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The New England Journal of Medicine May 2015Early clinical trials conducted primarily in Japan have shown that TAS-102, an oral agent that combines trifluridine and tipiracil hydrochloride, was effective in the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Early clinical trials conducted primarily in Japan have shown that TAS-102, an oral agent that combines trifluridine and tipiracil hydrochloride, was effective in the treatment of refractory colorectal cancer. We conducted a phase 3 trial to further assess the efficacy and safety of TAS-102 in a global population of such patients.
METHODS
In this double-blind study, we randomly assigned 800 patients, in a 2:1 ratio, to receive TAS-102 or placebo. The primary end point was overall survival.
RESULTS
The median overall survival improved from 5.3 months with placebo to 7.1 months with TAS-102, and the hazard ratio for death in the TAS-102 group versus the placebo group was 0.68 (95% confidence interval [CI], 0.58 to 0.81; P<0.001). The most frequently observed clinically significant adverse events associated with TAS-102 were neutropenia, which occurred in 38% of those treated, and leukopenia, which occurred in 21%; 4% of the patients who received TAS-102 had febrile neutropenia, and one death related to TAS-102 was reported. The median time to worsening performance status (a change in Eastern Cooperative Oncology Group performance status [on a scale of 0 to 5, with 0 indicating no symptoms and higher numbers indicating increasing degrees of disability] from 0 or 1 to 2 or more) was 5.7 months with TAS-102 versus 4.0 months with placebo (hazard ratio, 0.66; 95% CI, 0.56 to 0.78; P<0.001).
CONCLUSIONS
In patients with refractory colorectal cancer, TAS-102, as compared with placebo, was associated with a significant improvement in overall survival. (Funded by Taiho Oncology-Taiho Pharmaceutical; RECOURSE ClinicalTrials.gov number, NCT01607957.).
Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Colorectal Neoplasms; Double-Blind Method; Drug Combinations; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Proportional Hazards Models; Pyrrolidines; Survival Analysis; Thymine; Trifluridine; Uracil
PubMed: 25970050
DOI: 10.1056/NEJMoa1414325 -
Future Oncology (London, England) Jun 2021Trifluridine/tipiracil (FTD/TPI) is an orally active formulation of trifluridine, a thymidine-based nucleoside analog, and tipiracil hydrochloride, a thymidine...
Trifluridine/tipiracil (FTD/TPI) is an orally active formulation of trifluridine, a thymidine-based nucleoside analog, and tipiracil hydrochloride, a thymidine phosphorylase inhibitor that increases the bioavailability of trifluridine. Preliminary studies of FTD/TPI plus bevacizumab have produced encouraging results in the treatment of refractory metastatic colorectal cancer. Here, we describe the design of the multinational Phase III SUNLIGHT, an open-label study of FTD/TPI plus bevacizumab as third-line treatment for patients with unresectable metastatic colorectal cancer. A total of 490 patients will be randomized 1:1 to receive either FTD/TPI plus bevacizumab, or FTD/TPI monotherapy. The primary objective is to significantly improve overall survival with FTD/TPI plus bevacizumab compared with FTD/TPI monotherapy. The first patient was enrolled in November 2020.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Drug Combinations; Female; Humans; Male; Middle Aged; Multicenter Studies as Topic; Neoplasm Metastasis; Pyrrolidines; Randomized Controlled Trials as Topic; Thymine; Trifluridine; Young Adult
PubMed: 33569986
DOI: 10.2217/fon-2020-1238 -
Science (New York, N.Y.) Apr 2017Single-cell genomics is important for biology and medicine. However, current whole-genome amplification (WGA) methods are limited by low accuracy of copy-number...
Single-cell genomics is important for biology and medicine. However, current whole-genome amplification (WGA) methods are limited by low accuracy of copy-number variation (CNV) detection and low amplification fidelity. Here we report an improved single-cell WGA method, Linear Amplification via Transposon Insertion (LIANTI), which outperforms existing methods, enabling micro-CNV detection with kilobase resolution. This allowed direct observation of stochastic firing of DNA replication origins, which differs from cell to cell. We also show that the predominant cytosine-to-thymine mutations observed in single-cell genomics often arise from the artifact of cytosine deamination upon cell lysis. However, identifying single-nucleotide variations (SNVs) can be accomplished by sequencing kindred cells. We determined the spectrum of SNVs in a single human cell after ultraviolet radiation, revealing their nonrandom genome-wide distribution.
