Fluorinated Pyrimidines, A New Class of Tumour-Inhibitory Compounds

Heidelberger, Charles; Chaudhuri, Ν. Κ.; Danneberg, P; Mooren, Dorothy; Griesbach, Lois; Duschinsky, Robert; Schnitzer, R. J.; Pleven, E.; Scheiner, J.

doi:10.1038/179663a0

Cited by 1,436 publications

(656 citation statements)

References 9 publications

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“…5FU is an effective and widely used anti-cancer drug (Heidelberger et al, 1957). 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).…”

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

confidence: 99%

Pseudouridines in spliceosomal snRNAs

2011

Protein Cell

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“…This enzyme catalyses the intracellular conversion of deoxyuridylate to deoxythymidylate which is the sole de novo source of thymidylate, an essential precursor for DNA synthesis. 3 The active metabolite of 5-FU, 5-fluorodeoxyuridylate (5FdUMP), binds to TS and inhibits it by forming a stable ternary complex. 4 The human thymidylate synthase gene (hTS) is polymorphic with either double or triple tandem repeats of a 28 base-pair sequence downstream of the cap-site in the 5Ј terminal regulatory region.…”

Section: Introductionmentioning

confidence: 99%

Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy

et al. 2001

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Thymidylate synthase (TS) catalyses the conversion of deoxy-uridylate to deoxy-thymidylate and is essential for DNA synthesis. The human TS gene promoter is polymorphic, having either double or triple tandem repeats of a 28-bp sequence. Here we determined the significance of this polymorphism in humans and its prediction for clinical outcome of patients with metastatic colorectal cancer treated with 5-fluorouracil. The TS mRNA level was analyzed using RT-PCR. Individuals homozygous for the triple repeat variant (L/L) had 3.6 times higher TS mRNA levels compared to those homozygous for the double repeat variant (S/S) in tumor tissue (P = 0.004). We tested 50 patients with disseminated colorectal cancer who received 5-FU treatment to determine whether this TS polymorphism will predict clinical outcome. We found individuals with S/S genotype had a response rate of 50% (4/

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“…Since 1957, 5-fluorouracil (5-FU) has been the mainstay of therapy for disseminated colorectal cancer (Heidelberg, 1957). Biochemical modulation of the effect of 5-FU with methotrexate or with leucovorin has marginally improved survival (Moertel, 1994).…”

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confidence: 99%

Interleukin 2 and interferon alpha-2a do not improve anti-tumour activity of 5-fluorouracil in advanced colorectal cancer

Goey¹,

Gratama²,

Primrose³

et al. 1996

Br J Cancer

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Summary Treatment using a combination of 5-fluorouracil (5-FU), interferon-alpha (IFNa-2a) and interleukin 2 (IL-2) has been shown to mediate disease regression in selected patients with advanced colorectal cancer. This phase II study was designed to evaluate the anti-tumour activity and toxicity of the combination of IL-2, IFNot-2a and 5-FU in patients with advanced colorectal cancer. Forty-four patients with metastatic colorectal cancer were treated, predominantly on an outpatient basis, with subcutaneous IFNa-2a and IL-2 three times per week followed by once a week bolus intravenous 5-FU injections. There were six (14%) partial responses among the 43 evaluable patients [95% confidence interval (CI) 5-28%]. Twenty-four patients had stable disease (56%) and 13 patients (30%) showed progressive disease. The median time to progressive disease in 43 patients was 19 weeks (range 2 -72 weeks) and in responders 34 weeks (range 24 -30 weeks). The median overall survival was 47 weeks (range 2 -85 weeks) and in responders 60 weeks (range 35 -71 weeks). Treatment-related toxic effects included fatigue, nausea and vomiting. Granulocytopenia was the main reason for the dose reductions or treatment interruptions in 32 out of 44 patients. One patient died of toxicity due to renal failure. Serial assessments of immunophenotyping and cytolytic activities of peripheral blood lymphocytes did not show changes in the numbers of circulating natural killer (NK) cells or in the levels of NK and lymphokine-activated killer (LAK) cytolytic activities. This regimen of IL-2 and IFNa-2a with 5-FU has only modest anti-tumour activity in advanced colorectal cancer.

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Fluorinated Pyrimidines, A New Class of Tumour-Inhibitory Compounds

Cited by 1,436 publications

References 9 publications

Pseudouridines in spliceosomal snRNAs

Pseudouridines in spliceosomal snRNAs

Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy

Interleukin 2 and interferon alpha-2a do not improve anti-tumour activity of 5-fluorouracil in advanced colorectal cancer

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