Fluorinated Pyrimidines and Their Nucleosides

Heidelberger, Charles; Danenberg, Peter V.; Moran, Richard G.

doi:10.1002/9780470122990.ch2

Cited by 39 publications

(18 citation statements)

References 202 publications

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“…The nucleoside analogue 5-fluorouracil (5FU) was one of the first rationally designed chemotherapeutic agents (Heidelberger et al, 1983) and it remains in widespread clinical use for the treatment of colorectal, breast and other cancer types (Longley et al, 2003). 5-Fluorouracil rapidly enters tumour cells where it is converted to a variety of derivatives which exert pleiotropic effects on cell physiology including inhibition of DNA synthesis and incorporation into DNA and RNA (Longley et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Chk1-dependent slowing of S-phase progression protects DT40 B-lymphoma cells against killing by the nucleoside analogue 5-fluorouracil

et al. 2006

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Chk1 plays a crucial role in the DNA damage and replication checkpoints in vertebrates and may therefore be an important determinant of tumour cell responses to genotoxic anticancer drugs. To evaluate this concept we compared the effects of the nucleoside analogue 5-fluorouracil (5FU) on cell cycle progression and clonogenic survival in DT40 B-lymphoma cells with an isogenic mutant derivative in which Chk1 function was ablated by gene targeting. We show that 5FU activates Chk1 in wild-type DT40 cells and that 5FU-treated cells accumulate in the S phase of the cell cycle due to slowing of the overall rate of DNA replication. In marked contrast, Chk1-deficient DT40 cells fail to slow DNA replication upon initial exposure to 5FU, despite equivalent inhibition of the target enzyme thymidylate synthase, and instead accumulate progressively in the G1 phase of the following cell cycle. This G1 accumulation cannot be reversed rapidly by exogenous thymidine or removal of 5FU, and is associated with increased incorporation of 5FU into genomic DNA and severely diminished clonogenic survival. Taken together, these results demonstrate that a Chk1-dependent replication checkpoint which slows S phase progression can protect tumour cells against the cytotoxic effects of 5FU.

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Section: Introductionmentioning

confidence: 99%

Chk1-dependent slowing of S-phase progression protects DT40 B-lymphoma cells against killing by the nucleoside analogue 5-fluorouracil

et al. 2006

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“…The fluorinated pyrimidines (FPs) and their metabolism to DNA-level antimetabolites was developed in 1957 as a potential drug for the treatment of advanced cancers (Heidelberger et al, 1983). Investigation of its antimetabolites resulted in the development of an entire class of fluorinated pyrimidines (FPs).…”

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confidence: 99%

DNA mismatch repair (MMR)‐dependent 5‐fluorouracil cytotoxicity and the potential for new therapeutic targets

Morales

Veigl

et al. 2009

British J Pharmacology

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The metabolism and efficacy of 5-fluorouracil (FUra) and other fluorinated pyrimidine (FP) derivatives have been intensively investigated for over fifty years. FUra and its antimetabolites can be incorporated at RNA-and DNA-levels, with RNA level incorporation provoking toxic responses in human normal tissue, and DNA-level antimetabolite formation and incorporation believed primarily responsible for tumour-selective responses. Attempts to direct FUra into DNA-level antimetabolites, based on mechanism-of-action studies, have led to gradual improvements in tumour therapy. These include the use of leukovorin to stabilize the inhibitory thymidylate synthase-5-fluoro-2′-deoxyuridine 5′ monophoshate (FdUMP)-5,10-methylene tetrahydrofolate (5,10-CH2FH4) trimeric complex. FUra incorporated into DNA also contributes to antitumour activity in preclinical and clinical studies. This review examines our current state of knowledge regarding the mechanistic aspects of FUra:Gua lesion detection by DNA mismatch repair (MMR) machinery that ultimately results in lethality. MMR-dependent direct cell death signalling or futile cycle responses will be discussed. As 10-30% of sporadic colon and endometrial tumours display MMR defects as a result of human MutL homologue-1 (hMLH1) promoter hypermethylation, we discuss the use and manipulation of the hypomethylating agent, 5-fluorodeoxycytidine (FdCyd), and our ability to manipulate its metabolism using the cytidine or deoxycytidylate (dCMP) deaminase inhibitors, tetrahydrouridine or deoxytetrahydrouridine, respectively, as a method for re-expression of hMLH1 and re-sensitization of tumours to FP therapy. (2009) Keywords: 5-fluorouracil; DNA mismatch repair; thymidylate synthase; hypermethylation; hMLH1; MMR/c-Abl/p73a/ GADD45a signalling Abbreviations: 5,10-CH2FH4, 5,10-methylene tetrahydrofolate; 5′-dRP, 5′-deoxyribose phosphate; AM, adaptors/mediators; AP, apyrimidinic/apurinic site; APE, apurinic/apyrimidinic endonuclease; ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia-and-rad3-related; BER, base excision repair; CD, cytosine deaminase; dCMP, deoxycytidylate; dCMPD, deoxycytidylate deaminase; dH4Urd, deoxytetrahydrouridine; DS, damage sensors; DSBs, DNA double-strand breaks; dThyd, thymidine; ES, embryonic stem; FdCyd, 5-fluoro-2′-deoxycyticine; FdUDP, 5-fluoro-2′-deoxyuridine 5′-diphosphate; FdUMP, 5-fluoro-2′-deoxyuridine 5′-monophosphate; FdUTP, 5-fluoro-2′-deoxyuridine-5′-triphosphate; FdUrd, 5-fluoro-2′-deoxyuridine; FEN1, flap-endonuclease 1; FPs, fluorinated pyrimidines; FUDP, 5-fluorouridine 5′-diphosphate; FUra (or 5-FU), 5-fluorouracil; FUrd, fluorouridine; FUTP, 5-fluorouridine-5′-triphosphate; GADD45, growth arrest and DNA damage-inducible-45 gene/ protein; H4Urd, 3,4,5,6-tetrahydrouridine; hMLH1, human MutL homologue-1; hMSH2, human MutS homologue-2; hMSH3, human MutS homologue-3; hMSH6, human MutS homologue-6; hPMS2, postmeiotic segregation increased 2; IDL, insertion/deletion loop-type; MBD4, methyl-CpG binding domain protein 4; British Journal of Phar...

