Biomedical subjects

J Rieger

Publications and source records attributed to J Rieger.

At least 37 records · Page 2Linked to original sources

PubMed2002

[Primary hypertrophic osteoarthropathy (Touraine-Solente-Golé syndrome)].

HISTORY: A 29-year-old man had finger clubbing since the age of 15 years, and for the last 10 years his hands and feet had grown disproportionately. In addition he suffered from marked whole-body sweating, especially of the hands and feet, as well as persistent pain in the limbs and joints. INVESTIGATIONS: Biochemical and endocrinological tests were normal. Radiology of the hands and lower legs revealed marked periosteal thickening, while the substantia trabeculosa was unremarkable. Secondary causes having been excluded primary hypertrophic osteoarthropathy was diagnosed. TREATMENT AND COURSE: While there is no causal treatment, physio- and balneotherapy improved the symptoms. CONCLUSION: Early and accurate diagnosis of primary hypertrophic osteoarthropathy is essential, if only because of its favourable long-term prognosis.

Adult↗

PubMed2002

[Structured radiologic diagnosis in polytrauma].

PURPOSE: Development of a concept for structured diagnostic imaging in patients with multiple trauma. MATERIAL AND METHODS: Evaluation of data from a prospective trial with over 2400 documented patients with multiple trauma. All diagnostic and therapeutic steps, primary and secondary death and the 90 days lethality were documented. Structured diagnostic imaging of multiple injured patients requires the integration of an experienced radiologist in an interdisciplinary trauma team consisting of anesthesia, radiology and trauma surgery. Radiology itself deserves standardized concepts for equipment, personnel and logistics to perform diagnostic imaging for a 24-h-coverage with constant quality. RESULTS: This paper describes criteria for initiation of a shock room or emergency room treatment, strategies for documentation and interdisciplinary algorithms for the early clinical care coordinating diagnostic imaging and therapeutic procedures following standardized guidelines. Diagnostic imaging consists of basic diagnosis, radiological ABC-rule, radiological follow-up and structured organ diagnosis using CT. Radiological trauma scoring allows improved quality control of diagnosis and therapy of multiple injured patients. CONCLUSION: Structured diagnostic imaging of multiple injured patients leads to a standardization of diagnosis and therapy and ensures constant process quality.

Emergency Service, Hospital↗

PubMed2002

[Radiological diagnosis in acute craniocerebral trauma].

PURPOSE: Head injury alone or in combination with multiple trauma is the main cause of death and severe disability in individuals under 45 years old. This review is intended to describe the relevant imaging modalities, to analyze their specific value and limitations and to illustrate the most important radiologic findings. The indications for diagnostic imaging within the context of an interdisciplinary linkage of diagnostic and therapeutic measures are discussed. MATERIAL AND METHODS: Recent publications are analyzed and compared to the experiences of our own hospital. In terms of a critical synoptic assessment the currently best standard of care is described in consideration of an interdisciplinary care concept. RESULTS: Radiologic imaging modalities crucially contribute to the complete injury assessment and provide an indispensable basis for any therapeutic decision. Comprehensive neuromonitoring and reliable demonstration of delayed or secondary brain damage is impossible without modern imaging technology. Computed tomography (CT) further continues to be the most important imaging modality, while magnetic resonance imaging despite it's partly superior diagnostic informations remains reserved to particular diagnostic problems. CONCLUSIONS: Suitable constructive prerequisities, an interdisciplinary care concept and integration of the radiologist in hospital-adapted diagnostic and therapeutic algorithms significantly improves the outcome of patients with acute head injury. Beside the correct diagnosis itself the time to establish a diagnosis above all has a crucial impact on successful management and good outcome of these patients.

Angiography, Digital Subtraction↗

PubMed2002

[Interdisciplinary interventional therapy for tracheobronchial stenosis with modern metal net stents].

