Hydroxyurea Accelerates the Loss of Epidermal Growth Factor? Receptor Genes Amplified As Double-minute Chromosomes in Human Glioblastoma Multiforme

Canute, Gregory W.; Longo, John A.; Winfield, Jeffrey A.; Nevaldine, Barbara; Hahn, Peter

doi:10.1097/00006123-199611000-00019

Cited by 18 publications

(16 citation statements)

References 29 publications

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“…[12][13][14][15][16]32,33 In NB, MYCN amplification is associated with increased growth potential and tumorigenicity whereas down-regulation of MYCN expression correlates with decreased proliferation and differentiation induction. 34 Moreover, MNA late-stage tumors very often are refractory to chemotherapy, at least in part because the MYCN oncogene up-regulates expression of the MRP and MDR1 multidrug resistance genes in neuroblasts.…”

Section: Discussionmentioning

confidence: 99%

“…Agents such as hydroxyurea, to which MDR1 over-expressing cells exhibit little or no cross resistance, have been shown to promote elimination of extrachromosomally amplified MYCN gene from tumor cells. 32,33 Inclusion of such drugs in conventional regimens constitutes an as yet unexplored therapeutic option specifically targeting aggressive cancer cells in the 30% of tumors with MYCN oncogene amplification. …”

Section: Discussionmentioning

confidence: 99%

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In Vivo Elimination of Acentric Double Minutes Containing Amplified MYCN from Neuroblastoma Tumor Cells Through the Formation of Micronuclei

Valent¹,

Bénard²,

Clausse³

et al. 2001

The American Journal of Pathology

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Neuroblastoma (NB), a sympathetic nervous system-derived tumor, is the second most frequent solid tumor of early childhood. This tumor shows a wide spectrum of clinical behaviors, from spontaneous regression of even widespread tumors to rapidly progressing, metastatic disease resistant to intensive chemo-and radiotherapy.1,2 There have been several parameters proposed to refine diagnosis and to predict biological behavior. In addition to stage, patient age, and histology, important prognostic indicators include ploidy, MYCN amplification (MNA), 1p deletion, 17q overrepresentation and alteration in neurotrophin receptor gene expression. [3][4][5][6][7] In localized and stage IVS NB, amplification of the MYCN proto-oncogene is a highly significant marker for a poor prognosis independent of other biological or clinical parameters and the risk of treatment failure in patients whose tumors display MNA is still very high. 8,9 Experiments with animal models as well as clinical observations have confirmed that MNA clearly contributes to the malignant phenotype of this disease. 10,11The MYCN oncogene is amplified in ϳ30% of advanced stage tumors as well as in most cell lines, typically derived from advanced stage tumors. As shown previously in vitro, extrachromosomal amplified genes in acentric double-minutes chromosomes (dmin) can be expelled from the nucleus and lost from the cell. Loss of amplified sequences is correlated with a loss of malignant properties and cellular differentiation.12-16 Expelled material is seen as micronuclei, small nuclear-like structures. Micronuclei can arise from the nucleus by budding during S phase 17 or after mitosis as the nuclear membrane reforms. They can contain not only amplified oncogenes but also acentric chromosome fragments or whole damaged chromosomes. 18,19 In this study we assayed 46 NB tumors for MNA, 1p, and 17q status. We found 11 tumors with MNA and in at least 8 of the 11 we observed micronuclei comprising amplified MYCN sequences. Our work is the second report of spontaneous elimination of amplified genes occurring in vivo from NB cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

In Vivo Elimination of Acentric Double Minutes Containing Amplified MYCN from Neuroblastoma Tumor Cells Through the Formation of Micronuclei

Valent¹,

Bénard²,

Clausse³

et al. 2001

The American Journal of Pathology

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“…The accelerated expulsion of extrachromosomally amplified genes by HU has been shown by a number of other authors (Snapka and Varshavsky, 1983;Von Hoff et al, 1991;Christen et al, 1992;Canute et al, 1996). Although the molecular mechanism is only partially understood, it has been shown that HU stimulates the formation of micronuclei.…”

Section: Hu Effects On Mycn Amplified Neuroblastoma Cellsmentioning

confidence: 91%

“…Expulsion of amplified genes has been shown to be accelerated in several tumor cell lines by low concentrations of hydroxyurea (HU) (Snapka and Varshavsky, 1983;Von Hoff et al, 1991;Christen et al, 1992;Canute et al, 1996) and it has been shown that the elimination of extrachromosomally amplified MYC genes from human tumor cells reduces their tumorigenicity (Von Hoff et al, 1992). Recent work has revealed that cancer cells are also capable of undergoing replicative senescence via telomere shortening as well as of entering a senescence-like state by activation of cell cycle inhibitory pathways (Hwang, 2002).…”

