Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Temozolomide (TMZ) is a methylating agent with promising antitumor efficacy for the treatment of melanomas and intermediate-grade gliomas. Unfortunately, its use in the management of high-grade gliomas (glioblastomas) is limited by multifaceted resistance mechanisms. The aim of this study was to evaluate the possibility to improve the cytotoxic response of two human glioblastoma cell lines, U87MG and U373MG, to TMZ by the use of Tempol (TPL), a low molecular weight piperidine nitroxide that has been shown to inhibit in vitro and in vivo growth of murine glioma cells. To this purpose, we used two different schedules for the combined exposure to the two agents. Our data indicate that TPL synergizes with TMZ in both U87MG and U373MG cells for both schedules tested. This effect is accompanied by an increase in apoptotic cell death and by changes in the expression of genes involved in control of the apoptotic process. TPL was also observed to induce a cell-type specific decrease in GSH levels and in GSH-related enzyme activities that could contribute to its sensitizing effect.
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PMID:The piperidine nitroxide Tempol potentiates the cytotoxic effects of temozolomide in human glioblastoma cells. 1554 22

Standard treatment of high-grade glioma (HGG) is based on surgery followed by limited field radiotherapy, while the role of chemotherapy is still controversial. Many randomized trials addressing the role of post-radiation or "adjuvant" chemotherapy have been conducted in the last three decades, yielding negative or inconclusive results. A statistically significant survival benefit with adjuvant chemotherapy has been demonstrated in two meta-analyses. The estimated absolute increase in survival is modest (10% at 1 year) but significant, and it appears independent of age, Performance Status and histology. Nitrosourea-based regimens were long considered the standard chemotherapy options for HGG, but their toxicity is not negligible. Temozolomide (TMZ) is a promising new drug that seems to be effective in patients with recurrent disease. Clinically and statistically significant survival benefit with the administration of TMZ concomitant and after radiotherapy has been recently demonstrated, establishing a new standard in HGG adjuvant treatment. Randomized comparisons with nitrosoureas are lacking and represent a major issue to be studied in future phase III trials.
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PMID:Adjuvant chemotherapy in the treatment of high grade gliomas. 1584 78

Pharmacologic inhibition of the DNA signal transducers Chk1 and p38 blocks G2 arrest and sensitizes glioblastoma cells to chemotherapeutic methylating agent-induced cytotoxicity. Because Akt pathway activation has been suggested to also block G2 arrest induced by DNA-damaging agents and because glioma cells frequently have high levels of Akt activation, we examined the contribution of the Akt pathway to methylating agent-induced G2 arrest and toxicity. U87MG human glioma cells containing an inducible Akt expression construct were incubated with inducing agent or vehicle, after which the cells were exposed to temozolomide and assayed for activation of the components of the G2 arrest pathway and survival. Temozolomide-treated control cells activated the DNA damage signal transducers Chk1, Chk2, and p38, leading to Cdc25C and Cdc2 inactivation, prolonged G2 arrest, and loss of clonagenicity by a combination of senescence and mitotic catastrophe. Temozolomide-treated cells induced to overexpress Akt, however, exhibited significantly less drug-induced Cdc25C/Cdc2 inactivation and less G2 arrest. Akt-mediated suppression of G2 arrest was associated not with alterations in Chk1 or p38 activation but rather with suppression of Chk2 activation and reduced recruitment of Chk2 to sites of damage in chromatin. Unlike bypass of the G2 checkpoint induced by pharmacologic inhibitors of Chk1 or p38, however, Akt-induced bypass of G2 arrest suppressed, rather than enhanced, temozolomide-induced senescence and mitotic catastrophe. These results show that whereas Akt activation suppresses temozolomide-induced Chk2 activation and G2 arrest, the overriding effect is protection from temozolomide-induced cytotoxicity. The Akt pathway therefore represents a new target for the sensitization of gliomas to chemotherapeutic methylating agents such as temozolomide.
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PMID:Akt activation suppresses Chk2-mediated, methylating agent-induced G2 arrest and protects from temozolomide-induced mitotic catastrophe and cellular senescence. 1593 Mar 7

Systematic reviews and meta-analysis have demonstrated an improved prognosis by chemotherapy of malignant glioma patients. The effects of clinical research therefore have the aim to find more active drugs or new combination therapies. The combination of Temozolomide (TMZ) and nitrosoureas was evaluated preclinically with an evidence of therapeutic synergy. Based on these findings, we have carried out a phase I study with TMZ administered in low, prolonged doses of 75 mg/m2 per day, once a day for 21 days, escalated in cohorts of 3 patients, in combination with a fixed dose of Lomustine (CCNU) 100 mg/m2 orally on day 1. MTD was evident. The treatment was generally well tolerated. We did not observe bleeding or severe infections, as described for several combination chemotherapies with TMZ and other agents. In this study, for the first time in high grade malignant glioma, two orally administrated drugs were associated .TMZ 75 mg/m2 for 28 consecutive days and CCNU 100 mg/m2 on day 1 of every 6 weeks could be recommended as a safe treatment dosage. One of the ten patients evaluated for clinical response showed a partial response, while nine showed stability of disease, with a median duration of from 5 to 6 months.
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PMID:Phase I study of temozolomide and lomustine in the treatment of high grade malignant glioma. 1614 48