STUDY OBJECTIVES: Assessment of the therapeutic potential of tracheobronchial stenting for obstructive tracheobronchial disease, in-vivo comparison of different stent types and development of helpful criteria for choosing the suitable stent type. MATERIAL AND METHODS: Prospective case analysis. Between 1993 and 1999 53 stents were implanted into the tracheobronchial system of 39 consecutive patients with benign or malignant airway obstruction. Every single stent (26 Strecker Stents, 18 Wallstents, 6 Accuflex Nitinolstents, 1 Dumon-, 1 Rüsch- and 1 Palmazstent) was recorded in an unified database. Analysis comprised clinical effectiveness, lung function if possible, relevant complications and radiologic follow-up parameters. The probability of their remaining within the tracheobronchial system, of their remaining undislocated and uncompressed was calculated using Kaplan-Meier analysis for three stent types. RESULTS: Stent placement proved itself to be an effective treatment in 86 % of the patients. Resistance could be normalized in 9/9 patients. Kaplan-Meier analysis clearly revealed a higher probability for the Wall- and Nitinolstent to remain within the tracheobronchial system and to remain uncompressed. Dislocation also occurred more rarely. Explantation of the Wallstent, however, if desired, was much more difficult compared to the Strecker stent. The Wallstent also occasionally led to the formation of granulation tissue especially at the proximal stent end and, as such, required reintervention. CONCLUSION: Any of the 3 stent types proved to be an effective therapeutic option in the management of obstructive tracheobronchial disease. Choise of the stent type should be determined through definition of the therapeutic intention. It is useful to distinguish between (a) benign stenosis, (b) malignant stenosis but curative therapeutic situation and (c) malignant stenosis in a palliative therapeutic situation with limited life expectancy. In spite of its superior mechanical properties the Wallstent is rather suited for a palliative situation because explantation may be difficult. The Strecker Stent requires more reinterventions but removal is easy to perform. The Nitinolstent possibly represents a reasonable compromise.

Adolescent↗

PubMed2002

[Focal secondary malignant liver lesions: MnDPDP-enhanced MRT at 0.2 tesla vs. helical CT-arterioportography].

PURPOSE: Prospective evaluation of the efficacy of MnDPDP- enhanced MRI using an open low-field scanner for the detection of focal malignant liver lesions in comparison with helical CT- arterioportography (CT AP). MATERIAL AND METHODS: As part of a phase III study, 27 consecutive patients we enrolled for comparison, with seven patients later eliminated for failing the inclusion criteria. Native and MnDPDP-enhanced MRI of the liver at a field-strength of 0.2 Tesla (Siemens Magnetom Open) and DSA with helical CT AP (Siemens Somatom Plus 4) were performed within one week. The lesions were compared collectively and after categorization by size: (a) < 1 cm, (b) 1 - 2 cm, and (c) > 2 cm. For statistical evaluation, the sign test with a significance level of p < 0.05 was used. RESULTS: CT AP depicted 114 lesions, whereas native MRI detected 62 and MnDPDP-enhanced MRI revealed 69 lesions. Significant differences were shown for collective comparison and for selective comparison of category (b), and of categories (a) and (b) combined. No significant differences were found between native and contrast-enhanced MRI. CONCLUSION: MnDPDP should be reserved for high-field strengths since low field strengths cannot be expected to confirm or exclude malignant liver lesions reliably.

Adult↗

PubMed2001

Glioma cell sensitivity to topotecan: the role of p53 and topotecan-induced DNA damage.

Topotecan is a topoisomerase I inhibitor which is currently evaluated as an adjuvant agent for malignant glioma. Here, we analysed the effects of topotecan on 12 human malignant glioma cell lines in vitro. All cell lines expressed topoisomerase I mRNA. High p53 protein levels, but not genetic or functional p53 status, were associated with increased topotecan-induced DNA/topoisomerase I complex formation. Neither functional p53 status, nor p53 protein levels, nor complex formation predicted topotecan-induced growth inhibition. We thus confirm a possible role for p53 protein in modulating topoisomerase I activity but conclude that the major molecular determinants of topotecan sensitivity in glioma cells await identification.

