Metabolism and mechanism of action of 5-fluorouracil

Parker, William B.; Cheng, Yung Chi

doi:10.1016/0163-7258(90)90056-8

Cited by 389 publications

(244 citation statements)

References 64 publications

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“…Thus, the differences in the resistance of these particular human fibroblast cell lines to both MTX and PALA are clearly not only a function of differences in the salvage pathways but also of differences in the abilities of the cells to elicit a p53-dependent DNA damage response. In the case of 5-FU ( Figure 4C), one has to assume in the absence of an effect of dipyridamole that the drug is mediating its effects via its direct action on DNA (Parker and Cheng, 1990) and that, as stated previously, only the DNA damage response is important. No growth arrest was observed in any of the cell lines at concentrations of PALA up to and including 10 mm, except in the case of the normal cell line in the presence of dipyridamole.…”

Section: Is There a Role For Dna Damage Response In Resistance To Mtxmentioning

confidence: 90%

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: Is There a Role For Dna Damage Response In Resistance To Mtxmentioning

confidence: 90%

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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“…However, except for the postulation that it affects DNA metabolism, the mechanism of action of 5FU remained largely unclear (Parker and Cheng, 1990;Ghoshal and Jacob, 1997;Longley et al, 2003). Zhao and Yu applied 5FU to mammalian cell cultures, and found that 5FU was efficiently converted into 5-fluoroUTP, which was then readily incorporated into U2 snRNA at various positions (Zhao and Yu, 2007).…”

Section: -Fluorouracil (5fu) Functions As a Pseudouridylation Inhibimentioning

confidence: 99%

Pseudouridines in spliceosomal snRNAs

2011

Protein Cell

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Spliceosomal RNAs are a family of small nuclear RNAs (snRNAs) that are essential for pre-mRNA splicing. All vertebrate spliceosomal snRNAs are extensively pseudouridylated after transcription. Pseudouridines in spliceosomal snRNAs are generally clustered in regions that are functionally important during splicing. Many of these modified nucleotides are conserved across species lines. Recent studies have demonstrated that spliceosomal snRNA pseudouridylation is catalyzed by two different mechanisms: an RNA-dependent mechanism and an RNA-independent mechanism. The functions of the pseudouridines in spliceosomal snRNAs (U2 snRNA in particular) have also been extensively studied. Experimental data indicate that virtually all pseudouridines in U2 snRNA are functionally important. Besides the currently known pseudouridines (constitutive modifications), recent work has also indicated that pseudouridylation can be induced at novel positions under stress conditions, thus strongly suggesting that pseudouridylation is also a regulatory modification.

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“…It is thought that the major cytotoxic effects of 5-FU occur at the level of DNA synthesis as a competitive inhibitor of TS. 3 TS inhibition creates a dTTP/dUMP cellular pool imbalance with subsequent DNA damage, and cells die by a process called thymineless death. 4 However, a growing body of evidence suggests that additional mechanisms could be involved in the antiproliferative effects of 5-FU, including inhibition of RNA metabolism 2 and interference with polyamines metabolism.…”

mentioning

confidence: 99%

Transcriptional profiling of MCF7 breast cancer cells in response to 5‐Fluorouracil: Relationship with cell cycle changes and apoptosis, and identification of novel targets of p53

Hernández-Vargas

Ballestar

Carmona-Sáez

et al. 2006

Intl Journal of Cancer

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The availability of oral precursors of 5-Fluorouracil (5-FU) and its favorable results in treating advanced breast cancer have renewed the interest in the molecular mechanisms underlying its cytotoxicity. We have compared the changes in cell cycle and cell death parameters induced by 2 different concentrations of 5-FU (IC50 and IC80) in the breast adenocarcinoma cell line MCF7. G1/S cell cycle arrest was associated with both concentrations, whereas cell death was mainly induced after IC80 5-FU. These changes were correlated with gene expression assessed by cDNA microarray analysis. Main findings included an overexpression of p53 target genes involved in cell cycle and apoptosis (CDKN1A/ p21, TP53INP, TNFRSF6/FAS and BBC3/PUMA), and significant repression of Myc. High dose 5-FU also induced a higher regulation of the mitochondrial death genes APAF1, BAK1 and BCL2, and induction of genes of the ID family. Furthermore, we establish a direct causal relationship between p21, ID1 and ID2 overexpression, increased acetylation of histones H3 and H4 and binding of p53 to their promoters as a result of 5-FU treatment. The relevance of these findings was further studied after interfering p53 expression in MCF7 cells (shp53 cells), showing a lower induction of both, ID1 and ID2 transcripts, after 5-FU when compared with MCF7 shGFP control cells. This molecular characterization of dose-and time-dependent modifications of gene expression after 5-FU treatment should provide a resource for future basic studies addressing the molecular mechanisms of chemotherapy in breast cancer. ' 2006 Wiley-Liss, Inc.Key words: 5-Fluorouracil; cDNA microarrays; p53; E2F1; ID proteins Carcinogenesis is a multistep process involving genetic and epigenetic alterations that drive the progressive transformation of normal cells into malignant types. Deregulated processes involved in tumorigenesis, such as regulation of cell cycle progression, angiogenesis and apoptosis, provide rational targets for novel therapies. For this reason, there is now more emphasis on understanding the mechanisms of carcinogenesis and how these can be exploited when designing new therapeutic agents. 1 Capecitabine is an example of a rationally designed cytotoxic treatment. It is designed to generate 5-Fluorouracil (5-FU) preferentially in tumor cells, by exploiting the higher activity of the activating enzyme thymidine phosphorylase in tumors compared with healthy tissues. Tumor-specific activation has the potential to increase intratumor drug levels to enhance efficacy and minimize toxicity. Proof of this principle is provided by clinical trial results, showing that capecitabine is effective and has a favorable safety profile in the treatment of metastatic breast cancer. 1 Capecitabine active metabolite, 5-FU, is one of the most widely used chemotherapy drugs for the treatment of solid tumors. However, despite its extensive use in clinical practice, only in recent years we have began to understand the molecular basis for 5-FU toxicity on cancer cells. As a pyrimidine ana...

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Metabolism and mechanism of action of 5-fluorouracil

Cited by 389 publications

References 64 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

Pseudouridines in spliceosomal snRNAs

Transcriptional profiling of MCF7 breast cancer cells in response to 5‐Fluorouracil: Relationship with cell cycle changes and apoptosis, and identification of novel targets of p53

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