconomou G Kalofonos HP 《Critical reviews in oncology/hematology》2009,69(3):199-210
Malignant gliomas (MGs), including glioblastomas and anaplastic astrocytomas are the most common primary brain tumors. Despite treatment advances, the outcome of patients diagnosed with MGs is poor. The current standard treatment protocols for managing these tumors include maximally safe surgical resection, followed by fractioned radiation therapy of the tumor and surrounding brain parenchyma. Until recently, the use of systemic chemotherapy was restricted and ineffective, due to the fact that the blood brain barrier inhibits the adequate therapeutic concentrations of most chemotherapeutic agents into the tumor and peritumoral area. Genetic transformation, like the expression of the DNA repair enzyme methylguanine methyltransferase (MGMT) and specific characteristics of these neoplasms are also causal factors, accounting for the development of treatment resistance to standard chemotherapy options with alkylating compounds. Recent advances, mostly, in thorough understanding of the complex molecular pathogenesis of MGs have led to arousal of rational development of new molecularly targeted treatment options that simultaneously affect multiple signalling pathways. Currently, several molecularly targeted agents, like tyrosine kinase and growth factor inhibitors have been tested in clinical trials to establish future directions in the therapy of MGs. A number of novel targeted strategies, including among others radio-immuno and ligand-toxin conjugates and RNA-based therapies, are also under investigation. We herein review and discuss the standard treatment options and recent advances in the therapy of MGs, with emphasis on the current knowledge towards the molecular pathogenesis of MGs as well as molecularly targeted therapies. We also highlight areas of future research. 相似文献
54.
Gregoris Iconomou Apostolos G. Vagenakis Haralabos P. Kalofonos 《Supportive care in cancer》2001,9(8):591-596
The first objective of the study was to identify the specific informational needs of primary caregivers of cancer patients receiving chemotherapy in a Greek outpatient setting and to assess their preference for cancer-specific booklets, their levels of satisfaction with communication and their psychological status. The second objective was to examine whether their need for information was associated with their preference for written information, level of satisfaction, and levels of psychological distress. The final objective was to search for possible associations between satisfaction and psychological distress. Seventy-eight caregivers participated in the study and data were collected by structured individual interviews. The main findings to emerge were that a significant proportion of the caregivers had elevated needs for information, which were positively associated with a preference for cancer-specific printed material and negatively associated with satisfaction with the doctor's communication of information and affective behavior. Participants experienced heightened levels of anxiety and depression, which were independent of the need for information, preference for printed material or satisfaction with communication. The results suggest that the Greek cancer caregiver needs more factual information relevant to the patient's condition and that communication of information is critical if he or she is to be satisfied. The Greek oncologist should therefore not only try to detect the informational needs, but should also be qualified to meet them in the best possible way. In addition, the rates of anxiety and depression observed highlight the need for a more thorough evaluation and management of caregivers' psychological morbidity in the Greek oncology setting. 相似文献
55.
Kalofonos HP Kourousis C Karamouzis MV Iconomou G Tsiata E Tzorzidis F Megas P Lambiris E Georgoulias V 《Sarcoma》2004,8(4):129-133
Purpose: The aim of this study was to determine the efficacy and safety of docetaxel plus epirubicin combination as first-line chemotherapy in patients with locally advanced and/or metastatic adult STS.Patients and Methods: Eighteen patients were treated with epirubicin 30 mg/m(2) on days 1 to 3 and docetaxel 100 mg/m(2) on day 1 every 3 weeks.Results: Fifteen out of 18 patients (83.4%) were assessable for response. No complete response was recorded. Three (20%) patients achieved PR, 3 had SD and 9 PD. The overall median survival was 14 months (range, 3-48 months) and the median time to disease progression was 4 months (range, 2-45 months). Grade >/= 3 neutropenia occurred in 88% and neutropenic fever in 27.8% of patients. Other toxicities were mild. No treatment related deaths occurred.Discussion: Docetaxel plus epirubicin combination achieved low response rate with severe myelotoxicity in patients with advanced STS. 相似文献
56.
Argyriou AA Polychronopoulos P Iconomou G Koutras A Kalofonos HP Chroni E 《Journal of neurology》2005,252(12):1459-1464
Objective The current study intended to determine the incidence, severity and reversibility of paclitaxel plus carboplatin (CP)–induced
peripheral neuropathy (CPPN) and to describe its clinical and electrophysiological features.
Patients and methods We prospectively studied 21 adult patients scheduled to be treated with 6 courses of cumulative carboplatin plus paclitaxel
(CP) regimens for a non–myeloid malignancy. They were followed–up by neurological examination and electrophysiological study
during chemotherapy and 3 months after its discontinuation. The severity of neurotoxicity was assessed by means of a modified
peripheral neuropathy (PNP) score.
