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

Suramin is a novel anticancer agent that blocks the binding of growth factors, including basic fibroblast growth factor (bFGF), to their receptors. Prior studies showed human and experimental gliomas to upregulate and respond to autocrine stimulation by bFGF, the antiproliferative effects of suramin were therefore studied on glioma cell turnover in vitro and in the brain. Suramin inhibited the growth of rat (C6, 9L) and human (U-118, U-138, A-172, T98G) glioma cell lines in a dose-dependent manner. Suramin significantly reduced the bromodeoxyuridine (BUdR) labeling index of cultured glioma cells at 250 micrograms/ml, P < 0.0001. DNA flow cytometry revealed a significant decrease in the percentage of suramin-treated glioma cells in S-phase, P < 0.01. Using intracerebral rat C6 glioma model in vivo, suramin, 10-60 mg/kg, i.p., produced a dose-dependent reduction of BUdR labeling in both the glioma and endothelial cell subpopulations. Suramin, 200 mg/kg i.v., however, led to intratumoral hemorrhages that reduced survival. Electron microscopy revealed membranous inclusion bodies in the cytoplasm of C6 glioma and endothelial cells, an indication of excess glycosaminoglycans. Moreover, 46% of endothelial cells within the C6 glioma tumor treated with suramin, 60 mg/kg, i.p., developed membrane blebs. Suramin, in clinically relevant doses, significantly inhibits glioma cell growth and cytokinetics. The risk of intratumoral hemorrhage, possibly related to injury of endothelial cells or the accumulation of anticoagulant glycosaminoglycans, constitutes a major side effect and caution should be exercised in consideration of clinical application for intracerebral tumors.
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PMID:Suramin inhibits glioma cell proliferation in vitro and in the brain. 769 15

Bromodeoxyuridine (BUdR), a nonhypoxic radiosensitizing drug, is a halogenated pyrimidine analog that is incorporated into the DNA of dividing cells in a competitive process with thymidine. BUdR sensitizes cells to radiation therapy. 5-Fluorouracil (5-FU) inhibits the endogenous synthesis of thymidine, resulting in increased incorporation of the BUdR. Neurons and glial cells have a very low mitotic rate; they will not incorporate BUdR and will not be sensitized. BUdR and 5-FU are best delivered intra-arterially (IA) because of their regional advantage. We infused BUdR +/- 5-FU over 8 1/2 weeks, before and during 59.4-Gy focal conformal external beam radiation therapy, through a permanently implanted pump with a catheter placed retrograde through the external carotid artery to the carotid bifurcation. Sixty-two patients with grades III or IV glioma were entered into one of two trials, with 23 patients receiving BUdR alone and 39 patients receiving BUdR + 5-FU. The maximum tolerated dose (MTD) of BUdR alone was 400 mg/m2/d for 8 1/2 weeks. The Kaplan-Meier median survival (KMS) was 20 months. In the BUdR + 5-FU trial, the MTD of BUdR was also 400 mg/m2/d and 5-FU was 5 mg/m2/d with a KMS of 17 months. The KMS of all 62 patients in both trials 1 and 2 was 18 months. Pathologic grading used both the original World Health Organization (WHO) and 1993 modified WHO systems. The KMS of grade IV patients was 13.8 months (48 patients) with the original system and 17 months (58 patients) with the modified system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Radiosensitization with carotid intra-arterial bromodeoxyuridine +/- 5-fluorouracil biomodulation for malignant gliomas. 793 3

Astrocytomas are the most common primary gliomas, with the highly anaplastic glioblastoma multiforme being the most frequently occurring astrocytoma. Distinctive histological features permit astrocytomas to be graded into levels of anaplasia, and these histological grades correlate with biological behavior and patient prognosis. However, there is also a strong correlation between patient age, tumor grade, and prognosis. More objective indicators of tumor proliferative potential, such as BUdR or Ki-67 LI, are currently being investigated with the hope that these will be a more accurate means of predicting patient survival. Oligodendrogliomas are a much less common primary glioma, with a generally better survival rate than astrocytomas. However, grading systems for oligodendrogliomas are not well defined. For any type of glioma, subsequent surgery after radiation therapy may be required for treatment of therapeutic effects or for therapy planning at recurrence. The histological changes observed in these post-therapy biopsy specimens or resections may be difficult to distinguish from reactive changes that can simulate recurrent tumor and vice versa.
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PMID:Neuropathology of malignant gliomas. 815 59

