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91.
Erdlenbruch B Jendrossek V Kugler W Eibl H Lakomek M 《Cancer chemotherapy and pharmacology》2002,50(4):299-304
BACKGROUND: Erucylphosphocholine (ErPC) has been shown to exert strong antineoplastic effects against various brain tumor cell lines in vitro. Since ErPC only enters the brain after long-term treatment, ineffective drug delivery to the tumor is considered to be the reason for the moderate responses to chemotherapy with ErPC observed in animal brain tumor models. We investigated a recently described method for chemically opening the blood-brain barrier (BBB) using intraarterial administration of alkylglycerols to increase the transfer of ErPC into the brain. METHODS: ErPC (40 mg/kg) was given to C6 glioma-bearing rats either as a single intracarotid bolus injection in the presence or absence of 1- O-pentylglycerol (300 m M) or as an intracarotid infusion in conjunction with bradykinin. Brain tissue concentrations were analyzed and compared to values obtained after intravenous ErPC treatment over 14 and 30 days (cumulative ErPC doses of 210 and 350 mg/kg, respectively). RESULTS: Pentylglycerol-induced BBB opening resulted in a significant increase in ErPC delivery to the tumor (17-fold) and, to a lesser extent, to the surrounding ipsilateral brain (7-fold) compared to intraarterial ErPC administration without alkylglycerol ( P<0.05). Furthermore, the resulting ErPC concentrations in the brain tumor exceeded those obtained in tumor and tumor-free brain after long-term intravenous ErPC administration. In contrast to this, intracarotid bradykinin did not increase the transfer of ErPC to the tumor or tumor-free brain. CONCLUSIONS: The intracarotid administration of pentylglycerol represents a novel and nontoxic method of overcoming the limited access of ErPC to both brain tumors and brain tissue adjacent to tumors. The present results provide further evidence that chemical opening of the BBB by intraarterial alkylglycerols is a promising new concept for improving delivery of chemotherapeutic agents to brain tumors. 相似文献
92.
Effect of gemcitabine on acute and late radiation toxicity of skin and underlying soft tissues to single-dose irradiation in a nude mice model 总被引:1,自引:0,他引:1
Classen J Paulsen F Hehr T Bamberg M Budach W 《International journal of radiation oncology, biology, physics》2002,53(1):197-205
PURPOSE: To investigate the influence of gemcitabine (GEM) on acute and late toxicity of radiotherapy (XRT) in an in vivo model of acute skin reactions and late fibrotic sequelae of skin and underlying soft tissues. METHODS AND MATERIALS: Single-fraction XRT was applied to the right hind leg of nude mice under ambient conditions. Single-dose GEM was applied i.p. (550 mg/kg body weight). In a first set of experiments, the influence of timing of chemotherapy relative to the onset of irradiation was investigated with GEM application 36, 24, and 2 h before and 24 h subsequent to 40 Gy XRT. With a fixed interval between chemotherapy and XRT taken from these studies, the dose-response relationship was examined for XRT in the range of 20-65 Gy. Control mice were irradiated without GEM treatment. Using a scoring system, onset, duration, and extent of acute skin reactions were analyzed. Skin fibrosis was measured by intracutaneous ink-mark separation. Soft tissue fibrosis was assessed using the leg contracture assay. ED50 calculations were performed for extent of acute and late reactions. RESULTS: Timing of GEM application relative to XRT had no significant influence on acute skin reactions or on fibrotic changes. Onset, duration, and extent of acute skin toxicity, as well as skin and leg contracture, were not significantly modulated by GEM in the dose-response experiments with GEM applied 2 h before XRT. CONCLUSIONS: Acute and late toxicity of skin and underlying soft tissues is not significantly increased after single-fraction radiotherapy in combination with GEM in the nude mice model. 相似文献
93.
Harris IR Siefken W Beck-Oldach K Brandt M Wittern KP Pollet D 《Skin pharmacology and applied skin physiology》2002,15(Z1):59-67
There is an increasing need for in vitro testing of compounds for topical application. Reconstructed epidermal models may provide a suitable and relevant model for screening compounds that may affect the activities of phase I and II enzymes involved in epidermal detoxification. In this study, we measured the activity of a phase I enzyme, cytochrome P450 IA1, i.e. 7-ethoxyresorufin-O-deethylase (EROD) and 7-ethoxycoumarin-O-deethylase (ECOD) activities, and that of a phase II enzyme, glutathione S-transferase (GST). The enzyme activities were determined in cultured keratinocytes, reconstructed epidermal models and samples of human epidermis or hair follicle. EROD activity was detected in cultured keratinocytes and was induced by 3-methylcholanthrene (3-MC) and beta-naphthoflavone. The level of induction increased with increasing confluence. Induced EROD activity could be inhibited by clotrimazole in a dose-dependent manner. However, EROD activity was not detected in either hair follicles or untreated epidermal models but could be induced by 3-MC. The ability to induce EROD activity in epidermal models was batch dependent, and clotrimazole was able to inhibit the induced EROD activity. ECOD activity was detected in untreated models and paralleled EROD activity. GST activity was detected in cultured keratinocytes and all epidermal models. GST activity in models was equal or higher than the activity in epidermal samples. Reconstructed skin models may be useful to study the effects of non-water-soluble topical formulations on xenobiotic metabolism. 相似文献
94.
