Intracellular Thymidylate Synthase Inhibition by Trifluorothymidine in FM3A Cells

Temmink, Olaf H.; Comijn, E. M.; Fukushima, Masakazu; Peters, G.J.

doi:10.1002/chin.200512221

Cited by 5 publications

(8 citation statements)

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“…TS inhibition is a major mechanism of action of classical fluoropyrimidines such as 5‐FU (Van Triest and Peters, ). Although TS inhibition by FTD‐MP may partly account for the antitumor effects of FTD (Santi and Sakai, ; Temmink et al ., ), the incorporation of FTD‐TP into DNA and the resulting DNA damage appear to be the major mechanism of action of FTD (Tanaka et al ., ; Suzuki et al ., ; Matsuoka et al ., ). Importantly, TAS‐102 exhibits antitumor activity against FU‐resistant cell lines in preclinical xenograft models (Emura et al ., ; Emura et al ., ; van der Velden et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Panitumumab interaction with TAS‐102 leads to combinational anticancer effects via blocking of EGFR‐mediated tumor response to trifluridine

et al. 2017

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Panitumumab is a monoclonal antibody developed against the human epidermal growth factor receptor (EGFR). TAS‐102 is a novel chemotherapeutic agent containing trifluridine (FTD) as the active cytotoxic component. Both panitumumab and TAS‐102 have been approved for the treatment of metastatic colorectal cancer. In this study, we revealed the mechanism underlying the anticancer effects of panitumumab/TAS‐102 combination using preclinical models. Panitumumab/FTD cotreatment showed additive antiproliferative effects in LIM1215 and synergistic antiproliferative effects in SW48 colon cancer cells. Consistent with the in vitro effects, panitumumab/TAS‐102 combination caused tumor regression in LIM1215 and COL‐01‐JCK colon cancer patient‐derived xenograft models. In LIM1215 cells, FTD induced extracellular signal‐regulated kinase (ERK)/protein kinase B (AKT)/signal transducer and activator of transcription 3 (STAT3) phosphorylation and subsequent serine/threonine phosphorylation of EGFR, while it had no effects on EGFR tyrosine phosphorylation. Panitumumab and the tyrosine kinase inhibitor erlotinib reduced the basal level of EGFR tyrosine phosphorylation and reversed FTD‐induced ERK/AKT/STAT3 and EGFR serine/threonine phosphorylation. These results suggested that FTD in combination with the basal activity of EGFR tyrosine kinase induced downstream prosurvival signaling through ERK/AKT/STAT3 phosphorylation. Collectively, we propose that panitumumab interacts with FTD by targeting EGFR‐mediated adaptive responses, thereby exerting anticancer effects when used in combination with TAS‐102. These preclinical findings provide a compelling rationale for evaluating the combination of anti‐EGFR antibodies with TAS‐102 against metastatic colorectal cancer.

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Section: Introductionmentioning

confidence: 97%

Panitumumab interaction with TAS‐102 leads to combinational anticancer effects via blocking of EGFR‐mediated tumor response to trifluridine

et al. 2017

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“…FTD-resistant H630 colon cancer cells through intermittent exposure of FTD also decreased TK protein expression and activity, but FTD-resistant H630 cells through continuous exposure of FTD decreased hENT and increased secretory phospholipase-A2 (sPLA2) gene expression (4). A different approach using random mutagenesis and drug selection showed that loss of TK or TS activity in the mouse mammary carcinoma cell line FM3A is associated with severe FTD resistance (11). On the other hand, FTD-resistant DLD1 cells established by Tsunekuni and colleagues overexpress the miRNA let-7d-5p, which may be the cause of FTD resistance (14).…”

Section: Introductionmentioning

confidence: 99%

Thymidine Kinase 1 Loss Confers Trifluridine Resistance without Affecting 5-Fluorouracil Metabolism and Cytotoxicity

