The Hydroxyurea-induced Loss of Double-Minute Chromosomes Containing Amplified Epidermal Growth Factor Receptor Genes Reduces the Tumorigenicity and Growth of Human Glioblastoma Multiforme

Canute, Gregory W.; Longo, Sharon L.; Longo, John A.; Shetler, Michele; Coyle, Thomas; Winfield, Jeffrey A.; Hahn, Peter

doi:10.1097/00006123-199803000-00031

Cited by 29 publications

(20 citation statements)

References 29 publications

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“…The dmin are acentric, atelomeric autonomously replicating chromatin structures composed of circular DNA of a few megabases in size. Previously, we and others found that a decrease in the copy number of amplified protooncogenes leads to the loss of malignant phenotypes, or to apoptotic death or cellular differentiation, as has been shown for human promyelocytic leukemia (Eckhardt et al, 1994;Shimizu et al, 1994), colon cancer (Von Hoff et al, 1992), neuroblastoma (Ambros et al, 1997), and glioblastoma (Canute et al, 1998) cell lines. Amplified genes may be eliminated when they are localized on extrachromosomal dmin.…”

Section: Introductionsupporting

confidence: 62%

Nonselective DNA damage induced by a replication inhibitor results in the selective elimination of extrachromosomal double minutes from human cancer cells

Shimizu

Misaka

Utani

2007

Genes Chromosomes & Cancer

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Gene amplification plays a pivotal role in human malignancy. Highly amplified genes frequently localize to extrachromosomal double minutes (dmin), which usually segregate to daughter cells in association with mitotic chromosomes. We and others had shown that treatment with low-dose hydroxyurea (HU) results in the elimination of dmin and reversion of the cancer cell phenotype. HU treatment in early S-phase, when dmin are replicated, results in their detachment from chromosomes at the next M-phase, leading to the appearance of micronuclei enriched in dmin, followed by their elimination. In this article, we examined the effect of low-dose HU on the behavior of dmin in relation to DNA damage induction by simultaneously monitoring LacO-tagged dmin and phosphorylated histone H2AX (gammaH2AX). As expected, treatment with low-dose HU induced numerous gammaH2AX foci throughout the nucleus in early S-phase, and these rarely coincided with dmin. Most chromosomal gammaH2AX foci disappeared by metaphase, whereas, unexpectedly, those that persisted frequently associated with dmin. We found that these dmin aggregated, detached from anaphase chromosomes, and apparently formed micronuclei. Because gammaH2AX foci likely represent DNA double strand breaks (DSBs), the response to DSBs sustained by extrachromosomal dmin appears to be different from that sustained by chromosomal loci, which may explain why DSB-inducing agents cause the selective elimination of dmin.

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Section: Introductionsupporting

confidence: 62%

Nonselective DNA damage induced by a replication inhibitor results in the selective elimination of extrachromosomal double minutes from human cancer cells

Shimizu

Misaka

Utani

2007

Genes Chromosomes & Cancer

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“…Because gene amplification is responsible for the malignant transformation of certain cancer cells, a decrease in the copy number of amplified genes results in the reversion of tumor cell phenotypes [Von Hoff et al, 1992], the arrest of cell growth [Shimizu et al, 1994], the expression of differentiation markers [Shimizu et al, 1994;Eckhardt et al, 1994] or apoptotic cell death [Von Hoff et al, 1992]. This argument was made using human colorectal carcinoma COLO 320DM cells with amplified c-myc [Von Hoff et al, 1992], human promyelocytic leukemia HL-60 cells with amplified c-myc [Shimizu et al, 1994;Eckhardt et al, 1994], neuroblastoma cells with amplified N-myc [Ambros et al, 1997] and glioblastoma cells with amplified epidermal growth factor receptor genes (EGFR) [Canute et al, 1998]. Therefore, if we may artificially reduce the number of amplified genes, we may cure many cancers [Snapka, 1992;Van den Berg and Von Hoff, 1995;Stewart et al, 1996].…”

Section: Loss Of Amplified Genes From Cancer Cells Results In Reversimentioning

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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“…The feasibility of such approach was ®rst demonstrated by in vitro studies showing that DM loss from tumor cells is greatly accelerated by low concentration of hydroxyurea [Snapka and Varshavsky, 1983]. Other studies showed that treating DM-containing cells with hydroxyurea resulted in decreased plating ef®ciency in soft agar and reduced tumorigenicity in mouse xenograft models [Von Hoff et al, 1992;Canute et al, 1998]. The concentration of hydroxyurea required to accelerate DM loss (50100 mM) is at least an order of magnitude lower than its cytotoxic concentration.…”

Section: Dm Behavior In Interphase Nucleimentioning

confidence: 99%

The dynamics of acentric chromosomes in cancer cells revealed by GFP-based chromosome labeling strategies

Kanda

Wahl

2000

J. Cell. Biochem.

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Autonomous replicons, such as viral episomes and oncogene containing double minute chromosomes (DMs), lack centromeres and consequently should be lost rapidly when the nuclear membrane breaks down at mitosis. Surprisingly, they are not. This raises the important question of the mechanisms that enable their ef®cient transmission to daughter cells. We review recent developments in GFP-based chromosome labeling strategies that enable real time analyses using high resolution light microscopy to provide insights into this issue. The results reveal that episomes and DMs both adhere to host chromosomes, a process referred to as``chromosome tethering''. Such association enables acentric molecules to use the chromosomal centromere in trans, thereby achieving ef®cient transmission to daughter cells. This unique mechanism of mitotic segregation also raises the possibility of developing a new class of anti-cancer drugs that work by selectively eliminating growth enhancing genes from cancer cells.

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The Hydroxyurea-induced Loss of Double-Minute Chromosomes Containing Amplified Epidermal Growth Factor Receptor Genes Reduces the Tumorigenicity and Growth of Human Glioblastoma Multiforme

Cited by 29 publications

References 29 publications

Nonselective DNA damage induced by a replication inhibitor results in the selective elimination of extrachromosomal double minutes from human cancer cells

Nonselective DNA damage induced by a replication inhibitor results in the selective elimination of extrachromosomal double minutes from human cancer cells

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

The dynamics of acentric chromosomes in cancer cells revealed by GFP-based chromosome labeling strategies

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