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Biomedical subjects

M Weller

Publications and source records attributed to M Weller.

At least 19 recordsLinked to original sources
PubMed2006

Adenoviral expression of XIAP antisense RNA induces apoptosis in glioma cells and suppresses the growth of xenografts in nude mice.

The expression of inhibitor of apoptosis (IAP) family members contributes to the resistance of human cancers to apoptosis induced by radiotherapy and chemotherapy. We report that the infection of malignant glioma cells and several other tumor cell lines with adenoviruses encoding antisense RNA to X-linked IAP (XIAP) depletes endogenous XIAP levels and promotes global caspase activation and apoptosis. In contrast, non-neoplastic SV-FHAS human astrocytes and other non-neoplastic cells express XIAP at very low levels and resist these effects of adenovirus-expressing XIAP antisense RNA (Ad-XIAP-as). Caspase inhibitors such as z-Val-Ala-DL-Asp(OMe)-fluoromethylketone (zVAD-fmk) delay caspase processing and XIAP depletion, suggesting that XIAP depletion results both from antisense-mediated interference with protein synthesis and proteolytic cleavage by activated caspases. However, zVAD-fmk neither prevents nor delays cell death, indicating a caspase-independent pathway to cell death triggered by IAP depletion. Similarly, B-cell lymphoma-X(L) (BCL-X(L)) inhibits caspase activity, but fails to rescue from apoptosis. Loss of p65/nuclear factor-kappaB (NF-kappaB) protein and NF-kappaB activity is an early event triggered by Ad-XIAP-as and probably involved in Ad-XIAP-as-induced apoptosis. Finally, Ad-XIAP-as gene therapy induces cell death in intracranial glioma xenografts, prolongs survival in nude mice and may reduce tumorigenicity in synergy with Apo2L/TNF-related apoptosis-inducing ligand (TRAIL) in vivo. Altogether, these data define a powerful survival function for XIAP and reinforce its possible role as a therapeutic target in human glioma cells.

Adenoviridae↗
PubMed2006

Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine.

Methylating drugs such as temozolomide (TMZ) are widely used in the treatment of brain tumours (malignant gliomas). The mechanism of TMZ-induced glioma cell death is unknown. Here, we show that malignant glioma cells undergo apoptosis following treatment with the methylating agents N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and TMZ. Cell death determined by colony formation and apoptosis following methylation is greatly stimulated by p53. Transfection experiments with O(6)-methylguanine-DNA methyltransferase (MGMT) and depletion of MGMT by O(6)-benzylguanine showed that, in gliomas, the apoptotic signal originates from O(6)-methylguanine (O(6)MeG) and that repair of O(6)MeG by MGMT prevents apoptosis. We further demonstrate that O(6)MeG-triggered apoptosis requires Fas/CD95/Apo-1 receptor activation in p53 non-mutated glioma cells, whereas in p53 mutated gliomas the same DNA lesion triggers the mitochondrial apoptotic pathway. This occurs less effectively via Bcl-2 degradation and caspase-9, -2, -7 and -3 activation. O(6)MeG-triggered apoptosis in gliomas is a late response (occurring >120 h after treatment) that requires extensive cell proliferation. Stimulation of cell cycle progression by the Pasteurella multocida toxin promoted apoptosis whereas serum starvation attenuated it. O(6)MeG-induced apoptosis in glioma cells was preceded by the formation of DNA double-strand breaks (DSBs), as measured by gammaH2AX formation. Glioma cells mutated in DNA-PK(cs), which is involved in non-homologous end-joining, were more sensitive to TMZ-induced apoptosis, supporting the involvement of DSBs as a downstream apoptosis triggering lesion. Overall, the data demonstrate that cell death induced by TMZ in gliomas is due to apoptosis and that determinants of sensitivity of gliomas to TMZ are MGMT, p53, proliferation rate and DSB repair.

Antineoplastic Agents, Alkylating↗
PubMed2006

PCV chemotherapy for recurrent glioblastoma.

The authors administered procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU, lomustine), and vincristine (PCV) to 86 patients with recurrent glioblastoma. There were three partial responses, but no complete responses. Median progression-free survival was 17.1 weeks and progression-free survival at 6 months was 38.4%. World Health Organization grade III/IV hematologic toxicity was common (25.6%), but nonhematologic toxicity was mild.

Adult↗
PubMed2006

Surviving glioblastoma for more than 5 years: the patient's perspective.

The authors performed a comprehensive analysis of the functional outcome of 10 patients who had survived 5 years from a diagnosis of glioblastoma. Neurologic deficits were mild in most patients, but neuropsychological testing demonstrated cognitive deficits in all patients. Depression and anxiety were common. Although most patients thought that their social functioning and work ability were impaired, little reduction in overall quality of life was perceived.

