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)

We have previously shown that O6-benzylguanine can be used to deplete cells of the DNA repair protein O6-alkylguanine-DNA alkyltransferase and to enhance the sensitivity of human glioma (SF767) and colon tumor (HT29) cells to the cytotoxic effects of alkylnitrosoureas. In the present study, the combination of O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) was evaluated in vitro to determine the number of DNA interstrand cross-links formed and in vivo to compare the therapeutic index with that of BCNU alone. The number of DNA interstrand cross-links, as measured by alkaline elution, was increased in HT29 cells treated with 10 microM O6-benzylguanine for 2 h prior to BCNU exposure compared to cells treated with BCNU only. The number of single strand breaks was not increased by prior exposure to O6-benzylguanine. To evaluate the therapeutic index, HT29 and SF767 cells were grown as xenografts in nude mice and the tumor growth rate after treatment with BCNU alone was compared with the rate after treatment with O6-benzylguanine and BCNU. Treatment was administered i.p. when tumors reached 100-200 mm3. For animals bearing HT29 xenografts that were treated with 60 mg/kg O6-benzylguanine 1 h prior to 20 mg/kg BCNU, the average time for tumor volume to increase by 200% was 25 days, compared to 10 days for animals treated with 20 mg/kg BCNU alone. For animals bearing SF767 xenografts, the tumor growth of controls was not significantly different from that of animals treated with O6-benzylguanine alone or BCNU alone up to the maximally tolerated dose (50 mg/kg). For these 3 groups, the average time for tumors to reach 300 mm3 was 9-12 days. However, when animals were treated with 80 mg/kg O6-benzylguanine 1 h prior to receiving 20 mg/kg BCNU tumor size did not increase for at least 21 days. Our studies demonstrate that the therapeutic index of BCNU can be increased when given in combination with O6-benzylguanine.
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PMID:Effect of O6-benzylguanine on the sensitivity of human tumor xenografts to 1,3-bis(2-chloroethyl)-1-nitrosourea and on DNA interstrand cross-link formation. 173 76

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) has been implicated in resistance of human brain tumors to alkylating agents. We observed that 14 human medulloblastoma- and glioma-derived cell lines differ in sensitivity to the methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), as shown by their 28-fold range in 10% survival dose (LD10). By using the substrate analogue inhibitor O6-benzylguanine (O6-BG), we showed that the contribution of MGMT to resistance varies widely, as evidenced by 3- to 30-fold reductions in LD10 among the lines, and varies up to 20-fold among subpopulations of individual lines. Importantly, variability in resistance, manifested as a 20-fold range in LD10, persists after measurable MGMT is eliminated, disclosing differential contributions of other resistance mechanisms to survival. Cells exposed to MNNG while suspended in growth medium are more resistant than cells alkylated as subconfluent monolayers, and MGMT accounts for a smaller proportion of their resistance. Notably, the MGMT content of the lines is not statistically correlated with MNNG resistance or with potentiation of killing by O6-BG, even though MGMT is a biochemically demonstrated determinant of resistance. In contrast, the same lines vary less in resistance to the ethylating agent N-ethylnitrosourea (ENU), and MGMT makes only a small contribution to resistance. Our results strongly indicate that resistance to both MNNG and ENU is multifactorial.
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PMID:Contribution of O6-methylguanine-DNA methyltransferase to monofunctional alkylating-agent resistance in human brain tumor-derived cell lines. 760 82

To assess the possible role of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) in resistance of brain neoplasms to the clinically important chloroethylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), we quantitated MGMT activity, BCNU survival, and the effect of ablating MGMT activity on the sensitivity of 14 human medulloblastoma- and glioma-derived cell lines. BCNU resistance, measured as 10% survival dose (LD10), differed eightfold among the lines. Elimination of measurable MGMT activity with the substrate analogue inhibitor O6-benzylguanine (O6-BG) revealed a variable but limited contribution of MGMT to survival. In no case did O6-BG reduce LD10 by more than 3.4-fold. In contrast, O6-BG reduced the LD10 for N-methyl-N'-nitro-N-nitrosoguanidine up to 31-fold in the same cell lines (Bobola MS, Blank A, Berger MS, Silber JR, Mol Carcinog 13:70-80, 1995). Variability in BCNU survival, manifested as a sevenfold range of LD10, persists after measurable MGMT was eliminated, indicating that another mechanism or mechanisms is operating to limit cytotoxicity. Cells alkylated while suspended in growth medium are more resistant to BCNU and display less dependence on MGMT than cells treated while proliferating on a plastic substratum. When alkylated in suspension, most of the lines are either unresponsive to O6-BG or contain a subpopulation that did not respond to O6-BG. Our results demonstrate that BCNU resistance is multifactorial and that MGMT makes a modest contribution to resistance in our lines.
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PMID:Contribution of O6-methylguanine-DNA methyltransferase to resistance to 1,3-(2-chloroethyl)-1-nitrosourea in human brain tumor-derived cell lines. 760 83