We performed 201Tl SPECT and cell kinetic studies on 28 presurgical patients with supratentorial gliomas by administering bromodeoxyuridine (BUdR). All patients had surgery and had follow-up for more than 25 mo. In patients with grade IV glioma (198.1% +/- 32.8%, n = 10), the 201Tl index, expressed as the count rate of the tumor site to the count rate over the contralateral normal region, was significantly higher than that in patients with grade III glioma (140.5% +/- 15.1%, n = 4, p < 0.01) or low-grade glioma (104.1% +/- 22.6%, n = 14, p < 0.001). A significant correlation was observed between the 201Tl index and BUdR-positive cells in excised tumor specimens (r = 0.67, p < 0.001). The 201Tl index of the 12 patients who died was higher than those who survived (173.2% versus 122.4%, p < 0.01). These results show the clinical utility of 201Tl brain SPECT in imaging supratentorial glioma and that the 201Tl index is representative of proliferative activity of the tumor.
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PMID:Clinical evaluation of thallium-201 SPECT in supratentorial gliomas: relationship to histologic grade, prognosis and proliferative activities. 825 92

The growth potential of 174 intracranial gliomas was estimated by calculating the bromodeoxyuridine labeling index (BUdR LI). Each patient received a 30-min infusion of BUdR, 200 mg/m2, before tumor removal. Excised tumor specimens were stained immunohistochemically to determine the BUdR LI, or percentage of S-phase cells. A Cox proportional-hazards stepwise model was used to determine the correlation between the BUdR LI and survival. Among patients with glioblastomas, the BUdR LI did not improve the prediction once age was entered in the model. Among patients with malignant or low-grade astrocytomas, the BUdR LI was the best single predictor of survival. The relative predictive abilities of BUdR LI and histopathology were determined by analyzing malignant astrocytoma and glioblastomas together. Distinguishing between malignant astrocytomas and glioblastomas did not significantly improve the prediction of survival once the BUdR LI and age were entered into the model. Equations derived from the model indicate that the probability of survival is a function of age and BUdR LI in patients with glioblastoma or malignant astrocytoma, but is a function of BUdR LI alone in patients with low-grade astrocytoma. The equations also show a substantial difference in the impact of increased BUdR LI on survival among patients with glioblastoma or malignant astrocytoma and those with low-grade astrocytoma. Without highly effective treatments for specific tumor phenotypes, the survival of a patient with an intracranial glioma appears to depend strongly on the proliferative potential of the tumor. Thus, accurate estimates of the proliferative potential are important in predicting the survival of individual patients with gliomas as well as in evaluating the effectiveness of various types of treatment.
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PMID:Prognostic significance of the proliferative potential of intracranial gliomas measured by bromodeoxyuridine labeling. 838 91

We estimated the volume doubling time (Vd) of the ethyl-nitrosourea-induced rat glioma by serial magnetic resonance imaging, and the results were compared with potential doubling time (Tp) determined immunohistochemically. Vd ranged from 3.3 to 29.2 days (11.3 +/- 7.74) and Tp ranged from 2.3 to 13.3 days (6.81 +/- 3.33). Each tumour showed a wide range of bromodeoxyuridine (BUdR) labelling indices (LI), however, Vd and Tp correlated well with BUdR-LI. Vd was estimated as 17.6 x BUdR-LI-0.63 (R = -0.76, P < 0.001, n = 13) and Tp was estimated as 22.6 x BUdR-LI-1.02 (R = -0.92, P < 0.0001, n = 12). In addition, we compared the apoptotic indices (AI), determined by terminal deoxynucleotidyltransferase (Tdt)-mediated biotinylated dUTP-biotin nick-end labelling (TUNEL) techniques, with BUdR-LI and mitoses indices (MI). The results were: AI = 0.23 + 0.25Ln(BUdR-LI) (R = 0.971, n = 8, P < 0.0001) and AI = 1.05 + 0.29Ln(MI) (R = 0.937, n = 8, P < 0.001). Cell loss factors (CLF) also correlated well with BUdR-LI and MI. However, CLF calculated from Tp and Vd were lower than the values previously presumed, probably because of shorter Vd than true doubling time for tumour cell population. These results suggest that even malignant tumours retain a mechanism of adjusting their growth at least partly.
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PMID:Estimation of volume doubling time and cell loss in an experimental rat glioma model in vivo. 975 30