Edahiro

Iimori

Kobunai

et al. 2018

Molecular Cancer Research

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Acquired resistance to therapeutic drugs is a serious problem for patients with cancer receiving systemic treatment. Experimentally, drug resistance is established in cell lines by repeated, continuous exposure to escalating concentrations of the drug; however, the precise mechanism underlying the acquired resistance is not always known. Here, it is demonstrated that the human colorectal cancer cell line DLD1 with acquired resistance to trifluridine (FTD), a key component of the novel, orally administered nucleoside analogue-type chemotherapeutic drug trifluridine/tipiracil, lacks functional thymidine kinase 1 (TK1) expression because of one nonsense mutation in the coding exon. Targeted disruption of the gene also conferred severe FTD resistance, indicating that the loss of TK1 protein expression is the primary cause of FTD resistance. Both FTD-resistant DLD1 cells and DLD1- cells exhibited similar 5-fluorouracil (5-FU) sensitivity to that of the parental DLD1 line. The quantity of cellular pyrimidine nucleotides in these cells and the kinetics of thymidylate synthase ternary complex formation in 5-FU-treated cells is similar to DLD1 cells, indicating that 5-FU metabolism and cytotoxicity were unaffected. The current data provide molecular-based evidence that acquired resistance to FTD does not confer 5-FU resistance, implying that 5-FU-based chemotherapy would be effective even in tumors that become refractory to FTD during trifluridine/tipiracil treatment..

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“…Trifluridine exerts its cytotoxicity after transformation by thymidine kinase to trifluoromethyl deoxyuridine 5ʹ-monophosphate (F 3 dTMP) followed by conversion to F3dTTP, which is then incorporated into DNA, causing DNA single strand breaks along with a degree of TS inhibition. When trifluridine was administered as a twice daily dose in mouse models, there was greater DNA incorporation, whereas a continuous infusion resulted in greater TS inhibition [38,39].…”

Section: Oral Formulationsmentioning

confidence: 97%

Personalizing fluoropyrimidine administration in colorectal cancer patients

Patel

Fong

2016

Expert Review of Precision Medicine and Drug Development

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Introduction: Fluoropyrimidines have been a critical component to chemotherapy regimens to treat locally advanced and metastatic colorectal cancer since the 1950s. Clinicians should be aware of the methods that exist to personalize fluoropyrimidine administration to increase efficacy and reduce toxicity. Areas covered: The development of different administration methods (e.g. bolus versus continuous infusion, oral formulations) have advanced the clinical utility of fluoropyrimidines to treat colorectal cancer. Given the high inter-patient variation in fluoropyrimidine drug exposure and susceptibility to pharmacogenetic variation, pharmacokinetic-and pharmacogenetic-guided dosing may also prove fruitful in the quest to normalize drug exposure, reduce toxicity and enhance clinical efficacy. PubMed was used to search for relevant articles relating to 5-fluorouracil administration, fluoropyrimidines (S-1, tegafur, capecitabine, TAS-102), 5-fluorouracil pharmacokinetics and pharmacogenetics, and personalized 5-fluorouracil dosing. Expert commentary: Although fluoropyrimidines are effective against colorectal cancer, room for improvement still exist. Clinically applicable methods to personalize fluoropyrimidine administration include optimizing infusion methods, use of oral formulations, and application of pharmacokineticand/or pharmacogenetic-guided dosing.

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Intracellular Thymidylate Synthase Inhibition by Trifluorothymidine in FM3A Cells

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 5 publications

References 1 publication

Panitumumab interaction with TAS‐102 leads to combinational anticancer effects via blocking of EGFR‐mediated tumor response to trifluridine

Panitumumab interaction with TAS‐102 leads to combinational anticancer effects via blocking of EGFR‐mediated tumor response to trifluridine

Thymidine Kinase 1 Loss Confers Trifluridine Resistance without Affecting 5-Fluorouracil Metabolism and Cytotoxicity

Personalizing fluoropyrimidine administration in colorectal cancer patients

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