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“…Mechanisms underlying the formation of active FdUMP would require then multi-step reactions towards synthesis through UP or OPRT of fluorouridine diphosphate (FUDP) first, followed by reduction into fluorodeoxyuridine diphosphate (FdUDP) and backwards dephosphorylation to fluorodeoxyuridine monophosphate (FdUMP) [71]. As mentioned above, FdUMP could be alternatively obtained following the DNA pathway by a near-direct activation through TP to FdUrd first, then a single phosphorylation by TK.…”

Section: Activating the Drug: Tp Or Not Tp?mentioning

confidence: 98%

Thymidine Phosphorylase and Fluoropyrimidines Efficacy: A Jekyl and Hyde Story

Ciccolini¹,

Evrard²,

Cuq³

2004

CMCACA

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Thymidine phosphorylase (TP) is markedly upregulated in many solid tumors such as colorectal, breast and kidney cancers. Because TP is identical to platelet-derived endothelial cell growth factor, this enzyme is believed to have angiogenic properties, although the precise mechanisms through which it promotes neoangiogenesis are still not fully elucidated. TP is involved as well in the tumoral activation of widely prescribed pyrimidine-derived antimetabolites such as 5-FU, 5'-dFUR and newly marketed capecitabine, and, in this respect, has been presented as a determinant to fluoropyrimidine efficacy in various in vitro and in vivo models. This dual and apparently contradictory role that TP plays yields inconsistent results in the study of relationships between this enzyme expression and clinical outcome in patients treated with fluoropyrimidine analogs. Some studies have shown that high tumoral TP expression was associated indeed with poor clinical response and tumor aggressiveness. Conversely, other reports demonstrated that tumoral TP could be considered as a good response factor in patients exposed to fluoropyrimidine drugs. TP exhibits then its more favorable profile, probably in converting 5-FU to active metabolites responsible for its efficacy as antitumor agent. As a result, TP-targeting as a rationale for anticancer therapy remains unclear. TP inhibitors are being synthesized as an attempt to fight neoangiogenesis, whereas promising new strategies such as taxotere/capecitabine or radiotherapy/fluoropyrimidines associations aim at nothing but boosting TP activity to optimize drug activation in tumors. Such a discrepancy illustrates the complexity of understanding and predicting the exact role of TP in the clinical outcome of patients exposed to fluoropyrimidines, a group of major drugs extensively used in oncology.

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Fluorinated Pyrimidines and Their Nucleosides

Cited by 39 publications

References 202 publications

Chk1-dependent slowing of S-phase progression protects DT40 B-lymphoma cells against killing by the nucleoside analogue 5-fluorouracil

Chk1-dependent slowing of S-phase progression protects DT40 B-lymphoma cells against killing by the nucleoside analogue 5-fluorouracil

DNA mismatch repair (MMR)‐dependent 5‐fluorouracil cytotoxicity and the potential for new therapeutic targets

Thymidine Phosphorylase and Fluoropyrimidines Efficacy: A Jekyl and Hyde Story

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