Harris IR Siefken W Beck-Oldach K Wittern KP Pollet D 《Skin pharmacology and applied skin physiology》2002,15(Z1):68-73
Reconstructed epidermal models may provide a suitable and relevant model for screening compounds such as quinones, which affect the activities of phase I and II enzymes involved in epidermal detoxification. Reconstructed epidermis may also allow the study of the metabolism of topically applied compounds by the phase I and II enzymes. We demonstrate that NAD(P)H:quinone reductase (NQR) activity is present in three different types of reconstructed epidermal models and that levels vary depending on the type of model. We also determined the inter- and intrabatch variability and demonstrate that NQR activity can be significantly inhibited by dicumarol treatment. The NQR activity in reconstructed epidermis is similar to that in human epidermis and lower than in cultured keratinocytes. Therefore reconstructed epidermis is a more suitable model for testing the effects of topically applied compounds on NQR activity or the metabolism of the compound by NQR. 相似文献
95.
Multidisciplinary treatment focusing on impairments, activities and participation are an important component within the therapeutic regimen in musculoskeletal conditions. In Germany, for more than 95% of the patients multidisciplinary treatment is provided as inpatient rehabilitation. According to the results of a study from the Netherlands, inpatient rehabilitation is superior to usual care in terms of decreasing disease activity and improving emotional well-being in rheumatoid arthritis. Another randomized, controlled study gives evidence that rehabilitation is more effective as compared to usual care in ankylosing spondylitis. In patients suffering from fibromyalgia, after inpatient rehabilitation, symptoms improve significantly and this is true even one year after discharge. The results of a quality management project financed by the German health insurance and including several thousand patients with musculoskeletal diseases show an improvement in physical and emotional dimensions of health status at discharge and after a six month follow-up. Recent studies comparing inpatient with outpatient rehabilitation in patients with musculoskeletal diseases provide information that both forms are equally effective. Taking into account the high number of inpatient rehabilitation procedures in Germany, more outcomes research is required urgently. 相似文献
96.
Thomas Hehr Wilfried Budach Ilona Durst Stefan Glocker Johannes Classen Martin Weinmann Gunter Christ Michael Bamberg 《Strahlentherapie und Onkologie》2002,178(11):624-632
BACKGROUND: Different radiotherapy techniques are used for postmastectomy irradiation. We review the results with the electron-beam-rotation technique in advanced breast cancer patients. Main endpoint was local tumor control. PATIENTS AND METHODS: From 1990 to 1998 119 patients with adverse pathology features (pT3 17% of patients, pT4 42%, multicentricity 36%, pN >/= 3 positive nodes and/or pN1biii 81%, close margins 30%) underwent electron-beam-rotation irradiation of the chest wall with daily fractions of 2.0-2.5 Gy per day to 50 Gy total dose after modified radical mastectomy and axillary lymph node dissection. A local boost of 10 Gy and/or irradiation of locoregional lymph nodes were applied depending on the completeness of resection and lymph node involvement. RESULTS: After a median follow-up of 73 months for patients at risk the 5-year local tumor control, local tumor control first event, disease-free, and overall survival were 82%, 92%, 57%, and 63% (Kaplen Meier analysis), respectively. Significant predictors of poor local tumor control were maximal tumor diameter >/= 5 cm (p = 0.01), "close margins" or residual tumor (p < 0.01), four or more involved axillary lymph nodes (p = 0.02), two or more involved lymph node levels (p = 0.04), negative estrogen receptor status (p = 0.03), and high-grade histopathology (GIIb-III, p < 0.01). The subgroup analysis showed a high local failure rate of 37% for high-grade (GIIb-III) and estrogen receptor negative tumors, whereas no local recurrence was found in low-grade (GI-Iia) and receptor positive tumors (p = 0.01). The multivariate analysis revealed maximal tumor diameter >/= 5 cm, four or more involved axillary lymph nodes and high-grade histopathology (GIIb-III) as independent predictors of poor local tumor control. CONCLUSION: In high-risk breast cancer patients postmastectomy irradiation with the electron-beam-rotation technique is an effective therapy, resulting in a 5-year local failure rate of 8%. Intensified local therapy needs further investigation in subgroups of patients with additional risk factors. 相似文献
97.
