Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Temozolomide is an alkylating agent that mediates its cytotoxic effects via O(6)-methylguanine (O(6)-meG) adducts in DNA. O(6)-alkylguanine-DNA-alkyltransferase (MGMT) can repair such adducts and therefore constitutes a major resistance mechanism to the drug. MGMT activity can be attenuated in vitro and in vivo by the pseudosubstrate O(6)-(4-bromothenyl)guanine (PaTrin-2, Patrin, Lomeguatrib), which in clinical trials is in combination with temozolomide. Resistance to cytotoxic agents can also be mediated by the Bcl-2 protein, which inhibits apoptosis and is frequently up-regulated in tumor cells. Attenuation of Bcl-2 expression can be affected by treatment of cells with the antisense oligonucleotide, oblimersen sodium (Genasense), currently in phase III clinical trials in combination with the methylating agent dacarbazine. Using a human ovarian cancer cell line (A2780) that expresses both Bcl-2 and MGMT, we show that cells treated with active dose levels of either oblimersen (but not control reverse sequence or mismatch oligonucleotides) or PaTrin-2 are substantially sensitized to temozolomide. Furthermore, the exposure of oblimersen-pretreated cells to PaTrin-2 leads to an even greater sensitization of these cells to temozolomide. Thus, growth of cells treated only with temozolomide (5 microg/mL) was 91% of control growth, whereas additional exposure to PaTrin-2 alone (10 micromol/L) or oblimersen alone (33 nmol/L) reduced this to 81% and 66%, respectively, and the combination of PaTrin-2 (10 micromol/L) and oblimersen (33 nmol/L) reduced growth to 25% of control. These results suggest that targeting both Bcl-2 with oblimersen and MGMT with PaTrin-2 would markedly enhance the antitumor activity of temozolomide and merits testing in clinical trials.
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PMID:Sensitization of a human ovarian cancer cell line to temozolomide by simultaneous attenuation of the Bcl-2 antiapoptotic protein and DNA repair by O6-alkylguanine-DNA alkyltransferase. 1548 88

The use OF chemotherapy to treat patients with brain metastases has been viewed historically with skepticism. To date, a survival benefit has not been demonstrated with the use of systemic chemotherapy in patients with brain metastases. However, the introduction of novel agents and delivery techniques warrants a reexamination of the role of systemic chemotherapy in the management of brain metastases. Temozolomide has shown encouraging results in patients with nonsmall cell lung cancer, and implanted carmustine wafers have demonstrated excellent local tumor control rates. This review discusses clinical data from the past decade with emphasis on trial design, tumor histology, available agents, and multimodality strategies. In addition, delivery techniques that circumvent the blood-brain barrier are reviewed. Although chemotherapy is usually used as a salvage therapy, it may be considered for use in selected patients with newly diagnosed brain metastases. To better evaluate chemotherapy in brain metastases, future trials should evaluate novel agents in the preirradiation setting. Enhanced regional delivery methods warrant further investigation, and Phase III trials of current regimens stratified by histology and by prognostic factors will establish the role of specific chemotherapy regimens in the treatment of patients with brain metastases.
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PMID:Chemotherapy in brain metastases. 1623 90

Treatment results of the patients with central nervous system primary tumors are unsatisfactory. Nytrosomethylureal and vincaalkaloid preparations are rather ineffective in such cases. In recent years clinicians paid great attention to a new-generation chemotherapy drug, temozolomide (temozolomide - TMZ). Temozolomide is used for the treatment of primary malignant tumors of central nervous system, as well as for brain metastatic tumors and melanoma. In the National Cancer Center from 1996 to 2005, 140 patients with central nervous system primary tumors were selected and randomized into 2 groups. In these patients complex therapy using standard schemes of chemotherapy and complex treatment with temozolomide was conducted. 88 patients entered to the control group. 52 patients of the prospective group received temozolomide. Thus, clinical analysis is based on the treatment results of 140 patients. Data obtained have shown that median survival rate of the prospective group patients receiving temozolomide is 2,23 times better in comparison to that of the control group patients. On the basis of the detailed analysis of both retrospective and prospective materials it has been shown that histological type of the tumor is of great importance for the remote treatment results. Of all malignant tumors of central nervous system temozolomide is more effective in the treatment of astrocytomas in comparison with the tumors of other histological types. The use of temozolomide in complex treatment of the patients with malignant tumors of central nervous system resulted in marked effect. Median survival of the patients is 22,35 months.
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PMID:[Temozolomide--a new antitumor preparation in the treatment of central nervous system malignant tumors]. 1678 60