Activities of Daily Living↗
PubMed2006

PCTAIRE3: a putative mediator of growth arrest and death induced by CTS-1, a dominant-positive p53-derived synthetic tumor suppressor, in human malignant glioma cells.

Chimeric tumor suppressor-1 (CTS-1) is based on the sequence of p53 and was designed as a therapeutic tool resisting various mechanisms of p53 inactivation. We previously reported that an adenovirus expressing CTS-1 (Ad-CTS-1) has superior cell death-inducing activity in glioma cells compared with wild-type p53. Here, we used cDNA microarrays to detect changes in gene expression preferentially induced by Ad-CTS-1. The putative serine threonine kinase, PCTAIRE3, and the quinone oxireductase, PIG3, were strongly induced by Ad-CTS-1 compared with wild-type p53. An adenoviral vector encoding PCTAIRE3 (Ad-PCTAIRE3) induced growth arrest and killed a minor proportion of the glioma cells. Ad-PIG3 alone affected neither growth nor viability. However, coinfection with Ad-PCTAIRE3 and Ad-PIG3 resulted in enhanced growth inhibition compared with Ad-PCTAIRE3 infection alone. Ad-CTS1, Ad-PCTAIRE3 or Ad-PIG3 induced the formation of free reactive oxygen species (ROS). However, the prevention of ROS formation induced by Ad-PCTAIRE3 and Ad-CTS-1 did not block growth arrest and cell death, suggesting that ROS formation is not essential for these effects. Altogether, these data identify PCTAIRE3 as one novel growth-inhibitory and death-inducing p53 response gene and suggest that changes in the expression of specific target genes contribute to the superior anti-glioma activity of CTS-1.

Adenoviridae↗
PubMed2005

BCL-xL: time-dependent dissociation between modulation of apoptosis and invasiveness in human malignant glioma cells.

Conditionally BCL-xL-overexpressing LNT-229 Tet-On glioma cell clones were generated to investigate whether the 'antiapoptosis phenotype' and the 'motility phenotype' mediated by BCL-2 family proteins in glioma cells could be separated. BCL-xL induction led to an immediate and concentration-dependent protection of LNT-229 cells from apoptosis. BCL-xL induction for up to 3 days did not result in altered invasiveness. In contrast, long-term BCL-xL induction for 21 days resulted in increased transforming growth factor-beta2 expression, and in metalloproteinase-2 and -14 dependent, but integrin independent, increased invasiveness. Withdrawal of doxycycline (Dox) abolished the protection from apoptosis whereas the 'invasion phenotype' remained stable. Dox stimulation of BCL-xL-inducible LNT-229 cells conferred infiltrative growth to BCL-xL-positive glioma cells in vivo and reduced the survival of tumor-bearing mice. These data allow to dissect a direct antiapoptotic action of BCL-xL from an indirect effect, presumably mediated by altered gene expression, which modifies tumor cell invasiveness in vitro and in vivo.

Animals↗
PubMed2005

Primary central nervous system lymphomas (PCNSL): MRI response criteria revised.

The authors investigated the applicability of Macdonald response criteria to patients with primary CNS lymphoma (PCNSL). Four of 68 patients with persisting contrast-enhancing lesions after primary therapy did not receive further therapy, and none showed tumor progression after up to 54 months. Because contrast enhancement may not necessarily indicate residual, biologically active lymphoma, the authors propose a modification of the Macdonald response criteria.

Adult↗
PubMed2005

[Standards and new developments in the chemotherapy of glioblastomas].

For 25 years involved-field radiotherapy has remained the mainstay of postoperative treatment for glioblastoma. In contrast, the role of adjuvant chemotherapy in addition to radiotherapy has remained controversial. A recent randomized multinational phase III trial (EORTC 26 981/22 981/NCIC CE.3) assessing concomitant and adjuvant chemotherapy with the alkylating agent, temozolomide, in addition to radiotherapy in newly diagnosed glioblastoma defines an increase in median survival from 12.1 months with radiotherapy alone to 14.6 months with radiochemotherapy and an increase in the 2-year survival rate from 10 to 26 %. Subgroup analysis revealed that the gain in survival in the experimental arm was largely achieved in patients with glioblastomas which exhibited a methylation of the promoter region of the O (6)-methylguanine DNA methyltransferase (MGMT) gene and thus did not express MGMT. MGMT is a DNA repair enzyme which repairs DNA lesions induced by chemotherapy with alkylating agents. The cellular MGMT stores are consumed during DNA repair, suggesting that temozolomide itself may deplete MGMT and thus overcome its own most important pathway of resistance. EORTC 26 981/22 981/NCIC CE.3 thus defines a milestone in the treatment of glioblastoma and will provide a platform for further efforts at improving the outcome for patients suffering from this still invariably fatal neoplasm.