Activity of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) is an important determinant of responsiveness of tumor cells to chloroethylnitrosoureas (CENUs), representative chemotherapeutic agents for primary malignant gliomas. In order to assess the real states of this repair protein in human malignant gliomas, we assayed AGT activity in surgically extirpated 42 malignant glioma samples and studied the distribution of the activity under certain clinical conditions. There were wide variations in AGT activity between individuals. No significant difference in AGT activity on average was seen either between glioblastoma and anaplastic astrocytoma, nor between primary and recurrent tumors. Among 42 malignant gliomas, 7 samples (16.7%) had low AGT activity less than 0.1 pmoles/mg protein. In the case of glioblastoma, tumors possessing higher AGT activity tended to be less responsive to post-operation remission-induction therapy including CENUs. The result of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) chemosensitivity assay by using the corresponding surgical specimens suggested a close relationship between cellular resistance to CENUs and AGT activity. It was found to be unlikely that a short term administration of CENUs had a significant effect on AGT activity of brain tumors in human body. We could detect a bit of definite evidences of the relevance of AGT to resistance to CENUs and need to conduct further investigations for other resistance factors.
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PMID:O6-alkylguanine-DNA alkyltransferase activity of human malignant glioma and its clinical implications. 786 Nov 89

Temozolomide (8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4-(3H)-one) has shown promising activity in Phase I trials against some brain (glioma) and skin (melanoma, mycosis fungoides) cancers. Temozolomide and lomustine (CCNU) showed parallel toxicity in seven human tumour cell lines and this generally correlated (correlation coefficients 0.87 and 0.92 respectively) with the level of expression of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase, EC 2.1.1.63). Pretreating cells with the ATase inhibitor, O6-benzylguanine (BG), potentiated cytotoxicity to a similar degree with both drugs, but did not sensitise a cell line (ZR-75-1) expressing very low levels of this protein. When BG pretreatment was combined with repeat doses of temozolomide a dramatic potentiation (300 fold) was seen in MAWI cells, which express high levels of ATase, but not in a cell line (U373) expressing lower levels of ATase. [14C]-labelled temozolomide uptake was similar in sensitive and resistant lines. Human ATase-cDNA transfected xeroderma pigmentosum (XP) fibroblasts were more resistant than XP control cells to temozolomide and the related chloroethylating agent mitozolomide and although BG completely suppressed ATase activity in these cells, resistance was still greater than in control cells.
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PMID:Depletion of O6-alkylguanine-DNA alkyltransferase correlates with potentiation of temozolomide and CCNU toxicity in human tumour cells. 851 14

The inter- and intracellular distribution of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase) may be an important factor in the sensitivity or resistance of tumours to treatment with certain alkylating agents, including the methyltriazenes and nitrosoureas. In order to examine this issue 26 human brain tumour sections (23 high grade gliomas and three low grade gliomas) were examined for ATase expression by immunohistochemistry using a rabbit anti-human ATase polyclonal antibody. Positive staining, seen as fine black granules mainly confined to the nucleus, was observed in all the glioma sections examined. There was marked cellular heterogeneity, ranging from cells completely devoid of staining to cells with very intense staining. Semi-quantitatively, in the 23 high grade gliomas examined six had 1+ staining, seven had 2+ staining and 10 had 3+ staining, whereas all three low grade gliomas had 1+ staining. These results are in contrast to published reports showing that approximately 35% of human brain tumour-derived cell lines and xenografts had very low levels of ATase activity and suggest that the complete lack of ATase is not a common occurrence in high grade glioma.
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PMID:Inter- and intracellular heterogeneity of O6-alkylguanine-DNA alkyltransferase expression in human brain tumors: possible significance in nitrosourea therapy. 862 71

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) confers resistance to therapeutic methylating and chloroethylating agents in human brain tumor-derived cell lines. In this work, we assayed MGMT activity in 152 adult gliomas to establish correlates with patient and tumor characteristics. We also assayed MGMT in histologically normal brain adjacent to 87 tumors to characterize changes in activity accompanying neurocarcinogenesis. MGMT activity was detectable in 76% (115 of 152) of tumors, ranging approximately 300-fold from 0.30 to 89 fmol/10(6) cells (180-57,000 molecules/cell). Mean activity was 6.6 +/- 13 fmol/10(6) cells and varied 4-fold among diagnostic groups. The mean for oligodendrogliomas was 2-fold lower (P < 0.03), and for mixed oligodendroglioma-astrocytomas, the mean was 4-fold lower (P < 0.006) than for astroglial tumors. Twenty-five % of gliomas had no detectable MGMT activity (Mer- phenotype; < 0.25 fmol/10(6) cells or 150 molecules/cell). Glioma MGMT was inversely correlated with age (P < 0.01), consistent with the observed age dependence in the progenitor tissue of brain tumors (J. R. Silber et al., Proc. Natl. Acad. Sci. USA, 93: 6941-6946, 1996). Neither MGMT activity nor proportion of Mer- tumors differed by sex. Glioma MGMT was correlated with degree of aneuploidy (P < 0.006) but not with fraction of S-phase cells. Mean activity in tumors was 5-fold higher than in adjacent histologically normal brain (5.0 +/- 7.6 versus 1.1 +/- 1.9 fmol/10(6) cells; P < 0.001). Notably, elevation of tumor activity was observed in 62% of tissue pairs, ranging from 2-fold to > 105-fold. Moreover, 64% of Mer- normal tissue was accompanied by Mer+ tumor. These observations indicate that expression of MGMT activity is frequently activated and/or increased during human neurocarcinogenesis, and that the enhancement is not related to proliferation per se. Significantly, enhanced MGMT activity may heighten the resistance of brain tumors to therapeutic alkylating agents.
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PMID:O6-methylguanine-DNA methyltransferase activity in adult gliomas: relation to patient and tumor characteristics. 950 Apr 73