Antineoplastic Agents↗

PubMed2001

Chromosomal imbalances associated with response to chemotherapy and cytotoxic cytokines in human malignant glioma cell lines.

The median survival for human malignant glioma patients treated with neurosurgery and postoperative radiotherapy does not exceed one year. Only a minority of patients benefit from adjuvant chemotherapy. It was the aim of our study to determine which genomic alterations in malignant gliomas modulate the sensitivity to chemotherapy or cytotoxic cytokines such as CD95 ligand (CD95L) or Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL). Therefore, we analyzed 12 human malignant glioma cell lines for chromosomal gains and losses by comparative genomic hybridization (CGH). The gains most commonly identified were on chromosomes 7q, 19, 1, and 20q, whereas the most frequent losses were on 13q, 11q, 18q, and 4q. By comparison with previously published data on this panel of glioma cell lines1112, we defined candidate regions which may carry genes responsible for sensitivity to chemotherapy or cytotoxic cytokines. All but one of the chromosomal regions associated with response to chemotherapy, i.e. 1p12, 3p21, 11p11.2-p13, 12q23, 17p11. 2-p13, were different from those associated with response to cytotoxic cytokines, i.e. lp12, 1q22, 12q12-q21. Genomic regions known to harbor major candidate genes, including genes encoding death ligands, death receptors, caspases and BCL-2 family proteins, were not found to be imbalanced. In addition, we identified 5q13-q14, 5q34, 10p11.2, 9q21-q34 as genomic regions associated with the proliferative activity of malignant glioma cell lines. Cell lines with gain on proximal 5q, where CCNB1 and CCNH reside, showed an increased growth rate, suggesting that cyclins activating cdc2, the dominant G2/M phase kinase, may play a role in glioma tumorigenes.

Apoptosis↗

PubMed2001

[Evaluation of spine boards for X-Ray diagnostics].

PURPOSE: Spine boards are frequently used in preclinical emergency care. Different models were examined with regard to their feasibility for plain film radiography and computed tomography (CT). METHODS: Five current spine board models were measured for their dimensions and weight. Transmission of radiation [microGyls] and dose area product [cGy x cm(2)] were determined with a patient equivalent aluminium phantom. Image artifacts, image quality and resolution of anatomic details were evaluated with an anthropomorphic Alderson phantom. RESULTS: With only 6.3 kg new models show a 28 % reduction in weight, three spine boards generate lateral artifacts due to a narrow width of 41 - 42 cm. Radiation transmission of all boards was similar, however dose area products differed by up to 59 %. Image quality was impaired in 4 out of 5 boards because of image artifacts, CT scanning was not impaired with all boards. CONCLUSION: Only one board (Ferno Millenia(R)) showed sufficient properties for plain film radiography and CT. There is no suitable spine board for preclinical and clinical applications as well as for trauma radiology, further improvements of current designs are essential.

Artifacts↗

PubMed2001

Traumatic cranial injury sustained from a fall on the rigid external distraction device.

Distraction osteogenesis has become a popular treatment of congenital maxillocraniofacial anomalies. Many ingenious internal and external devices have been developed and used. The rigid external distraction system based on systems previously used in correction of maxillary retrusion offers postoperative adjustment in two dimensions. Figueroa and Polley reported the use of this device with minimal morbidity in children as young as 5 years of age. They reported no problems with infection, bleeding, pain, loosening of the intraoral splint, dental injury, or wear problems in a series of 14 consecutive cleft patients. Recent modification of the system, rigid external distraction II, has allowed it to be applied to more complex craniofacial deformities that require a LeFort III osteotomy. A review of the neurosurgery and orthopedic literature revealed that halo complications relate primarily to the skull pins. In most cases, these complications can be prevented if the device is carefully applied and monitored. Early recognition and prompt treatment of complications are important. After experience with this system for advancement at the LeFort III level, six patients with various syndromes involving the craniofacial skeleton have undergone LeFort III level distraction osteogenesis with the rigid external distraction device in combination with a planned and stabilized frontosupraorbital advancement. In one of these cases, a 7-year-old child fell on the device after discharge from the hospital and sustained a compound depressed skull fracture that required debridement and repair.