Antineoplastic Agents, Alkylating↗
PubMed2005

Adult medulloblastoma: prognostic factors and response to therapy at diagnosis and at relapse.

Adult medulloblastoma is a rare tumor with few retrospective studies published so far. The role of adjuvant chemotherapy or chemotherapy at relapse is unclear. This study reports therapy and outcome in all adult (>or=16 years old) medulloblastoma (n=34) and supratentorial primitive neuroectodermal tumor (PNET) patients (n=2) treated in 2 neuro-oncological centers between 1976 and 2002. The median age was 24.5 years (range 16-76). After resection, 16 patients were treated with craniospinal radiotherapy alone, 20 patients also received adjuvant chemotherapy (8 vincristine, CCNU, cisplatin; 7 methotrexate alone or methotrexate/vincristine-based polychemotherapy; 5 other protocols). Median survival in the whole cohort was 126 months (2+ - 200+months). Five-year and 10-year survival rates were 79 % and 56%. Adjuvant chemotherapy was associated with a non-significant trend to prolonged survival (relative risk (RR) 1.89; p=0.068). The median progression-free survival (PFS) after primary therapy was 83 months. At relapse, 10 of 12 evaluable patients achieved a complete response upon second-line therapy. The median survival times from first (n=17) and second relapse (n=9) were 21 months (0-67+ months; 5/17 without second relapse) and 20 months (1-29 months). Cox regression analysis revealed the infiltration of the floor of the 4(th) ventricle at diagnosis as the only therapy-independent prognostic factor (RR 0.48; p=0.03). In conclusion, adjuvant chemotherapy may prolong survival in adult medulloblastoma patients. Moreover, second-line therapy may be beneficial for these patients. As in pediatric medulloblastoma patients, primary infiltration of the floor of the 4(th) ventricle indicates a poor prognosis.

Adolescent↗
PubMed2005

High-dose methotrexate toxicity in elderly patients with primary central nervous system lymphoma.

BACKGROUND: The dose of high-dose methotrexate (HDMTX) in elderly patients often has to be reduced, resulting in a loss of treatment efficacy. We evaluated HDMTX-related toxicity with special regard to age distribution in patients with primary central nervous system lymphoma (PCNSL) in a phase IV multicenter trial. PATIENTS AND METHODS: One hundred and fifty-four patients (median age 61 years; 89 patients >60 years old, 21 patients >70 years old) received 619 HDMTX cycles. Toxicity was evaluated prospectively using the WHO classification. Unless a reduced dose was required after calculating a decreased glomerular filtration rate (GFR), the patients received 4 g/m(2) HDMTX followed by leucovorin rescue. RESULTS: Toxicity was generally mild with toxicities of WHO grade > or =3 usually <10%. The differences in the incidence and severity of toxicity were not statistically significant between patients >60 years and < or =60 years old. The same was true for therapy termination owing to MTX toxicity and for delayed serum MTX clearance. Dose reduction significantly differed between patients < or =60 years and those >60 years old (18% versus 44%; P = 0.001). CONCLUSIONS: HDMTX is a safe treatment for PCNSL patients regardless of age, with adherence to dose reduction determined by calculating the GFR before each treatment cycle.

Adult↗
PubMed2004

Vascular endothelial growth factor (VEGF) in leptomeningeal metastasis: diagnostic and prognostic value.

This study examined the diagnostic and prognostic value of vascular endothelial growth factor (VEGF) levels in the cerebrospinal fluid (CSF) of 39 patients with leptomeningeal metastasis (LM). Vascular endothelial growth factor levels at diagnosis were significantly higher in patients with LM (median 359 pg ml(-1)) than in patients with other neurological diseases (median <25 pg ml(-1)). The specificity of VEGF levels above 250 pg ml(-1) for LM was high (98.3%), while the sensitivity was low (51.4%; 73% for VEGF values above 100 pg ml(-1)). In 49% of the LM patients, particularly with lymphoma or medulloblastoma, VEGF levels were below 250 pg ml(-1) and thus in the range of VEGF levels in other neurological diseases. Vascular endothelial growth factor levels correlated significantly with CSF lactate and albumin. Vascular endothelial growth factor levels mirrored the clinical course with a marked reduction in response to therapy and an increase at relapse in some patients who had serial CSF samples available. Multivariate Cox regression analysis showed VEGF below 100 pg ml(-1) (relative risk (RR)=4.24, P=0.0002) and age below 60 years (RR=2.5, P=0.004) to be associated with longer survival in LM. In conclusion, CSF VEGF levels in LM vary considerably. High VEGF levels have a very high specificity for LM and may help to establish the diagnosis. The role of VEGF as a predictor of outcome should be substantiated in prospective studies.