Fotemustine is a chloroethylnitrosourea with antitumor activity in disseminated melanoma and adult primary brain tumors. Because new drugs are required for the treatment of medulloblastoma in children, we evaluated the preclinical antitumor activity of fotemustine in four s.c. medulloblastoma xenografts, in comparison with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Both drugs were administered as a single i.p. injection to nude mice bearing advanced-stage tumor. Fotemustine displayed significant antitumor activity in three of four medulloblastoma xenografts; two, IGRM34 and IGRM57, were highly sensitive, with 37 and 100% tumor-free survivors, respectively, more than 120 days after treatment at the highest nontoxic dose (50 mg/kg). Fotemustine was also highly active in a malignant glioma xenograft (IGRG88; five of six tumor-free survivors on day 177). Fotemustine proved to be significantly more active than BCNU in IGRM34 and the glioma xenograft IGRG88. The DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase) was detected in all tumor xenografts, ranging in activity from 6 to 892 fmol/mg protein. The high in vivo sensitivity to fotemustine and BCNU observed in three xenografts was clearly associated with a low ATase activity (> 20 fmol/mg), whereas the two poorly sensitive or refractory medulloblastoma xenografts showed high ATase activity (> 500 fmol/mg). Alkylpurine-DNA N-glycosylase activity was detected in all tumor xenografts but at levels ranging only from 513 to 1105 fmol/mg/h; no consistent relationship was found between alkylpurine-DNA N-glycosylase activity and the in vivo sensitivity to the two chloroethylnitrosoureas. The improved activity and tolerance of fotemustine in comparison with BCNU in pediatric medulloblastoma xenografts strongly support the clinical development of this agent in children with brain tumors, in which ATase should be examined as a potential prognostic indicator.
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PMID:Activity of fotemustine in medulloblastoma and malignant glioma xenografts in relation to O6-alkylguanine-DNA alkyltransferase and alkylpurine-DNA N-glycosylase activity. 951 37

Chloroethylnitrosoureas (CENUs) are commonly used in the treatment of pediatric and adult central nervous system (CNS) tumors. The antitumor activity of CENUs has been hypothesized to be due to an alkylation occurring at the O6-position of guanine in DNA. The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is responsible for the repair of these potentially cytotoxic lesions and may underlie tumor resistance to CENUs. The current study is the largest report of MGMT levels among newly diagnosed pediatric CNS tumors and the only study that has quantitated MGMT by both biochemical and Western immunoblot assays. Our results show a good correlation between the two methods (r = 0.66). Medulloblastoma/primitive neuroectodermal tumor and ependymoma had the highest level of MGMT, followed by high-grade glioma and low-grade glioma. These data may provide a guide to the use of CENUs in the treatment of pediatric CNS tumors.
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PMID:O6-Methylguanine-DNA methyltransferase protein levels in pediatric brain tumors. 981 47

Microsatellite instability (MSI) is a form of genomic instability in tumors that may reflect mechanisms underlying carcinogenesis. Assessment of MSI in various types of sporadic tumors is therefore relevant to an understanding of molecular pathogenesis. In the case of sporadic adult gliomas, destabilization of mononucleotide, dinucleotide, and longer repeat sequences has been reported in high-grade tumors, though published estimates of the frequency of MSI vary widely. In the present work, we quantitated the frequency of length alterations at three microsatellite loci in 26 glioma/normal tissue pairs and at nine additional loci in 16 of the pairs. We analyzed di- and tetranucleotide markers, including five previously reported to be unstable in gliomas. and examined mostly high-grade tumors, both diploid and aneuploid. A large proportion of the tumor and normal brain specimens had no detectable activity of the DNA repair protein O6-methylguanine-DNA methyltransferase, a prevalent phenotypic trait in these tissues that we thought might be associated with MSI. We observed no length alterations in 222 sequence analyses, and estimate the frequency of MSI in our tumor sample as < 0.45% unstable sequences among all sequences examined, or < 3.9% gliomas with unstable sequences. We conclude that microsatellite length alterations are infrequent in our tumor population, and interpret currently available literature to indicate that the frequency of MSI is low in sporadic adult gliomas.
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PMID:Microsatellite instability is infrequent in sporadic adult gliomas. 1010 Jul 59


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