Temozolomide (TMZ) is a methylating agent which prolongs survival when administered during and after radiotherapy in the first-line treatment of glioblastoma and which also has significant activity in recurrent disease. O6-methylguanine DNA methyltransferase (MGMT) is a DNA repair enzyme attributed a role in cancer cell resistance to O6-alkylating agent-based chemotherapy. Using a panel of 12 human glioma cell lines, we here defined the sensitivity to TMZ in acute cytotoxicity and clonogenic survival assays in relation to MGMT, mismatch repair and p53 status and its modulation by dexamethasone, irradiation and BCL-X(L). We found that the levels of MGMT expression were a major predictor of TMZ sensitivity in human glioma cells. MGMT activity and clonogenic survival after TMZ exposure are highly correlated (p < 0.0001, r2 = 0.92). In contrast, clonogenic survival after TMZ exposure does not correlate with the expression levels of the mismatch repair proteins mutS homologue 2, mutS homologue 6 or post-meiotic segregation increased 2. The MGMT inhibitor O6-benzylguanine sensitizes MGMT-positive glioma cells to TMZ whereas MGMT gene transfer into MGMT-negative cells confers protection. The antiapoptotic BCL-X(L) protein attenuates TMZ cytotoxicity in MGMT-negative LNT-229 but not in MGMT-positive LN-18 cells. Neither ionizing radiation (4 Gy) nor clinically relevant concentrations of dexamethasone modulate MGMT activity or TMZ sensitivity. Abrogation of p53 wild-type function strongly attenuates TMZ cytotoxicity. Conversely, p53 mimetic agents designed to stabilize the wild-type conformation of p53 sensitize glioma cells for TMZ cytotoxicity. Collectively, these results suggest that the determination of MGMT expression and p53 status will help to identify glioma patients who will or will not respond to TMZ.
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PMID:O6-methylguanine DNA methyltransferase and p53 status predict temozolomide sensitivity in human malignant glioma cells. 1640 12

The purpose of this study was to define the maximum tolerated dose of erlotinib and characterize its pharmaco-kinetics and safety profile, alone and with temozolomide, with and without enzyme-inducing antiepileptic drugs (EIAEDs), in patients with malignant gliomas. Patients with stable or progressive malignant primary glioma received erlotinib alone or combined with temozolomide in this dose-escalation study. In each treatment group, patients were stratified by coadministration of EIAEDs. Erlotinib was started at 100 mg orally once daily as a 28-day treatment cycle, with dose escalation by 50 mg/day up to 500 mg/day. Temozolomide was administered at 150 mg/m2 for five consecutive days every 28 days, with dose escalation up to 200 mg/m2 at the second cycle. Eightythree patients were evaluated. Rash, fatigue, and diarrhea were the most common adverse events and were generally mild to moderate. The recommended phase 2 dose of erlotinib is 200 mg/day for patients with glioblastoma multiforme who are not receiving an EIAED, 450 mg/day for those receiving temozolomide plus erlotinib with an EIAED, and at least 500 mg/day for those receiving erlotinib alone with an EIAED. Of the 57 patients evaluable for response, eight had a partial response (PR). Six of the 57 patients had a progression-free survival of longer than six months, including four patients with a PR. Coadministration of EIAEDs reduced exposure to erlotinib as compared with administration of erlotinib alone (33%-71% reduction). There was a modest pharmacokinetic interaction between erlotinib and temozolomide. The favorable tolerability profile and evidence of antitumor activity indicate that further investigation of erlotinib is warranted.
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PMID:Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma. 1644 50

Treatment of malignant glioma requires a multidisciplinary team. Treatment includes surgery, radiotherapy, and chemotherapy. Recently developed agents have demonstrated activity against recurrent malignant glioma and efficacy if given concurrently with radiotherapy in the upfront setting. Oligodendroglioma with 1p/19q deletions has been recognized as a distinct pathologic entity with particular sensitivity to radiotherapy and chemotherapy. Randomized trials have shown that early neoadjuvant or adjuvant administration of procarbazine, lomustine, and vincristine chemotherapy prolongs disease-free survival; however, it has no impact on overall survival. Temozolomide, a novel alkylating agent, has shown modest activity against recurrent glioma. In combination with radiotherapy in newly diagnosed patients with glioblastoma, temozolomide significantly prolongs survival. Molecular studies have demonstrated that the benefit is mainly observed in patients whose tumors have a methylated methylguanine methyltransferase gene promoter and are thus unable to repair some of the chemotherapy-induced DNA damage. For lower-grade glioma, the use of chemotherapy remains limited to recurrent disease, and first-line administration is the subject of ongoing clinical trials. Irinotecan and agents like gefitinib, erlotinib, and imatinib targeting the epidermal growth factor receptor and platelet-derived growth factor receptor have shown some promise in recurrent malignant glioma. This review summarizes recent developments, focusing on the clinical management of patients in daily neuro-oncology practice.
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PMID:Changing paradigms--an update on the multidisciplinary management of malignant glioma. 1647 37