Biomarkers, Tumor↗
PubMed2004

One week on/one week off: a novel active regimen of temozolomide for recurrent glioblastoma.

Twenty-one patients with recurrent or progressive glioblastoma were enrolled in a prospective phase II trial to determine the safety and efficacy of a 1-week on/1-week off regimen of temozolomide administered at 150 mg/m2 on days 1 to 7 and days 15 to 21 of 28-day treatment cycles. Two patients achieved a partial response (10%), and 17 patients (81%) had stable disease. The median progression-free survival was 5 months. The progression-free survival at 6 months was 48%.

Adult↗
PubMed2004

Alkylphosphocholine-induced glioma cell death is BCL-X(L)-sensitive, caspase-independent and characterized by massive cytoplasmic vacuole formation.

Alkylphosphocholines (APC) are candidate anticancer agents. We here report that APC induce the formation of large vacuoles and typical features of apoptosis in human glioma cell lines, but not in immortalized astrocytes. APC promote caspase activation, poly(ADP-ribose)-polymerase (PARP) processing and cytochrome c release from mitochondria. Adenoviral X-linked inhibitor of apoptosis (XIAP) gene transfer, or exposure to the caspase inhibitor, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoro-methylketone zVAD-fmk, blocks caspase-7 and PARP processing, but not cell death, whereas BCL-X(L) blocks not only caspase-7 and PARP processing but also cell death. APC induce changes in Delta Psi m in sensitive glioma cells, but not in resistant astrocytes. The changes in Delta Psi m are unaffected by crm-A (cowpox serpin-cytokine response modifier protein A), XIAP or zVAD-fmk, but blocked by BCL-X(L), and are thus a strong predictor of cell death in response to APC. Free radicals are induced, but not responsible for cell death. APC thus induce a characteristic morphological, BCL-X(L)-sensitive, apparently caspase-independent cell death involving mitochondrial alterations selectively in neoplastic astrocytic cells.

Antineoplastic Agents↗
PubMed2004

The innate immune response in the central nervous system and its role in glioma immune surveillance.

The innate immune system encompasses natural killer (NK) cells, macrophages and granulocytes, the complement system and antimicrobial peptides. Recognition pathways of the innate immune system include microbial non-self recognition, missing-self recognition and induced- self recognition. The central nervous system (CNS) participates in responses of the innate immune system. However, immune inhibitory and anti-inflammatory mechanisms physiologically outbalance and counteract immune activity and thereby limit immune-mediated tissue damage in the brain. Human gliomas appear to take advantage of this immunosuppressive milieu. Moreover, glioma cells themselves interfere with anti-tumor immune responses by expressing immune inhibitory cell surface molecules, such as HLA-G, or by releasing soluble immunosuppressants such as transforming growth factor (TGF)-beta. Yet, although glioma cells exhibit all cellular features of malignancy, these tumors very rarely metastasize outside the brain, raising the possibility of immune-mediated control of these cells outside, but not inside, the brain. Accordingly, activating the innate immune system by forcing glioma cells to express danger signals such as NKG2D ligands is a promising strategy of immunotherapy for these tumors.

Animals↗
PubMed2003

CP-31398, a novel p53-stabilizing agent, induces p53-dependent and p53-independent glioma cell death.

CP-31398 is a prototype small molecule that stabilizes the active conformation of p53 and promotes p53 activity in cancer cell lines with mutant or wild-type p53. Here, we report that CP-31398 induces p53 reporter gene activity and p21 expression in all of 11 glioma cell lines harboring wild-type or mutant p53, but not in p53-null LN-308 cells. Upon prolonged exposure to CP-31398, all glioma cell lines undergo caspase-independent and bcl-x(L)-insensitive cell death with EC(50) concentrations of 10-36 microM. By comparing p53 wild-type U87MG and p53-null LN-308 cells expressing the temperature-sensitive p53(V135A) mutant, we delineate two pathways of CP-31398-induced cell death: an early, p53-dependent pathway that requires (new p53) protein synthesis and a late, p53-independent pathway characterized by aurintricarboxylic acid -sensitive calcium release and epiphenomenal free radical formation. Post-transcriptional repression of p53 synthesis by an intracellularly transcribed short interfering RNA confirmed the presence of these two pathways of cell death. These observations point out some of the liabilities of CP-31398 as a prototype p53-based therapeutic and define a rationale for further refinement of small molecules that specifically target the p53 pathway, but lack the p53-independent effects.

Antineoplastic Agents↗