Absorbable Implants↗

PubMed2000

Defective localization of the Wilson disease protein (ATP7B) in the mammary gland of the toxic milk mouse and the effects of copper supplementation.

Toxic milk (tx) is a copper disorder of mice that causes a hepatic accumulation of copper similar to that seen in patients with Wilson disease. Both disorders are caused by a defect in the ATP7B copper-transporting ATPase. A feature of the tx phenotype is the production of copper-deficient milk by lactating dams homozygous for the tx mutation; the milk is lethal to the pups. It has not been determined whether the production of copper-deficient milk is a direct consequence of impaired expression of ATP7B protein in the mammary gland. With the use of immunohistochemistry, our study demonstrated that the ATP7B protein was mislocalized in the lactating tx mouse mammary gland, which would explain the inability of the tx mouse to secrete normal amounts of copper in milk. Confocal microscopy analysis showed that, in the lactating tx mammary gland, ATP7B was predominantly perinuclear in comparison with the diffuse, cytoplasmic localization of ATP7B in the lactating normal mammary gland. Lactating tx mice showed impaired delivery of copper from the mammary gland to the milk and this was not ameliorated by dietary copper supplementation. In contrast, the normal mouse mammary gland responded to increased dietary copper by increasing the amount of copper in milk. A change in the distribution of the ATP7B protein from perinuclear in the non-lactating gland to a diffuse, cytoplasmic localization in the lactating gland of the normal (DL) mouse suggests that the relocalization of APT7B is a physiological process that accompanies lactation. We conclude that the impaired copper transport from the mammary gland into milk in lactating tx mice is related to the mislocalization of ATP7B.

Adenosine Triphosphatases↗

PubMed2000

Glutathione S-transferase and drug sensitivity in malignant glioma.

Malignant gliomas are largely resistant to current approaches of adjuvant chemotherapy. Gluthatione S-transferases (GST) have been attributed a role in the resistance of cancer cells, e.g., to nitrosoureas. Here, we assessed the expression levels of GST-pi and GST-mu RNA and protein as well as total GST activity in a panel of 12 human glioma cell lines and correlated these data with p53 status, BCL-2 family protein expression and drug sensitivity in these cells. Neither GST protein levels nor GST activity correlated with genetic or functional p53 status or with the expression of various BCL-2 family proteins. No evidence for GST-mediated protection from chemotherapeutic drugs became apparent. In contrast, high levels of GST-pi protein, probably the major source of GST activity in glioma cells, and of total GST activity correlated with enhanced sensitivity to vincristine-induced clonogenic cell death. Expression of GST-pi in human glioblastomas in vivo was confirmed by immunohistochemistry. Neither total, nor cytoplasmic or nuclear, GST-pi immunoreactivity correlated with the response to adjuvant radiotherapy or radiochemotherapy. A comparative analysis of primary and recurrent tumors showed that GST expression was not enhanced by radiochemotherapy in vivo. We conclude that GST does not account for the differential chemosensitivity of glioma cell lines in vitro and does not accumulate in glioma subpopulations that form recurrent tumors after radiochemotherapy in vivo.

Adult↗

PubMed2000

Sensory and cognitive contributions of color to the recognition of natural scenes.