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

Glioblastoma multiforme is the most common primary brain tumor in adults. Until recently, the standard of care consisted of maximal surgical resection followed by external beam radiotherapy. The role of adjuvant chemotherapy for newly diagnosed glioblastoma has been controversial; most of the numerous randomized phase III trials conducted over the past 40 years have failed to show a statistically significant and clinically meaningful survival advantage for patients randomized to the chemotherapy arm. Consequently, the choices of chemotherapeutics for patients with glioblastoma have been limited, and cytotoxic treatment regimens have usually included a nitrosourea. Temozolomide, a relatively new orally administered methylating agent, has demonstrable activity in glioma. A recent trial conducted under the auspices of the European Organization for the Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) has defined a role for temozolomide in the initial management of glioblastoma. A companion correlative tumor-biology study has identified epigenetic silencing of the promoter of the gene that encodes MGMT (O6-methylguanine-DNA methyltransferase) in tumor specimens as a strong and independent prognostic factor for survival among patients with a newly diagnosed glioblastoma, as well as a predictor of survival benefit from chemoradiotherapy with temozolomide. This review briefly summarizes the development of temozolomide as a therapy for patients with malignant brain tumors, emphasizing recent trials that have established a new standard of care for patients with glioblastoma and speculating on how these advances might influence future therapeutic investigations for malignant primary brain tumors.
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PMID:Drug Insight: temozolomide as a treatment for malignant glioma--impact of a recent trial. 1693 4

Gliomas are highly lethal neoplasms that cannot be cured by currently available therapies. Temozolomide is a recently introduced alkylating agent that has yielded a significant benefit in the treatment of high-grade gliomas. However, either de novo or acquired chemoresistance occurs frequently and has been attributed to increased levels of O6-methylguanine-DNA methyltransferase or to the loss of mismatch repair capacity. However, very few gliomas overexpress O6-methylguanine-DNA methyltransferase or are mismatch repair-deficient, suggesting that other mechanisms may be involved in the resistance to temozolomide. The purpose of the present study was to generate temozolomide-resistant variants from a human glioma cell line (SNB-19) and to use large-scale genomic and transcriptional analyses to study the molecular basis of acquired temozolomide resistance. Two independently obtained temozolomide-resistant variants exhibited no cross-resistance to other alkylating agents [1,3-bis(2-chloroethyl)-1-nitrosourea and carboplatin] and shared genetic alterations, such as loss of a 2p region and loss of amplification of chromosome 4 and 16q regions. The karyotypic alterations were compatible with clonal selection of preexistent resistant cells in the parental SNB-19 cell line. Microarray analysis showed that 78 out of 17,000 genes were differentially expressed between parental cells and both temozolomide-resistant variants. None are implicated in known resistance mechanisms, such as DNA repair, whereas interestingly, several genes involved in differentiation were down-regulated. The data suggest that the acquisition of resistance to temozolomide in this model resulted from the selection of less differentiated preexistent resistant cells in the parental tumor.
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PMID:Genetic alterations associated with acquired temozolomide resistance in SNB-19, a human glioma cell line. 1698 51

Data from a prospective trial large enough to provide a reliable analysis of outcome and prognostic factors in elderly patients with glioblastoma (GBM) are not yet available in the literature. Extensive tumor removal appears to offer patients the best possible chance of a speedy neurological recovery. Adequate radiotherapy (RT) should always be given to elderly patients if they have undergone gross total debulking and have maintained a good performance status. It is, however important to bear in mind that the risk of long-term cognitive impairment may be higher in patients on high-dose RT and that a short course of accelerated RT can achieve the same survival. Rather than being ruled out on principle, chemotherapy should be considered on the basis of an accurate assessment of the factors that might compromise the individual patient's tolerance to drugs administered. Temozolomide appears to be the best available chemotherapy in this population of patients.
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PMID:Glioblastoma in the elderly: current and future trends. 1702 78