Amelie Rübel René Handrick Lars H Lindner Matthias Steiger Hansjörg Eibl Wilfried Budach Claus Belka Verena Jendrossek 《Radiation oncology (London, England)》2006,1(1):1-17
Cervical cancer continues to be a significant health burden worldwide. Globally, the majority of cancers are locally advanced at diagnosis; hence, radiation remains the most frequently used therapeutical modality. Currently, the value of adding cisplatin or cisplatin-based chemotherapy to radiation for treatment of locally advanced cervical cancer is strongly supported by randomized studies and meta-analyses. Nevertheless, despite these significant achievements, therapeutic results are far from optimal; thus, novel therapies need to be assayed. A strategy currently being investigated is the use of newer radiosensitizers alone or in combination with platinum compounds. In the present work, we present preclinical information on known and newer cytotoxic agents as radiosensitizers on cervical cancer models, as well as the clinical information emanating from early phase trials that incorporate them to the cervical cancer management. In addition, we present the perspectives on the combined approach of radiation therapy and molecular target-based drugs with proven radiosensitizing capacity. 相似文献
98.
Immunomagnetic enrichment and detection of micrometastases in colorectal cancer: correlation with established clinical parameters. 总被引:6,自引:0,他引:6
Martin R Weihrauch Edmund Skibowski Thomas C Koslowsky Wilfried Voiss Daniel Re Ferdinand Kuhn-Regnier Carolin Bannwarth Michel Siedek Volker Diehl Heribert Bohlen 《Journal of clinical oncology》2002,20(21):4338-4343
PURPOSE: Micrometastatic disease in bone marrow is of prognostic significance in colorectal cancer patients. However, detection rates of standard immunocytology are relatively low. We used magnetic activated cell sorting (MACS), a highly sensitive method, to increase detection rates and correlated the presence of cytokeratin (CK)-expressing cells with clinical parameters. PATIENTS AND METHODS: Bone marrow was obtained from 51 consecutive patients with newly diagnosed colorectal adenocarcinoma who underwent primary surgery and 18 control subjects. International Union Against Cancer (UICC) stage I disease was diagnosed in 11 patients, stage II disease was diagnosed in 14 patients, stage III disease was diagnosed in 12 patients, and stage IV disease was diagnosed in 14 patients. CK-positive cells were enriched and stained with magnetically labeled CAM 5.2 antibodies directed to CK 7 and 8. RESULTS: CK-positive cells were found in 33 (65%) patients and were absent in 18 (35%). Four of 11 (36%) patients with UICC stage I disease, nine of 14 (64%) with stage II diease, eight of 12 (67%) with stage III disease, and 12 of 14 (86%) with stage IV disease were CK-positive. Epithelial cells were more frequently found in pT3/4 (72%) than in pT1/2 (36%) tumors (P =.026), but there was no difference for lymph node status. CK-positive patients had a higher chance for elevated carcinoembryonic antigen (85% v 15%, P = NS) and CA 19-9 levels (92% v 8%, P =.019). There were no significant differences in CA 72-4, sex, age, tumor grading, or tumor localization regarding the presence of CK-positive cells. All control subjects were CK-negative. CONCLUSION: In searching for micrometastases in colorectal cancer patients, we have achieved high detection rates by using MACS. The presence of these cells correlated significantly with tumor stage, tumor extension, and the tumor marker CA 19-9. 相似文献
99.
Gruber EM Tschernko EM Kritzinger M Deviatko E Wisser W Zurakowski D Haider W 《Anesthesia and analgesia》2001,92(4):1015-1019
Optimal analgesia is important after thoracotomy in pulmonary-limited patients to avoid pain-related pulmonary complications. Thoracic epidural anesthesia (TEA) can provide excellent pain relief. However, potential paralysis of respiratory muscles and changes in bronchial tone might be unfavorable in patients with end-stage chronic obstructive pulmonary disease (COPD). Therefore, we evaluated the effect of TEA on maximal inspiratory pressure, pattern of breathing, ventilatory mechanics, and gas exchange in 12 end-stage COPD patients. Pulmonary resistance, work of breathing, dynamic intrinsic positive end-expiratory pressure, and peak inspiratory and expiratory flow rates were evaluated by assessing esophageal pressure and airflow. An increase in minute ventilation (7.50 +/- 2.60 vs 8.70 +/- 2.10 L/min; P = 0.04) by means of increased tidal volume (0.46 +/- 0.16 vs 0.53 +/- 0.14 L/breath; P = 0.003) was detected after TEA. These changes were accompanied by an increase in peak inspiratory flow rate (0.48 +/- 0.17 vs 0.55 +/- 0.14 L/s; P = 0.02) and a decrease in pulmonary resistance (20.7 +/- 9.9 vs 16.6 +/- 8.1 cm H(2)O. L(-1). s(-1); P = 0.02). Peak expiratory flow rate, dynamic intrinsic positive end-expiratory pressure, work of breathing, PaO(2), and maximal inspiratory pressure were unchanged (all P > 0.50). We conclude that TEA with bupivacaine 0.25% can be used safely in end-stage COPD patients. IMPLICATIONS: Thoracic epidural anesthesia with bupivacaine 0.25% does not impair ventilatory mechanics and inspiratory respiratory muscle strength in severely limited chronic obstructive pulmonary disease patients. Thus, thoracic epidural anesthesia can be used safely in patients with end-stage chronic obstructive pulmonary disease. 相似文献