Although color plays a prominent part in our subjective experience of the visual world, the evolutionary advantage of color vision is still unclear [1] [2], with most current answers pointing towards specialized uses, for example to detect ripe fruit amongst foliage [3] [4] [5] [6]. We investigated whether color has a more general role in visual recognition by looking at the contribution of color to the encoding and retrieval processes involved in pattern recognition [7] [8] [9]. Recognition accuracy was higher for color images of natural scenes than for luminance-matched black and white images, and color information contributed to both components of the recognition process. Initially, color leads to an image-coding advantage at the very early stages of sensory processing, most probably by easing the image-segmentation task. Later, color leads to an advantage in retrieval, presumably as the result of an enhanced image representation in memory due to the additional attribute. Our results ascribe color vision a general role in the processing of visual form, starting at the very earliest stages of analysis: color helps us to recognize things faster and to remember them better.

Cognition↗

PubMed2000

Expression and functional activity of heat shock proteins in human glioblastoma multiforme.

OBJECTIVE: To assess the expression of heat shock proteins (HSP) in glioma cells in vitro and in vivo and to examine their role in resistance to apoptosis. BACKGROUND: HSP are expressed in response to various forms of stress. Constitutive HSP expression may confer resistance to cytotoxic stimuli in human cancers. METHODS: HSP expression was assessed by immunoblot analysis in glioma cells in vitro and by immunocytochemistry in human glioblastomas in vivo. Modulation of apoptosis by hyperthermia-mediated HSP induction was examined in glioma cell lines in vitro. RESULTS: Immunoblot analysis revealed constitutive expression of HSP27, HSP72, HSP73, and HSP90 in all 12 human glioma cell lines. B-crystallin (alphaBC) was expressed in 3 of 12 cell lines. High levels of alphaBC and HSP72 correlated with drug resistance and high p53 levels in vitro. Transient hyperthermia (43 degrees C/2 hours) induced HSP27 and HSP72 expression but had no effect on the levels of alphaBC, HSP73, or HSP90. HSP induction provided no survival advantage against subsequent cytotoxic challenges, including cytotoxic cytokines and radiochemotherapy. Immunohistochemistry showed strong expression of all HSP in vivo. The comparative analysis of HSP27, alphaBC, HSP72, HSP73, and HSP90 expression in 24 paired samples of first resections and recurrences of human glioblastoma multiforme revealed no impact of HSP expression on response to adjuvant radiochemotherapy and no modulation of HSP expression by radiochemotherapy. CONCLUSIONS: High constitutive, as opposed to inducible, expression of HSP may play a role in the primary resistance of human malignant gliomas to cytotoxic radiochemotherapy. Superinduction of HSP levels by hyperthermia in vitro provided no further survival advantage.

Adult↗

PubMed2000

APO2L/TRAIL expression in human brain tumors.

APO2 ligand (APO2L)/TRAIL is a novel member of the tumor necrosis factor cytokine family and a potent inducer of apoptosis in tumor cell lines. We recently reported that APO2L is consistently expressed in low-grade astrocytomas, anaplastic astrocytomas, glioblastomas, and cell lines derived thereof, and that malignant glioma cell lines are susceptible to APO2L-induced apoptosis. In this study, we investigated whether APO2L is expressed in medulloblastoma or neuroblastoma cell lines and whether these cells are sensitive to APO2L-induced apoptosis. Immunoblot analyses revealed full-length APO2L protein expression in one (DAOY) of three medulloblastoma cell lines but not in two neuroblastoma cell lines (SKN-BE and SKN-LE). Viability assay performed after exposure to soluble APO2L for 16 h showed that DAOY medulloblastoma cells were the most sensitive and that apoptosis induced by APO2L was greatly enhanced when protein synthesis was inhibited by cycloheximide. Neuroblastoma cell lines were almost completely resistant to APO2L-induced apoptosis. We also carried out APO2L immunohistochemistry in a total of 115 tumors of the nervous system with different histogenesis and biological behavior. In all 9 pilocytic astrocytomas, the areas of dense fibrillary network showed diffuse and strong APO2L expression. In oligodendrogliomas, APO2L expression was observed in areas with a significant admixture of astrocytic cells, but was absent in neoplastic oligodendrocytes. In 13 of 14 ependymomas, APO2L was expressed in perivascular pseudorosettes. In all 12 medulloblastomas, strong APO2L expression was observed in intra-tumoral-reactive astrocytes, but neoplastic cells did not show APO2L immunoreactivity. Thus, the pattern of APO2L expression was largely similar to that of glial fibrillary acidic protein (GFAP), except for choroid plexus tumors and 3 of 8 anaplastic meningiomas, in which APO2L was focally expressed without concomitant GFAP expression. APO2L expression was absent in meningiomas, neurocytomas, and schwannomas. Thus, there is considerable heterogeneity of APO2L expression and susceptibility to APO2L-induced apoptosis among human brain tumors.