Despite recent successes in the treatment of cancer with multidisciplinary multimodal treatment approaches, the duration of survival for patients with malignant glioma remains limited. Malignant gliomas represent a class of infiltrative, aggressive neoplasms that are generally resistant to combination therapies. The basic approach to treatment has involved a combination of surgery and radiotherapy. The use of chemotherapy has been met with skepticism because of its limited efficacy and the significant side effects demonstrated in clinical trials. Nevertheless, based on findings in randomized trials of new agents, it has been suggested that further evaluation of the role of chemotherapy is warranted. Temozolomide and Gliadel (carmustine wafers) are generally well tolerated due to their limited systemic toxicity. These agents appear particularly well suited for incorporation into multimodal treatment strategies. Proposed investigations and ongoing clinical trials will be conducted to assess the use of these agents in novel combination therapies. Future treatment strategies may include a wide variety of biological response modifiers, but will need to continue to address local control with surgery, radiation, and adjuvant chemotherapy.
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PMID:Management of malignant glioma: steady progress with multimodal approaches. 1670 34

Glioblastoma is a highly angiogenic tumor with a dismal prognosis. Temozolomide (TMZ), a methylating agent is one of the most effective chemotherapeutic agents against glioblastoma. To overcome the problem that most of these tumors become resistant to chemotherapeutic regimens within a year, we investigated the antitumor efficacy of metronomic administration of low-dose TMZ in in vitro cell proliferation/cytotoxicity assay and in vivo rat and nude mouse orthotopic glioma model. By in vitro assay, we elucidated that C6/LacZ rat glioma cells were more resistant to metronomic treatment of TMZ than U-87MG human glioblastoma cells and bEnd.3 mouse brain endothelial cells. Compared with the conventional chemotherapeutic regimen of TMZ, we found that frequent administration of TMZ at a low dose (metronomic treatment) markedly inhibited angiogenesis as well as tumor growth in a TMZ-resistant C6/LacZ rat glioma model. In addition, metronomic treatment of TMZ significantly augmented apoptosis of tumor cells in this model. For the TMZ-sensitive U-87MG cells, even with a very low dose of TMZ, which is not effective to reduce tumor mass, the metronomic treatment of TMZ reduced the microvessel density, i.e. angiogenesis, in a nude mouse orthotopic model. In conclusion, for both models, the metronomic treatment of TMZ decreased angiogenesis. Especially, in TMZ-resistant glioma cells, this regimen increased apoptosis of tumor cells and decreased tumor growth. The metronomic treatment of TMZ in orthotopic glioma models demonstrated a successful antiangiogenic effect which can overcome the chemoresistance in conventional TMZ chemotherapy.
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PMID:Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas. 1678 20

Previously we defined a pathway of transforming growth factor beta (TGF-beta) and stromal cell-derived factor-1/CXC chemokine ligand 12 (SDF-1alpha/CXCL12) dependent migration of adult haematopoietic stem and progenitor cells (HPC) towards glioma cells in vitro and their homing to experimental gliomas in vivo. Hypoxia is a critical aspect of the microenvironment of gliomas and irradiation is an essential part of the standard therapy. To evaluate the therapeutic potential of HPC as vectors for a cell-based therapy of gliomas, we investigated the impact of hypoxia and irradiation on the attraction of HPC by glioma cells. Temozolomide (TMZ) treatment and hyperthermia served as controls. Supernatants of irradiated or hypoxic LNT-229 glioma cells promote HPC migration in vitro. Reporter assays reveal that the CXCL12 promoter activity is enhanced in LNT-229 cells at 24 h after irradiation at 8 Gy or after exposure to 1% oxygen for 12 h. The irradiation- and hypoxia-induced release of CXCL12 depends on hypoxia inducible factor-1 alpha (HIF-1alpha), but not on p53. Induction of transcriptional activity of HIF-1alpha by hypoxia or irradiation requires an intact TGF-beta signalling cascade. This delineates a novel stress signalling cascade in glioma cells involving TGF-beta, HIF-1alpha and CXCL12. Stress stimuli can be irradiation, hypoxia or TMZ, but not hyperthermia. Cerebral irradiation of nude mice at 21 days after intracerebral implantation of LNT-229 glioma induces tumour satellite formation and enhances the glioma tropism of HPC to the tumour bulk and even to these satellites in vivo. These data suggest that the use of HPC as cellular vectors in the treatment of glioblastoma may well be combined with irradiation or other anti-angiogenic therapies that induce tumour hypoxia.
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PMID:Irradiation and hypoxia promote homing of haematopoietic progenitor cells towards gliomas by TGF-beta-dependent HIF-1alpha-mediated induction of CXCL12. 1683 50


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