Enhancement of methotrexate resistance and dihydrofolate reductase gene amplification by treatment of mouse 3T6 cells with hydroxyurea.

Brown, P. S.; Tlsty, Thea D.; Schimke, Robert T.

doi:10.1128/mcb.3.6.1097

Cited by 170 publications

(81 citation statements)

References 16 publications

(19 reference statements)

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“…Resistance to MTX is conferred on cells by a variety of mechanisms which include: alteration of MTX transport, resulting in a non-inhibitory cell concentration; mutation of the DHFR gene, resulting in a protein product with a reduced binding affinity for MTX; and overproduction of the DHFR gene product as a consequence of gene amplification (Schimke, 1984a (Brown et al, 1983) or UV irradiation (Tlsty et al, 1984) or in hamster cells transient hypoxia (Rice et al, 1986) or pretreatment with MTX itself (Tlsty et al, 1982) or AraC (Goz et al, 1989) enhanced the appearance of MTX-resistant clones in clonogenic assays. Molecular analysis of the basis for these changes showed all three mechanisms (altered transport, altered affinity and gene amplification) to be increased (Flintoff et al, 1976;Brown et al, 1983;Tlsty et al, 1984).…”

Section: Methotrexatementioning

confidence: 99%

“…Molecular analysis of the basis for these changes showed all three mechanisms (altered transport, altered affinity and gene amplification) to be increased (Flintoff et al, 1976;Brown et al, 1983;Tlsty et al, 1984). Administration of the tumour promoter TPA was shown to enhance the emergence of MTX resistance in mouse but not in hamster cells in the absence of gene amplification (Bojan et al, 1983).…”

Section: Methotrexatementioning

confidence: 99%

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Resistance to chemotherapeutic antimetabolites: a function of salvage pathway involvement and cellular response to DNA damage

Kinsella

Smith²,

Pickard³

1997

Br J Cancer

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Summary The inherent or acquired (induced) resistance of certain tumours to cytotoxic drug therapy is a major clinical problem. There are many categories of cytotoxic agent: the antimetabolites, e.g. methotrexate (MTX), N-phosphonacetyl-L-aspartate (PALA), 5-fluorouracil (5-FU), 6-mercaptopurine (6-TG), hydroxyurea (HU) and 1-pB-D-arabinofuranosylcytosine (AraC); the alkylating agents, e.g. the nitrogen mustards and nitrosoureas; the antibiotics, e.g. doxorubicin and mitomycin C; the plant alkaloids, e.g. vincristine and vinblastine; and miscellaneous compounds, such as cisplatin. There are also many mechanisms of drug resistance elucidated principally from in vitro studies. These include mutation of target genes, amplification of target and mutated genes, differences in repair capacity, altered drug transport and differences in nucleoside and nucleobase salvage pathways (Fox et al, 1991). The aim of the present review is to evaluate in detail the mechanisms of response of both normal and tumour cells to three chemotherapeutic antimetabolites, MTX, PALA and 5-FU, which are routinely used in the clinic either alone or in combination to treat some of the commonest solid tumours, e.g. breast, colon, gastric and head and neck. The normal and tumour cell response to these agents will be discussed in relation to the operation of the known alternative 'salvage pathways' of DNA synthesis and current theories of DNA damage response.

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Section: Methotrexatementioning

confidence: 99%

Section: Methotrexatementioning

confidence: 99%

Resistance to chemotherapeutic antimetabolites: a function of salvage pathway involvement and cellular response to DNA damage

Kinsella

Smith²,

Pickard³

1997

Br J Cancer

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“…Gene ampli®cation has been studied in in vitro models, mostly using DNA synthesis-inhibiting drugs (Wahl et al, 1979;Brown et al, 1983;Johnston et al, 1983;Knudson, 1986;Meinkoth et al, 1987;Schimke, 1988;Tlsty et al, 1989;Smith et al, 1990Smith et al, , 1992. Gene ampli®cation is thought to initiate through either replication-or segregation-driven mechanisms.…”

Section: Introductionmentioning

confidence: 99%

c-Myc initiates illegitimate replication of the ribonucleotide reductase R2 gene

Kuschak

Taylor

et al. 2002

Oncogene

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The mechanisms through which the oncoprotein c-Myc initiates locus-speci®c gene ampli®cation are not understood. When analysing the initiation mechanism of cMyc-dependent ampli®cation of the mouse ribonucleotide reductase R2 (R2) gene, we observe c-Myc-dependent initiation of illegitimate DNA replication of the R2 gene. We demonstrate multiple simultaneous c-Myc-induced R2 replication forks, whereas R2 normally replicates with a single fork. In contrast, cyclin C replicates with only a single replication fork irrespective of c-Myc deregulation. In addition to de novo replication forks, cMyc also initiates bi-allelic replication of R2, abrogating its normal mono-allelic replication pattern. Moreover, several chromosomal regions also display c-Myc-induced illegitimate replication pro®les. Thus, c-Myc can act as an illegitimate replication-licensing factor that promotes de novo replication initiation and illegitimate replication timing that adversely impacts upon genomic stability. Oncogene (2002) 21, 909 ± 920.

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“…Mammalian cells treated with either radiation, DNA replication inhibitors, or other DNA-damaging agents show increased frequencies of gene amplification, suggesting chromosome breaks as initiating lesions (4,12,24,39). In fact, either a chromosome break at a fragile site or a site-specific chromosomal DNA double-strand break (DSB) induced by I-SceI endonuclease leads to gene amplification by initiating the formation of large palindromic chromosomes (9,37).…”

mentioning

confidence: 99%

Intrastrand Annealing Leads to the Formation of a Large DNA Palindrome and Determines the Boundaries of Genomic Amplification in Human Cancer

Tanaka

Cao

Bergstrom

et al. 2007

Molecular and Cellular Biology

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Amplification of large chromosomal regions (gene amplification) is a common somatic alteration in human cancer cells and often is associated with advanced disease. A critical event initiating gene amplification is a DNA double-strand break (DSB), which is immediately followed by the formation of a large DNA palindrome. Large DNA palindromes are frequent and nonrandomly distributed in the genomes of cancer cells and facilitate a further increase in copy number. Although the importance of the formation of large DNA palindromes as a very early event in gene amplification is widely recognized, it is not known how a DSB is resolved to form a large DNA palindrome and whether any local DNA structure determines the location of large DNA palindromes. We show here that intrastrand annealing following a DNA double-strand break leads to the formation of large DNA palindromes and that DNA inverted repeats in the genome determine the efficiency of this event. Furthermore, in human Colo320DM cancer cells, a DNA inverted repeat in the genome marks the border between amplified and nonamplified DNA. Therefore, an early step of gene amplification is a regulated process that is facilitated by DNA inverted repeats in the genome.

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Enhancement of methotrexate resistance and dihydrofolate reductase gene amplification by treatment of mouse 3T6 cells with hydroxyurea.

Abstract: We investigated various parameters associated with the initial selection of mouse 3T6 cells for resistance to

Cited by 170 publications

References 16 publications

Resistance to chemotherapeutic antimetabolites: a function of salvage pathway involvement and cellular response to DNA damage

Resistance to chemotherapeutic antimetabolites: a function of salvage pathway involvement and cellular response to DNA damage

c-Myc initiates illegitimate replication of the ribonucleotide reductase R2 gene

Intrastrand Annealing Leads to the Formation of a Large DNA Palindrome and Determines the Boundaries of Genomic Amplification in Human Cancer

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