The plasma pharmacokinetics and cerebrospinal fluid penetration of the thymidylate synthase inhibitor raltitrexed (Tomudex TM ) in a nonhuman primate model

Widemann, Brigitte C.; Balis, Frank M.; Godwin, Karen; McCully, Cindy; Adamson, Peter C.

doi:10.1007/s002800051116

Cited by 27 publications

(17 citation statements)

References 10 publications

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“…Moreover, RTX has a terminal glutamyl moiety that is polyglutamylated in vivo by FPGS (51). RTX is fully active after polyglutamylation (52) resulting in tighter binding to its target TS and improved cellular retention. RTX has shown to be more potent against whole parasites than against recombinant TbDHFR or TbTS (13) suggesting that polyglutamylation is likely to occur inside T. brucei .…”

Section: Discussionmentioning

confidence: 99%

The Role of Folate Transport in Antifolate Drug Action in Trypanosoma brucei

Dewar

Sienkiewicz

Ong³

et al. 2016

Journal of Biological Chemistry

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The aim of this study was to identify and characterize mechanisms of resistance to antifolate drugs in African trypanosomes. Genome-wide RNAi library screens were undertaken in bloodstream form Trypanosoma brucei exposed to the antifolates methotrexate and raltitrexed. In conjunction with drug susceptibility and folate transport studies, RNAi knockdown was used to validate the functions of the putative folate transporters. The transport kinetics of folate and methotrexate were further characterized in whole cells. RNA interference target sequencing experiments identified a tandem array of genes encoding a folate transporter family, TbFT1–3, as major contributors to antifolate drug uptake. RNAi knockdown of TbFT1–3 substantially reduced folate transport into trypanosomes and reduced the parasite's susceptibly to the classical antifolates methotrexate and raltitrexed. In contrast, knockdown of TbFT1–3 increased susceptibly to the non-classical antifolates pyrimethamine and nolatrexed. Both folate and methotrexate transport were inhibited by classical antifolates but not by non-classical antifolates or biopterin. Thus, TbFT1–3 mediates the uptake of folate and classical antifolates in trypanosomes, and TbFT1–3 loss-of-function is a mechanism of antifolate drug resistance.

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Section: Discussionmentioning

confidence: 99%

The Role of Folate Transport in Antifolate Drug Action in Trypanosoma brucei

Dewar

Sienkiewicz

Ong³

et al. 2016

Journal of Biological Chemistry

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“…The most commonly used chemotherapeutics are gemcitabine and 5-fluorouracil (5-FU). Both chemotherapeutics inhibit DNA synthesis and thereby induce apoptosis [80,81,82,83]. The antimetabolite 5-FU has been developed for the treatment of cancer in 1957 [84,85], and has since been used as a therapeutic for pancreatic cancer despite the marginal efficacy of this agent [86].…”

Section: Treatment Of Pancreatic Cancermentioning

confidence: 99%

Cancer Stem Cells, EMT, and Developmental Pathway Activation in Pancreatic Tumors

Hindriksen

Bijlsma

2012

Cancers

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Pancreatic cancer is a disease with remarkably poor patient survival rates. The frequent presence of metastases and profound chemoresistance pose a severe problem for the treatment of these tumors. Moreover, cross-talk between the tumor and the local micro-environment contributes to tumorigenicity, metastasis and chemoresistance. Compared to bulk tumor cells, cancer stem cells (CSC) have reduced sensitivity to chemotherapy. CSC are tumor cells with stem-like features that possess the ability to self-renew, but can also give rise to more differentiated progeny. CSC can be identified based on increased in vitro spheroid- or colony formation, enhanced in vivo tumor initiating potential, or expression of cell surface markers. Since CSC are thought to be required for the maintenance of a tumor cell population, these cells could possibly serve as a therapeutic target. There appears to be a causal relationship between CSC and epithelial-to-mesenchymal transition (EMT) in pancreatic tumors. The occurrence of EMT in pancreatic cancer cells is often accompanied by re-activation of developmental pathways, such as the Hedgehog, WNT, NOTCH, and Nodal/Activin pathways. Therapeutics based on CSC markers, EMT, developmental pathways, or tumor micro-environment could potentially be used to target pancreatic CSC. This may lead to a reduction of tumor growth, metastatic events, and chemoresistance in pancreatic cancer.

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“…1A) is a novel quinazoline folate analog that selectively inhibits thymidylate synthase [1]. It has activity in advanced colorectal cancer comparable with that of fluorouracil (5-fluorouracil) plus folinic acid.…”

Section: Introductionmentioning

confidence: 99%

“…Its activity is enhanced by rapid cellular entry and polyglutamation, with the polyglutamated derivatives having approximately 100-fold greater inhibitory potency than the parent compound [2]. Several articles reported the pharmacokinetic profiles of raltitrexed in animals [1,[3][4][5] and patients [2,[6][7][8][9]], but few articles described the determination methods of raltitrexed in human plasma. A method based on high-performance liquid chromatography with UV detection had been developed to determine the concentrations of raltitrexed in rat plasma [10], in which the lower limit of quantification (LLOQ) was 25 ng/ml.…”

Section: Introductionmentioning

confidence: 99%