Apoptosis↗

PubMed2000

Evidence for a constitutive, verapamil-sensitive, non-P-glycoprotein multidrug resistance phenotype in malignant glioma that is unaltered by radiochemotherapy in vivo.

Human malignant gliomas are commonly resistant to chemotherapy. Here, we examined the role of the multidrug resistance (mdr) mechanism in the chemo-resistance of these tumors, using a twofold approach: (i) by assessing a possible mdr phenotype before and after chronic drug exposure of glioma cells in vitro, and (ii) by assessing the modulation of expression of the mdr-associated P-glycoprotein (Pgp) using radiotherapy and serial cycles of chemotherapy in human glioblastoma patients in vivo. T98G, and to a lesser degree, LN-229 human malignant glioma cells exhibit a constitutive mdr phenotype as determined by the modulation of dye transport and by the augmentation of chemosensitivity by the mdr antagonist, verapamil. Thus, coexposure to verapamil enhances the cytotoxicity of vincristine, doxorubicin and VM26 in T98G cells and that of vincristine in LN-229 cells. Chronic exposure of the cells to low concentrations of vincristine and doxorubicin, but not VM26, topotecan or BCNU, moderately enhances the mdr-like phenotype, as assessed by drug expulsion assays. However, chronic exposure to increasing drug concentrations does not significantly alter the sensitivity to the respective drugs. These data are consistent with a constitutive, but not drug-inducible, mdr-like drug resistance in glioma cells in vitro. Immunocytochemical analysis of human malignant gliomas in vivo reveals that Pgp expression is more abundant in endothelial cells within the gliomas, than in the glioma cells proper. Importantly, Pgp expression is unaltered by radiochemotherapy, assessed by comparative immunocytochemistry of glioma specimens obtained serially before and after radiochemotherapy. We conclude that (i) glioma cells exhibit constitutive mdr-like drug resistance that is not significantly altered by chronic drug exposure in vitro; (ii) endothelial cells may play an important role in Pgp-mediated drug resistance of gliomas in vivo; (iii) radiotherapy and repeated chemotherapy cycles do not modulate Pgp expression in human malignant gliomas in vivo; (iv) there is preliminary evidence for a non-Pgp, verapamil-sensitive drug transport activity in glioma cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

[Concept for a health care economic evaluation of short- and long-term costs and effectiveness parameters of an expanded ambulatory psychosomatic rehabilitation program].