Topics: Cell Line; Cytosine; DNA Copy Number Variations; DNA Transposable Elements; Deamination; Genome, Human; Genomics; Humans; Mutagenesis, Insertional; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Replication Origin; Sequence Analysis, DNA; Single-Cell Analysis; Thymine
PubMed: 28408603
DOI: 10.1126/science.aak9787 -
Cancer Science Jul 2021Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor... (Observational Study)
Observational Study Randomized Controlled Trial
Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA (ctDNA) prior to and post surgery has been reported across various solid tumors. We initiated a new type of adaptive platform trials to evaluate the clinical benefits of ctDNA analysis and refine precision adjuvant therapy for resectable colorectal cancer, named CIRCULATE-Japan including three clinical trials. The GALAXY study is a prospectively conducted large-scale registry designed to monitor ctDNA for patients with clinical stage II to IV or recurrent colorectal cancer who can undergo complete surgical resection. The VEGA trial is a randomized phase III study designed to test whether postoperative surgery alone is noninferior to the standard therapy with capecitabine plus oxaliplatin for 3 months in patients with high-risk stage II or low-risk stage III colon cancer if ctDNA status is negative at week 4 after curative surgery in the GALAXY study. The ALTAIR trial is a double-blind, phase III study designed to establish the superiority of trifluridine/tipiracil as compared with placebo in patients with resected colorectal cancer who show circulating tumor-positive status in the GALAXY study. Therefore, CIRCULATE-Japan encompasses both "de-escalation" and "escalation" trials for ctDNA-negative and -positive patients, respectively, and helps to answer whether measuring ctDNA postoperatively has prognostic and/or predictive value. Our ctDNA-guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy. Analysis of ctDNA status could be utilized as a predictor of risk stratification for recurrence and to monitor the effectiveness of adjuvant chemotherapy. ctDNA is a promising, noninvasive tumor biomarker that can aid in tumor monitoring throughout disease management.
Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Circulating Tumor DNA; Colonic Neoplasms; Colorectal Neoplasms; Double-Blind Method; Humans; Japan; Neoplasm Recurrence, Local; Oxaliplatin; Prospective Studies; Pyrrolidines; Thymine; Trifluridine
PubMed: 33931919
DOI: 10.1111/cas.14926 -
ChemistryOpen Apr 2020Dynamic and reversible non-covalent interactions endow synthetic systems and materials with smart adaptive functions that allow them to response to diverse stimuli,... (Review)
Review
Dynamic and reversible non-covalent interactions endow synthetic systems and materials with smart adaptive functions that allow them to response to diverse stimuli, interact with external agents, or repair structural defects. Inspired by the outstanding performance and selectivity of DNA in living systems, scientists are increasingly employing Watson-Crick nucleobase pairing to control the structure and properties of self-assembled materials. Two sets of complementary purine-pyrimidine pairs (guanine:cytosine and adenine:thymine(uracil)) are available that provide selective and directional H-bonding interactions, present multiple metal-coordination sites, and exhibit rich redox chemistry. In this review, we highlight several recent examples that profit from these features and employ nucleobase interactions in functional systems and materials, covering the fields of energy/electron transfer, charge transport, adaptive nanoparticles, porous materials, macromolecule self-assembly, or polymeric materials with adhesive or self-healing ability.
Topics: Adenine; Base Pairing; Coordination Complexes; Cytosine; DNA; Electron Transport; Energy Transfer; Guanine; Molecular Conformation; Oxidation-Reduction; Surface Properties; Thymine; Uracil
PubMed: 32257750
DOI: 10.1002/open.201900363 -
Future Oncology (London, England) Apr 2022Trifluridine/tipiracil is a compound drug, approved in 2015 by the US FDA, and in 2016 by the EMA, for the treatment of chemorefractory metastatic colorectal cancers,... (Review)
Review
Trifluridine/tipiracil is a compound drug, approved in 2015 by the US FDA, and in 2016 by the EMA, for the treatment of chemorefractory metastatic colorectal cancers, after the phase III RECOURSE trial demonstrated significant benefit. Another phase III trial (TAGS) showed significant improvement of overall survival and progression-free survival in refractory gastric cancer and gastroesophageal junction cancer, leading to further approval from the FDA on February 2019, followed by Japan in August 2019 and the EU in September 2019. As promising results have already been observed in the chemorefractory gastric and gastroesophageal-junction cancers, ongoing trials are assessing the use of trifluridine/tipiracil with other standard of care agents, aiming to further improve the survival rate of these patients.
Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Drug Combinations; Humans; Pyrrolidines; Stomach Neoplasms; Thymine; Trifluridine
PubMed: 35081748
DOI: 10.2217/fon-2021-0754 -
Current Opinion in Structural Biology Dec 2018The generation, alteration, recognition, and erasure of epigenetic modifications of DNA are fundamental to controlling gene expression in mammals. These covalent DNA... (Review)
Review
The generation, alteration, recognition, and erasure of epigenetic modifications of DNA are fundamental to controlling gene expression in mammals. These covalent DNA modifications include cytosine methylation by AdoMet-dependent methyltransferases and 5-methylcytosine oxidation by Fe(II)-dependent and α-ketoglutarate-dependent dioxygenases. Sequence-specific transcription factors are responsible for interpreting the modification status of specific regions of chromatin. This review focuses on recent developments in characterizing the functional and structural links between the modification status of two DNA bases: 5-methylcytosine and 5-methyluracil (thymine).