Section: Introductionmentioning

confidence: 99%

Induction of senescence in MYCN amplified neuroblastoma cell lines by hydroxyurea

Narath

Ambros

Kowalska

et al. 2006

Genes Chromosomes & Cancer

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Recently, it was shown that MYCN amplified cells spontaneously expulse extrachromosomally amplified gene copies by micronuclei formation. Furthermore, it was shown that these cells lose their malignant phenotype and start to age. We tested whether it is possible to encourage neuroblastoma tumor cells to enter the senescence pathway by low concentrations of the micronuclei-inducing drug hydroxyurea (HU). We studied the effect of HU on 12 neuroblastoma cell lines with extra- or intrachromosomally amplified MYCN copies and without amplification. Two extrachromosomally amplified neuroblastoma cell lines (with double minutes) were investigated in detail. Already after 3 weeks of HU treatment, the BrdU uptake dropped to 25% of the starting cells. After 4 weeks, enlarged and flattened cells (F-cells) and increased granularity in the majority of cells were observed. A drastic reduction of the MYCN copy number-down to one copy per cell-associated with CD44 and MHCI upregulation in up to 100% of the HU treated neuroblastoma cells was found after 5-8 weeks. Telomere length was reduced to half the length within 8 weeks of HU treatment, and telomerase activity was not detectable at this time, while being strongly expressed at the beginning. All these features and the expression of senescence-associated-beta-galactosidase (SA-beta-GAL) in up to 100% of the cells support the hypothesis that these cells entered the senescence pathway. Thus, low-dose HU is a potent senescence elicitor for tumor cells with gene amplification, possibly representing an attractive additional strategy for treatment of this subset of tumors.

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“…Such drug-induced loss of amplified genes was most frequently reported for the DNA replication inhibitors such as hydroxyurea (HU) at lower concentrations (50 to 150 M ) than those that completely stopped DNA replication (1 to 2 m M ). This HU treatment resulted in a copy number decrease of the amplified DHFR in hamster CHO cells [Snapka and Varshavsky, 1983;Nevaldine et al, 1999], amplified c-myc in human colorectal carcinoma COLO 320DM cells [Von Hoff et al, 1990, 1992 or human promyelocytic leukemia HL-60 cells [Eckhardt et al, 1994] and amplified EGFR in human glioblastoma cells [Canute et al, 1996]. The HU treatment reduced the number of DMs in advanced ovarian carcinoma in vivo [Raymond et al, 2001].…”

Section: An Active Mechanism May Eliminate Amplifiedmentioning

confidence: 99%

Extrachromosomal Double Minutes and Chromosomal Homogeneously Staining Regions as Probes for Chromosome Research

Shimizu

2009

Cytogenet Genome Res

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Gene amplification in human cancer cells generates two cytogenetically identifiable structures: extrachromosomal double minutes (DMs) and the chromosomal homogeneously staining region (HSR). DMs are composed of autonomously replicating circular DNA of genomic origin, and they tell us about how the extrachromosomal elements may behave in the cells, how they were entrapped by the micronuclei and how they were eliminated from the cells. On the other hand, the episome model predicts that extrachromosomal elements excised from the chromosome arm might generate DMs, and the breakage-fusion-bridge (BFB) cycle model explains the generation of the HSR. In accordance with this, a plasmid bearing a mammalian replication initiation region (IR) and a matrix attachment region (MAR) mimics gene amplification and generates DMs and HSRs de novo. The IR/MAR gene amplification system extends our understanding on the mechanism of gene amplification and the behavior of amplified genes. Furthermore, the system may suggest the way how extrachromosomal elements in general may alter the chromosome architecture and function.

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Hydroxyurea Accelerates the Loss of Epidermal Growth Factor? Receptor Genes Amplified As Double-minute Chromosomes in Human Glioblastoma Multiforme

Abstract: These studies suggest the potential use of low-dose hydroxyurea in the treatment of GBMs.

Cited by 18 publications

References 29 publications

In Vivo Elimination of Acentric Double Minutes Containing Amplified MYCN from Neuroblastoma Tumor Cells Through the Formation of Micronuclei

In Vivo Elimination of Acentric Double Minutes Containing Amplified MYCN from Neuroblastoma Tumor Cells Through the Formation of Micronuclei

Induction of senescence in MYCN amplified neuroblastoma cell lines by hydroxyurea

Extrachromosomal Double Minutes and Chromosomal Homogeneously Staining Regions as Probes for Chromosome Research

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