Results Evidence of CPPN was recorded in 14 of the 21 patients (66.6 %). The sensory symptoms were present in the lower limbs first
and then involved the upper limbs. No statistical significance, concerning the changes from baseline to subsequent mean scores
in all motor conduction parameters examined,was revealed. By contrast, comparisons of the mean changes at baseline and each
of the follow–up studies showed significant decrease in all sensory action potentials examined. The mean PNP scores for patients
that manifested some grade of neurotoxicity were 17.9 ± 9.8. The followup data 3 months after the discontinuation of chemotherapy
showed that the CP–induced neuropathy was at least partially reversed.
Conclusions CP–induced neuropathy was symmetrical, distal and predominately sensory in character, though minor to moderate motor signs
were only evident in severely affected patients. Reversibility of CPinduced neuropathy was partially observed after the suspension
of chemotherapy. 相似文献
57.
58.
Beneficial effect of nerve growth factor-7S on peripheral nerve regeneration through inside-out vein grafts: an experimental study 总被引:15,自引:0,他引:15
Gravvanis AI Tsoutsos DA Tagaris GA Papalois AE Patralexis CG Iconomou TG Panayotou PN Ioannovich JD 《Microsurgery》2004,24(5):408-415
This study investigated the effect of local administration of nerve growth factor-7S (NGF-7S) on the axonal regrowth of mixed peripheral nerves through inside-out vein grafts. Sixty male Wistar rats were randomized into two groups (n = 30). A defect 12 mm long in the right sciatic nerve was created and repaired with an inside-out vein graft from the right jugular vein. NGF-7S (group A) or phosphate-buffered saline (group B; control) was locally administered daily during the first 3 weeks. Walking-track analysis and electrophysiological and histological-morphometric studies were carried out 4, 6, 8, 10, and 12 weeks postoperatively (subgroups a, b, c, d, and e, respectively, n = 6 each). Data analysis showed that 1) the recovery of motor function, as measured by walk pattern analysis and evoked muscle action potential, and 2) the orientation, number, myelin thickness, and diameter of myelinated fibers were better in the NGF-7S than in the control group. These findings present strong evidence of the beneficial effect of NGF-7S on peripheral nerve regeneration through inside-out vein grafts. 相似文献
59.
This study assessed the information needs of Greek cancer patients and examined whether awareness of diagnosis had any impact on patients. One hundred patients were interviewed about overall and specific information needs, satisfaction, emotional distress, and quality of life. Patients exhibited a great desire for information overall. The need to have more information was high especially regarding the aftermath of chemotherapy, prognosis, how chemotherapy worked, and diagnosis. Patients were more satisfied with care but less satisfied with the information received. Only 37% knew they had cancer, especially the younger, the better educated, and those with breast cancer. Awareness was not related to satisfaction, emotional distress, or quality of life. Our findings suggest that Greek cancer patients need more factual information about their condition and management. Greek oncologists may feel freer to inform their patients about the diagnosis and other issues following their judgement, rather than employing the policy of concealing the truth. 相似文献
60.
Evaluation of the chronic toxicity and oncogenicity of N,N-diethyl-m- toluamide (DEET) 总被引:1,自引:0,他引:1
Schoenig GP; Osimitz TG; Gabriel KL; Hartnagel R; Gill MW; Goldenthal EI 《Toxicological sciences》1999,47(1):99-109
Chronic toxicity and/or oncogenicity studies were conducted in rats, mice,
and dogs with the insect repellent DEET. DEET was mixed in the diet and
administered to CD rats for two years at concentrations that corresponded
to dosage levels of 10, 30 or 100 mg/kg/day for males and 30, 100, or 400
mg/kg/day for females; to CD-1 mice for 18 months at dosage levels of 250,
500, or 1000 mg/kg/day; and to dogs for one year, via gelatin capsules, at
dosage levels of 30, 100, or 400 mg/kg/day. In the rodent studies, each
group consisted of 60 animals of each sex, and two concurrent independent
control groups, each containing 60 animals/sex were included in each study.
Each group in the dog study consisted of four male and four female dogs and
one control group was included in the study. Treatment-related effects were
observed at the highest dose level in all three studies. For rats, the
effects included decreases in body weight and food consumption and an
increase in serum cholesterol in females only. In mice, the effects
observed were decreases in body weight and food consumption in both sexes.
The effects observed in dogs included increased incidences of emesis and
ptyalism, and levels of transient reduction in hemoglobin and hematocrit,
increased alkaline phosphatase (males only), decreased cholesterol, and
increased potassium. One male dog in the high-dose group also exhibited
ataxia, tremors, abnormal head movements, and/or convulsions on several
occasions during the study. The highest no- observed-effect levels (NO-ELs)
for rats, mice and dogs were determined to be 100, 500, and 100 mg/kg/day,
respectively. No specific target organ toxicity or oncogenicity was
observed in any of the studies.
相似文献