Topics: 5-Methylcytosine; Animals; DNA; DNA Methylation; DNA-Binding Proteins; Epigenesis, Genetic; Humans; Methyltransferases; Oxidation-Reduction; Thymine; Transcription Factors
PubMed: 30031306
DOI: 10.1016/j.sbi.2018.06.004 -
Proceedings of the National Academy of... Feb 2021In this study, absorption, fluorescence, synchronous fluorescence, and Raman spectra of nonirradiated and ultraviolet (UV)-irradiated thymine solutions were recorded in...
In this study, absorption, fluorescence, synchronous fluorescence, and Raman spectra of nonirradiated and ultraviolet (UV)-irradiated thymine solutions were recorded in order to detect thymine dimer formation. The thymine dimer formation, as a function of irradiation dose, was determined by Raman spectroscopy. In addition, the formation of a mutagenic (6-4) photoproduct was identified by its synchronous fluorescence spectrum. Our spectroscopic data suggest that the rate of conversion of thymine to thymine dimer decreases after 20 min of UV irradiation, owing to the formation of an equilibrium between the thymine dimers and monomers. However, the formation of the (6-4) photoproduct continued to increase with UV irradiation. In addition, the Raman spectra of nonirradiated and irradiated calf thymus DNA were recorded, and the formation of thymine dimers was detected. The spectroscopic data presented make it possible to determine the mechanism of thymine dimer formation, which is known to be responsible for the inhibition of DNA replication that causes bacteria inactivation.
Topics: Animals; Cattle; DNA; DNA Damage; Pyrimidine Dimers; Spectrometry, Fluorescence; Spectrum Analysis, Raman; Thymine; Ultraviolet Rays
PubMed: 33526704
DOI: 10.1073/pnas.2025263118 -
Nucleic Acids Research Mar 2022Thymine dimers are a major mutagenic photoproduct induced by UV radiation. While they have been the subject of extensive theoretical and experimental investigations,...
Thymine dimers are a major mutagenic photoproduct induced by UV radiation. While they have been the subject of extensive theoretical and experimental investigations, questions of how DNA supercoiling affects local defect properties, or, conversely, how the presence of such defects changes global supercoiled structure, are largely unexplored. Here, we introduce a model of thymine dimers in the oxDNA forcefield, parametrized by comparison to melting experiments and structural measurements of the thymine dimer induced bend angle. We performed extensive molecular dynamics simulations of double-stranded DNA as a function of external twist and force. Compared to undamaged DNA, the presence of a thymine dimer lowers the supercoiling densities at which plectonemes and bubbles occur. For biologically relevant supercoiling densities and forces, thymine dimers can preferentially segregate to the tips of the plectonemes, where they enhance the probability of a localized tip-bubble. This mechanism increases the probability of highly bent and denatured states at the thymine dimer site, which may facilitate repair enzyme binding. Thymine dimer-induced tip-bubbles also pin plectonemes, which may help repair enzymes to locate damage. We hypothesize that the interplay of supercoiling and local defects plays an important role for a wider set of DNA damage repair systems.
Topics: DNA Damage; DNA Repair; DNA, Superhelical; Nucleic Acid Conformation; Pyrimidine Dimers; Thymine; Ultraviolet Rays
PubMed: 35188542
DOI: 10.1093/nar/gkac082 -
Expert Review of Clinical Pharmacology 2016TAS-102 is a new oral anti-tumor drug, composed of a thymidine-based nucleoside analog (trifluridine: FTD) and a thymidine phosphorylase inhibitor (tipiracil... (Review)
Review
TAS-102 is a new oral anti-tumor drug, composed of a thymidine-based nucleoside analog (trifluridine: FTD) and a thymidine phosphorylase inhibitor (tipiracil hydrochloride: TPI). TAS-102 has been shown to significantly improve overall survival and progression-free survival in patients with refractory metastatic colorectal cancer (mCRC) in placebo-controlled randomized phase II and III trials. The current review summarizes mechanisms of action, pharmacokinetics/dynamics and preclinical and clinical data of TAS-102 in colorectal cancer. TAS-102 is a new salvage-line treatment option for patients with mCRC. TAS-102 is well tolerated and has great potential in future clinical drug combination therapies.
Topics: Animals; Antineoplastic Agents; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Humans; Neoplasm Metastasis; Pyrrolidines; Randomized Controlled Trials as Topic; Survival Rate; Thymine; Trifluridine; Uracil
PubMed: 26677869
DOI: 10.1586/17512433.2016.1133285