Chemical carcinogenesis in the nervous system: past and future

Schlegel, Jürgen; Stumm, Gabriele; Mennel, H. D.

doi:10.1016/s0940-2993(11)80504-x

Cited by 12 publications

(4 citation statements)

References 51 publications

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“…Histopathologically, these experimental rat tumors closely resemble human gliomas, but data concerning their genetic alterations are lacking [16]. Here we demonstrate homozygous deletions of the p16/Cdkn2a/Ink4a locus in four of five chemically induced rat glioma cell lines, resulting in loss of p16 and p19ARF mRNA expression in the respective cell lines.…”

Section: Methods Results and Discussionmentioning

confidence: 61%

The <i>p16/Cdkn2a/Ink4a</i> Gene Is Frequently Deleted in Nitrosourea-Induced Rat Glial Tumors

et al. 1999

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The present study investigates nitrosourea-induced rat (Rattus norvegicus) glioma cell lines for the functional status of the p16/Cdkn2a/Ink4a gene, which encodes the p16 cdk4 inhibitor and the alternative reading frame protein, p19ARF. We detected homozygous deletions of the p16/Cdkn2a/Ink4a gene locus in 4 of 5 glioma cell lines (C6, F98, RG2, and RGL.3), but not in the 9L gliosarcoma cell line or in a rat primary fibroblast cell line. RT-PCR demonstrated expression of the p16 and p19ARF mRNAs only in 9L cells and in rat fibroblasts. Comparative genomic in situ hybridization showed that the copy number of rat chromosome RNO5 was not altered in any of the glioma cell lines investigated, indicating that the deletions result from a discrete loss in the region of the p16/Cdkn2a/Ink4a locus. This is the first report of p16/Cdkn2a/Ink4a deletions present in nitrosourea-induced rat glioma cell lines. Since this genetic alteration is also commonly observed in human malignant glial tumors, our results validate the use of chemically induced rat glioma cell lines as an experimental model in the development of gene therapy strategies.

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Section: Methods Results and Discussionmentioning

confidence: 61%

The <i>p16/Cdkn2a/Ink4a</i> Gene Is Frequently Deleted in Nitrosourea-Induced Rat Glial Tumors

et al. 1999

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“…The ENU dose and gestational age were chosen to match those previously demonstrated to produce neural tumors in geneticallysusceptible experimental animals (Bilzer et al, 1989;Diwan and Meier, 1974;Schlegel et al, 1993). At this gestational age, the murine telencephalon consists predominantly of nestin immunoreactive NPCs localized in the mitotically active ventricular zone.…”

mentioning

confidence: 99%

“…(c) Immunostaining of tumor sections with antibodies to PCNA (green) and Bcl-X L (red) demonstrated colocalization of PCNA and Bcl-X L within a subpopulation of tumor cells (arrow). Scale bar=10 mm dendrogliomas, mixed glial tumors, schwannomas, meningiomas, and/or medulloblastomas depending on dose, injection schedule, age of the animal, and species susceptibility (Bilzer et al, 1989;Diwan and Meier, 1974;Druckrey et al, 1966;Schlegel et al, 1993). Single intrauterine exposure to ENU may produce central nervous system tumors in rats (Wechsler et al, 1969); however, mice are relatively insensitive to this eect (Diwan and Meier, 1974;Wechsler et al, 1979).…”

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confidence: 99%

Neural precursor cell apoptosis and glial tumorigenesis following transplacental ethyl-nitrosourea exposure

et al. 2001

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Neural precursor cells (NPCs) populate the embryonic ventricular zone and persist in the subependymal zone of the adult brain. We hypothesized that hereditary and/or acquired mutations in apoptosis-associated genes, such as p53 and caspases, may protect NPCs from DNA damage-induced death and predispose them to subsequent neoplastic transformation. To test this hypothesis, we exposed NPCs from wild-type and targeted gene-disrupted mouse embryos (p53, caspase-9, caspase-3, and bax mutants) to ethyl-nitrosourea (ENU), a known DNA mutagen and neural carcinogen, and measured NPC viability. We found that ENU produced caspase-3 activation and apoptotic NPC death 6 ± 24 h after administration both in vivo and in vitro. This eect was critically dependent on p53 and caspase-9 expression. The long-term eect of intrauterine ENU exposure was examined in control and p53-de®cient mice. High grade glial tumors were found in 60% of p53 7/7 young adult mice exposed to ENU on gestational day 12.5 but not in p53 +/7 or p53 +/+ littermates or in untreated p53-de®cient mice. All the tumors were located supratentorially and possessed strong immunoreactivity for glial ®brillary acidic protein and the anti-apoptotic molecule Bcl-X L . These results suggest that intrauterine exposure of NPCs to certain DNA damaging agents may synergistically interact with speci®c genetic abnormalities (e.g. p53 de®ciency) to produce glial neoplasms in the adult brain. Oncogene (2001) 20, 8281 ± 8286.

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“…O 6 -alkylguanines are potent mutagenic lesions that characteristically produce point mutations, as well as gross chromosomal deletions and rearrangements that are associated with tumor formation and malignant progression [9]. It has long been recognized that O 6 -methyl and O 6 -ethylguanine are strong neurocarcinogens in rodents and primates [15,16]. Human exposure to endogenous and exogenous alkylators is believed to be continuous and life-long and there is epidemiologic evidence implicating environmental alkylator exposure with increased risk for human primary brain tumors, including adult gliomas [17 and refs therein].…”

Section: Biochemical Genetic and Biological Characteristicsmentioning

confidence: 99%

O6-Methylguanine-DNA methyltransferase in glioma therapy: Promise and problems

Silber

Bobola

Blank

et al. 2012

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Gliomas are the most frequent adult primary brain tumor, and are invariably fatal. The most common diagnosis glioblastoma (GBM) afflicts 12,500 new patents in the U.S. annually, and has a median survival of approximately one year when treated with the current standard of care. Alkylating agents have long been central in the chemotherapy of GBM and other gliomas. The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), the principal human activity that removes cytotoxic O6-alkylguanine adducts from DNA, promotes resistance to anti-glioma alkylators, including temozolomide and BCNU, in GBM cell lines and xenografts. Moreover, MGMT expression assessed by immunohistochemistry, biochemical activity or promoter CpG methylation status is associated with the response of GBM to alkylator-based therapies, providing evidence that MGMT promotes clinical resistance to alkylating agents. These observations suggest a role for MGMT in directing adjuvant therapy of GBM and other gliomas. Promoter methylation status is the most clinically tractable measure of MGMT, and there is considerable enthusiasm for exploring its utility as a marker to assign therapy to individual patients. Here, we provide an overview of the biochemical, genetic and biological characteristics of MGMT as they relate to glioma therapy. We consider current methods to assess MGMT expression and discuss their utility as predictors of treatment response. Particular emphasis is given to promoter methylation status and the methodological and conceptual impediments that limit its use to direct treatment. We conclude by considering approaches that may improve the utility of MGMT methylation status in planning optimal therapies tailored to individual patients.

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Chemical carcinogenesis in the nervous system: past and future

Cited by 12 publications

References 51 publications

The <i>p16/Cdkn2a/Ink4a</i> Gene Is Frequently Deleted in Nitrosourea-Induced Rat Glial Tumors

The <i>p16/Cdkn2a/Ink4a</i> Gene Is Frequently Deleted in Nitrosourea-Induced Rat Glial Tumors

Neural precursor cell apoptosis and glial tumorigenesis following transplacental ethyl-nitrosourea exposure

O6-Methylguanine-DNA methyltransferase in glioma therapy: Promise and problems

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