Hyperthermic isolated limb perfusion (HILP) with L-phenylalanine mustard (L-PAM) represents an effective treatment for locally advanced melanoma of the limbs. However, regional chemotherapy of melanoma still needs to be improved. Temozolomide (TMZ) is a methylating agent that spontaneously decomposes into the active metabolite of dacarbazine, the most effective agent for the systemic treatment of melanoma. Tumor cells with high levels of O6-methylguanine-DNA methyltransferase (MGMT) and/or with a defective DNA mismatch repair (MMR) are resistant to TMZ. Inhibition of MGMT activity increases TMZ sensitivity of MMR-proficient, but not of MMR-deficient cells, while inhibition of base excision repair (BER) potentiates TMZ cytotoxicity in both cell types. Recent studies, performed in an animal model, have shown that TMZ is more effective than L-PAM when applied regionally and that hyperthermia can increase the antitumor activity of TMZ. In this study, three thermoresistant human melanoma cell lines, endowed with different MGMT activity and functional status of the MMR system, were treated with TMZ at 37 degrees C or 41.5 degrees C for 90 min, and then analyzed for cell growth and MGMT activity. Hyperthermia significantly enhanced TMZ cytotoxicity in MMR-proficient cells, either endowed or not with MGMT activity, and in MMR-deficient cells. Endogenous MGMT activity was not affected by hyperthermia that, however, enhanced the enzyme depletion induced by TMZ treatment. Moreover, MGMT recovery after drug removal was delayed in cells that had been treated at 41.5 degrees C. Taken together, these findings confirm the therapeutic potential of a combined treatment of hyperthermia and TMZ. They also suggest that inhibition of BER and/or increased DNA methylation may be involved in the thermal enhancement of TMZ cytotoxicity. Additional studies are necessary to better clarify the mechanisms underlying hyperthermia-induced potentiation of TMZ activity. However, the present investigation provides further support to the development of clinical trials of HILP with TMZ.
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PMID:Combined effect of temozolomide and hyperthermia on human melanoma cell growth and O6-methylguanine-DNA methyltransferase activity. 1720 27

An 80-year-old woman presented with primary central nervous system (CNS) lymphoma manifesting as progressive disorientation and loss of activity. She received three cycles of high-dose methotrexate. The tumor shrank after two cycles and her mental status improved, but she suffered tumor recurrence. The second-line treatment consisted of four cycles of rituximab but the tumor enlarged. She was then treated with three cycles of temozolomide. Magnetic resonance imaging revealed no evidence of disease. Her mental status and performance status improved, and she suffered no toxicity. She is able to pursue her daily life without recurrence after 16 cycles of temozolomide. Temozolomide may be effective against relapsed primary CNS lymphoma without causing neurotoxicity in the elderly.
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PMID:Complete response to temozolomide treatment in an elderly patient with recurrent primary central nervous system lymphoma--case report. 1752 51

Astroblastoma is a historically traded microscopic diagnosis to denote a rare neuroepithelial tumor of uncertain nosology, involving a distinctive pattern of pseudorosette arrangement of neoplastic cells. While displaying some glial properties, the latter shall not - by definition - be either reducible to or part of any conventional glioma type. We report on clinicopathologic correlations in a case of astroblastoma involving an extensive rhabdoid phenotype of tumor cells. The male patient was operated on at the age of 53 and 59 years for a left parietal tumor measuring 5.8 cm in diameter at the first presentation. On magnetic resonance imaging and angiography, both the primary and its recurrence were discrete, highly vascularized, and contrast-enhancing. The second surgery was complemented with radiotherapy of 66 Gy, followed by chemotherapy with Temozolomide. Twelve years into clinical history, the patient has stable minimal residual disease at the age of 65. A review of pathology samples from both surgeries showed well-differentiated astroblastoma according to current standards, with an MIB-1 labeling index of 1% and 4%, respectively. Neither of the specimens involved cellular anaplasia, overt mitotic activity, microvascular proliferation, or palisading necrosis. Most tumor cells harbored paranuclear filamentous rhabdoid inclusions that were immunostained for vimentin and, in part, also for GFAP. No polyantigenic reactivity was observed. This example contributes another facet to the spectrum of the so-called composite rhabdoid tumors. Involving a low-grade parent neoplasm, it also further substantiates the incipient perception that the rhabdoid phenotype neither is a peculiar but nonspecific convergence point of anaplastic evolution, nor are such lesions indiscriminately bound for a relentless course.
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PMID:Astroblastoma with rhabdoid features and favorable long-term outcome: report of a case with a 12-year follow-up. 1828 55


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