5-Bromo-2'-deoxyuridine (BrdUrd) was found to increase the cytotoxicity induced by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and cisplatin in human glioma cells. At a fixed concentration of BrdUrd and BCNU, the greatest cell loss was observed in exponentially growing cells. As cells approached plateau growth, cytotoxicity was reduced as indicated by greater cell viability. Under varying growth conditions the percentage of thymine replacement by bromouracil in DNA, as determined by gas chromatography/mass spectrometry analysis, declined as cultures approached maximum density. These data indicate BrdUrd must be incorporated into DNA for the enhanced effect to be observed. In exponentially growing cells, sensitization was dependent upon both the concentration of BrdUrd and alkylating agent. Using regression analysis (at 95% CL), a relationship between the level of bromouracil in DNA and the extent of enhanced cytotoxicity was observed at two concentrations of BCNU (r2 = 0.99, 0.96). Although it is known that bifunctional alkylating agents exert cytotoxicity by forming cross-links between cDNA strands, increased cross-link formation was not observed in BrdUrd substituted DNA as determined by alkaline elution. The data suggest that DNA damage induced by halogenated pyrimidines may not involve interstrand cross-links and that these agents may be useful in the treatment of glioma in combination with alkylating agents.
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PMID:Sensitization of 1,3-bis(2-chloroethyl)-1-nitrosourea and cisplatin cytotoxicity by 5-bromo-2'-deoxyuridine in human glioma. 1033 33

The thymidine analog bromodeoxyuridine (BrdU) is incorporated into newly synthesized DNA and has been shown to increase the susceptibility of incorporating cells to ionizing radiation. However, in the absence of secondary stressors, BrdU is thought to substitute relatively benignly for thymidine and is commonly used to "birth-date" proliferative cells. We report a novel antiproliferative effect of BrdU on cancer cells, which is independent of its role in radiosensitization. A single, brief in vitro exposure to BrdU induces a profound and sustained reduction in the proliferation rate of all cancer cells examined. Cells do not die but variably up-regulate some senescence-associated proteins as they accumulate in the G1 phase of the cell cycle. Bromodeoxyuridine also impairs the proliferative capacity of primary tumor-initiating human glioma cells and may therefore represent a means of targeting cancer stem cells. Finally, conservative in vivo BrdU regimens--in the absence of any other treatment--significantly suppress the progression of gliomas in the highly aggressive, syngeneic RG2 model. These results suggest that BrdU may have an important role as an adjunctive therapeutic for a wide variety of cancers based on new insights into its effect as a negative regulator of cell cycle progression.
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PMID:Bromodeoxyuridine inhibits cancer cell proliferation in vitro and in vivo. 1868 Aug 82

A disintegrin and metalloproteinase-17 (ADAM17) is involved in proteolytic ectodomain shedding of several membrane-bound growth factors and cytokines. The expression and activity of ADAM17 increase under some pathological conditions such as stroke and glioma. ADAM17 promotes neural progenitor cell migration and contributes to stroke-induced neurogenesis after stroke and brain tumor growth and invasion. In the present study, we sought to elucidate whether ADAM17 contributes to breast cancer progression and its mechanisms. To this end, we examined the role of ADAM17 in the proliferation, invasion and tube formation of MDA-MB-231 breast cancer cells in vitro. Stable transfection of the MDA-MB-231 cell line with either a plasmid for overexpression of human ADAM17, or a siRNA to ADAM17 was employed in this study to establish high or low ADAM17 expression in breast cancer cells, respectively. For study of mechanism, the ADAM17 inhibitor TAPI-2 and the PI3K-AKT inhibitor LY294002 were used to counteract high ADAM17 expression or the activated PI3K-AKT pathway. Proliferation of MDA-MB-231 breast cancer cells were tested by MTT, Bromodeoxyuridine incorporation assay, growth curve and sulforhodamine B assay. Matrigel invasion assays were used to assess the ability of MDA-MB-231 cells to penetrate the Extra Cellular Matrix. A Matrigel tube formation assay was performed to test capillary tube formation ability. EGFR-PI3K-Akt pathway activation in MDA-MB-231 cells under different ADAM17 expression levels were tested by western blot and ELISA. Our data show that ADAM17 promotes the MDA-MB-231 malignant phenotype by increased proliferation, invasion and angiogenesis. TGFalpha, VEGF secretion and VEGF expression was increasing by ADAM17 and counteracted by ADAM17 siRNA, TAPI-2 and LY294002 in MDA-MB-231 cells. ADAM17 activated, whereas ADAM17 siRNA, TAPI-2 and LY294002 deactivated the EGFR-PI3K-AKT signal pathway, which correlated with MDA-MB-231 cell malignant phenotype changes. This study suggests ADAM17 contributes to breast cancer progression through activation of the EGFR-PI3K-AKT signal pathway.
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PMID:ADAM17 promotes breast cancer cell malignant phenotype through EGFR-PI3K-AKT activation. 1943 Feb 1


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