There are only few ambulatory rehabilitation concepts for mothers with psychosomatic disorders (prevalence 5%). Also, only little is known about the evaluation of these programmes. This study compares the socioeconomic evaluations of an ambulatory rehabilitation programme with a post-assistance programme and one without a post-assistance programme. The superior programme should be determined by weighing all relevant costs and benefits. The intensive phase of the ambulatory rehabilitation programme consists of an eight-week treatment with group, single, body and art therapy. The post-assistance programme spans a period of nine-months with 36 sessions of psychoanalytic group therapy. The evaluation of both programme alternatives is made by with the evaluation tool of socioeconomic analyses. For consideration and pricing of costs all direct medical costs, direct non-medical costs and indirect costs are being monitored. Outcomes assessment is realised by cost-effectiveness analysis, cost-utility analysis and cost-benefit analysis. Utilisation of the health care system is being assessed with questionnaires. Measurements are being performed at the beginning and the end of the rehabilitation programme and three, six, nine and twelve months later. Mothers with children aged six years and younger and suffering from various psychosomatic disorders were included in this study. The costs identified for the rehabilitation programme are DM 5571.10 (intensive care and post-assistance programme) and DM 1512.40 (intensive care) per patient. Further progress of the study will show if future cost will differ between the two alternatives. For the comparison of both alternatives all costs will be linked with outcomes. It remains to be seen that additional costs of the post-assistance programme will be compensated with positive outcomes. A sensitivity analysis will show if variation of assumptions will influence the cost-benefit-ratio of the different alternatives.

Adult↗

PubMed1999

Inhibition of experimental rat glioma growth by decorin gene transfer is associated with decreased microglial infiltration.

Decorin gene therapy for experimental malignant glioma is thought to involve antagonism of immunosuppression induced by glioma-derived transforming growth factor-beta (TGF-beta). TGF-beta is chemotactic for cells of the monocyte macrophage lineage but inhibits their functional activity in many in vitro paradigms. Here, we examined changes in the patterns of microglial infiltration of rat C6 gliomas expressing a decorin transgene. We find that the number of OX42/ED-1-positive microglial cells is reduced rather than enhanced in the presence of decorin. Decorin-expressing gliomas contain lower numbers of MHC class II antigen-expressing microglial cells whereas the relative frequency of MHC I immunoreactivity among microglial cells is increased. Interestingly, the reduction of TGF-beta levels in the tumors by decorin is associated with the de novo expression of inducible nitric oxide synthase (iNOS) in a minority of microglial cells. These data suggest that microglial cells do not participate in the regression of decorin-expressing rat C6 gliomas.

Animals↗

PubMed1999

Gemcitabine cytotoxicity of human malignant glioma cells: modulation by antioxidants, BCL-2 and dexamethasone.

Gemcitabine is a novel antimetabolite drug that acts by multiple mechanisms, including inhibition of ribonucleoside diphosphate reductase, of dCMP deaminase and of dCTP incorporation into DNA and RNA. Here, we report that gemcitabine induces cytotoxic and clonogenic death of 12 human malignant glioma cell lines at clinically relevant concentrations around 1 microM. Gemcitabine is thus approximately 100-fold more active than the congener drug, cytarabine. Gemcitabine cytotoxicity of glioma cells does not require wild-type p53 activity: (i) there was no difference in the susceptibility to gemcitabine between cell lines with wild-type p53 and cell lines with mutant or deleted p53; (ii) ectopic expression of a temperature-sensitive p53 protein either at wild-type (32.5 degrees C) or at mutant (38.5 degrees C) conformation had no significant influence on gemcitabine-induced cell death. Gemcitabine cytotoxicity was unaffected by the antioxidants, N-acetylcysteine and phenyl-N-tert-butyl-alpha-phenylnitrone. There was no correlation between the susceptibility to gemcitabine and the endogenous expression of the B cell lymphoma-2 (BCL-2)-family proteins BCL-2, BCL-XL, myeloid cell leukemia-1 (MCL-1), BCL-2-associated X protein (BAX), BCL-2 homologous antagonist/killer (BAK) and BCL-XS. Ectopic expression of BCL-2 moderately attenuated gemcitabine-induced cell death. Similarly, preexposure to the synthetic steroid, dexamethasone, which is commonly used to control cerebral edema in brain tumor patients, reduced gemcitabine cytotoxicity. We conclude that the clinical evaluation of gemcitabine for the adjuvant chemotherapy of malignant glioma is warranted.

Antimetabolites, Antineoplastic↗