Increased Cytotoxicity and Decreased In Vivo Toxicity of FdUMP[10] Relative to 5-FU

Liu, Jinqian; Skradis, Alan; Kolar, Carol; Kolath, Jeff; Anderson, James; Lawson, Terrence A.; Talmadge, James E.; Gmeiner, William H.

doi:10.1080/07328319908044843

Cited by 26 publications

(26 citation statements)

References 15 publications

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“…28 Because FdUMP [10] is primarily metabolized to the DNA-directed metabolite, FdUMP, it should exhibit reduced GI tract toxicity compared with 5-FU. To compare the toxicity of FdUMP [10] with 5-FU and Ara/Dox, we treated C57/Bl6 mice with these agents as in the efficacy studies with animals dosed on days 1, 3, 5, and 7.…”

Section: Fdump[10] Causes Less Toxicity Than Either 5-fu or Ara-c Plumentioning

confidence: 99%

Unique dual targeting of thymidylate synthase and topoisomerase1 by FdUMP[10] results in high efficacy against AML and low toxicity

Pardee

Gomes²,

Jennings-Gee

et al. 2012

Blood

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Section: Fdump[10] Causes Less Toxicity Than Either 5-fu or Ara-c Plumentioning

confidence: 99%

Unique dual targeting of thymidylate synthase and topoisomerase1 by FdUMP[10] results in high efficacy against AML and low toxicity

Pardee

Gomes²,

Jennings-Gee

et al. 2012

Blood

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“…After relaxing the SufC–SufD complex for 1 microsecond as described above, we used AutoDock Vina [46] to predict docking poses for ATP binding. We used this same software to predict docking poses for F10 [73–78,12,13,15,14] and human serum albumin [79]. For the purpose of the simple example in Fig.…”

Section: Methodsmentioning

confidence: 99%

Visualizing ensembles in structural biology

Melvin

Salsbury

2016

Journal of Molecular Graphics and Modelling

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Displaying a single representative conformation of a biopolymer rather than an ensemble of states mistakenly conveys a static nature rather than the actual dynamic personality of biopolymers. However, there are few apparent options due to the fixed nature of print media. Here we suggest a standardized methodology for visually indicating the distribution width, standard deviation and uncertainty of ensembles of states with little loss of the visual simplicity of displaying a single representative conformation. Of particular note is that the visualization method employed clearly distinguishes between isotropic and anisotropic motion of polymer subunits. We also apply this method to ligand binding, suggesting a way to indicate the expected error in many high throughput docking programs when visualizing the structural spread of the output. We provide several examples in the context of nucleic acids and proteins with particular insights gained via this method. Such examples include investigating a therapeutic polymer of FdUMP (5-fluoro-2-deoxyuridine-5-O-monophosphate) – a topoisomerase-1 (Top1), apoptosis-inducing poison – and nucleotide-binding proteins responsible for ATP hydrolysis from Bacillus subtilis. We also discuss how these methods can be extended to any macromolecular data set with an underlying distribution, including experimental data such as NMR structures.

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“…The inefficient metabolism of 5FU to FdUMP coupled with the rapid catabolism of 5FU to toxic metabolites makes novel chemical strategies to develop Liu et al, 2002;J. Liu et al, 1999J.…”

Section: Fps: Current Clinical Use and Pre-clinical Developmentmentioning

confidence: 99%

Genetic determinants for activated fluoropyrimidine chemotherapy

Gmeiner

2006

Drug Development Research

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Fluoropyrimidines (FPs) remain widely used for the treatment of diverse malignancies more than four decades following the initial report of 5-fluorouracil (5FU), the archetypal FP, as a novel compound with potential anti-neoplastic activity. Subsequent decades of research have enriched our understanding of the biochemical mechanisms that are important for FP activation as well as the genetic determinants that are predictive of the likely success, or failure, of FP chemotherapy for a particular individual. The concept that chemotherapy should be customized to complement the genetic profiles of cancer patients has become increasingly important as genotyping of tumor samples has become possible and as the number of available anticancer drugs has increased. Significant progress has been made in identifying the gene expression profiles for cancer patients who are likely to benefit from treatment with FPs. In this review, we will summarize the results of retrospective clinical studies correlating response to FP chemotherapy with the expression of specific genes, such as TS and DPD. We will also present a summary of FPs in current clinical use, including orally bioavailable FPs such as capecitabine, as well as FPs that are in pre-clinical development, such as FdUMP [10]. Refinement of a target population through pharmacogenetic analysis and development of novel FPs that evoke very high response rates in this target population will likely result in the use of FP regimens in the coming era when cancer becomes a largely manageable disease. Drug Dev.

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Increased Cytotoxicity and Decreased In Vivo Toxicity of FdUMP[10] Relative to 5-FU

Cited by 26 publications

References 15 publications

Unique dual targeting of thymidylate synthase and topoisomerase1 by FdUMP[10] results in high efficacy against AML and low toxicity

Unique dual targeting of thymidylate synthase and topoisomerase1 by FdUMP[10] results in high efficacy against AML and low toxicity

Visualizing ensembles in structural biology

Genetic determinants for activated fluoropyrimidine chemotherapy

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