Identification

Name
Trifluridine
Accession Number
DB00432  (APRD01275)
Type
Small Molecule
Groups
Approved, Investigational
Description

Trifluridine is a fluorinated pyrimidine nucleoside that is structurally related to Idoxuridine [1]. It is an active antiviral agent in ophthalmic solutions used mainly in the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus. It displays effective antiviral activity against Herpes simplex virus type 1 and 2 [1].

The combination product of trifluridine with tipiracil marketed as Lonsurf has been approved in Japan, the United States, and the European Union for the treatment of adult patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. In the anticancer therapy, trifluridine acts as a thymidine-based nucleoside metabolic inhibitor that gets incorporated into DNA of cancer cells following cell uptake to aberrate DNA function during cell replication [5].

Structure
Thumb
Synonyms
  • 5-(Trifluoromethyl)deoxyuridine
  • 5-Trifluoromethyl-2-deoxyuridine
  • F₃T
  • TFT
  • Trifluoromethyldeoxyuridine
  • Trifluorothymidine
  • Trifluorothymine deoxyriboside
  • Trifluridin
  • Trifluridina
  • Trifluridine
  • Trifluridinum
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Sandoz TrifluridineSolution1 %OphthalmicSandoz Canada Incorporated2004-01-23Not applicableCanada
ViropticSolution1 g/100mLOphthalmicPfizer Laboratories Div Pfizer Inc.1980-04-10Not applicableUs
ViropticSolution1 %OphthalmicValeant Canada Lp Valeant Canada S.E.C.1987-12-31Not applicableCanada
ViropticSolution1 g/100mLOphthalmicPhysicians Total Care, Inc.1980-04-102012-06-30Us
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-trifluridine Ophthalmic SolutionSolution1 %OphthalmicApotex CorporationNot applicableNot applicableCanada
TrifluridineSolution10 mg/1mLOphthalmicSandoz2001-05-14Not applicableUs
TrifluridineSolution / drops10 mg/1mLOphthalmicHi Tech Pharmacal Co., Inc.2017-07-28Not applicableUs
TrifluridineSolution1 g/100mLOphthalmicGreenstone, Llc1980-04-102017-11-30Us
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
LonsurfTrifluridine (20 mg/1) + Tipiracil hydrochloride (8.19 mg/1)Tablet, film coatedOralTaisho Pharmaceutical Co., Ltd.2015-09-22Not applicableUs
LonsurfTrifluridine (15 mg) + Tipiracil (6.14 mg)TabletOralTaiho Pharma Canada, Inc.2018-03-22Not applicableCanada
LonsurfTrifluridine (15 mg/1) + Tipiracil hydrochloride (6.14 mg/1)Tablet, film coatedOralTaisho Pharmaceutical Co., Ltd.2015-09-22Not applicableUs
LonsurfTrifluridine (20 mg) + Tipiracil (8.19 mg)TabletOralTaiho Pharma Canada, Inc.2018-03-22Not applicableCanada
International/Other Brands
Thilol (Pharmex) / Triflumann (Dr. Gerhard Mann) / Triherpine (Medivis) / Virophta (Horus) / Viroptic
Categories
UNII
RMW9V5RW38
CAS number
70-00-8
Weight
Average: 296.1999
Monoisotopic: 296.062006087
Chemical Formula
C10H11F3N2O5
InChI Key
VSQQQLOSPVPRAZ-RRKCRQDMSA-N
InChI
InChI=1S/C10H11F3N2O5/c11-10(12,13)4-2-15(9(19)14-8(4)18)7-1-5(17)6(3-16)20-7/h2,5-7,16-17H,1,3H2,(H,14,18,19)/t5-,6+,7+/m0/s1
IUPAC Name
1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione
SMILES
OC[C@H]1O[C@H](C[C@@H]1O)N1C=C(C(=O)NC1=O)C(F)(F)F

Pharmacology

Indication

Trifluridine is used for the treatment of primay keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, types 1 and 2 in ophthalmic solutions.

Trifluridine, in combination with tipiracil as oral tablets, is indicated for the treatment of adult patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy [Label].

Associated Conditions
Pharmacodynamics

Trifluridine exhibits an antiviral effect against herpes simplex virus, types 1 and 2 and vacciniavirus both in vitro and in vivo [1]. Some strains of adenovirus that contribute to the pathology of keratoconjunctivitis were shown to be susceptible to trifluridine in vitro [1]. While there is evidence from a study that cross-resistance may develop between trifluridine and Idoxuridine or Vidarabine, trifluridine was shown to effective in treating dendritic ulcers in patients with herpetic keratitis who are unresponsive to Idoxuridine or Vidarabine based on the results from masked comparative trials [1]. In nonclinical studies, trifluridine/tipiracil hydrochloride demonstrated antitumour activity against both 5-fluorouracil (5-FU) sensitive and resistant colorectal cancer cell lines [5]. The cytotoxic activity of trifluridine and tipiracil against several human tumour xenografts show high correlation with the amount of trifluridine incorporated into DNA, indicating that the primary mechanism of action of trifluridine involves the direct incorporation into the cancer cell DNA [5]. Trifluridine and tipiracil demonstrated anti-tumor activity against KRAS wild-type and mutant human colorectal cancer xenografts in mice [Label].

In clinical studies comprised of patients with previously treated metastatic colorectal cancer, treatment of trifluridine in combination with tipiracil in addition to best supportive care over a 5- or 7-month period resulted in increased progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) compared to placebo [5]. In an open-label study, administration of trifluridine at the recommended dosage in patients with advanced solid tumors had no clinically relevant effect on QT/QTc prolongation compared with placebo [Label]. Two out of 48 patients displayed had QTc greater than 500 msec and 1 of 42 patients (2.4%) had a QTc increase from baseline greater than 60 msec [Label].

Mechanism of action

The mechanism of action of trifluridine as an antiviral agent has not been fully elucidated, but appears to involve the inhibition of viral replication. Trifluridine gets incorporated into viral DNA during replication, which leads to the formation of defective proteins and an increased mutation rate. Trifluridine also mediates antineoplastic activities via this mechanism; following uptake into cancer cells, trifluridine is rapidly phosphorylated by thymidine kinase to its active monophosphate form [2]. Subsequent phosphorylation produces trifluridine triphosphate [2], which is readily incorporated into the DNA of tumour cells in place of thymidine bases to perturb DNA function, DNA synthesis, and tumour cell proliferation [Label]. As trifluridine is subject to rapid degradation by TPase and readily metabolised by a first-pass effect following oral administration, tipiracil is added in the antineoplastic combination product as an inhibitor of TPase to increase the bioavailability of trifluridine [5]. Trifluridine monophosphate also reversibly inhibits thymidylate synthetase (TS), an enzyme that is necessary for DNA synthesis and which levels are shown to be elevated different cancer cell lines [3]. Up-regulation of the expression of the TS enzyme may also lead to the resistance to antineoplastic therapies, such as 5-fluorouracil (5-FU) [3]. However, this inhibitory effect is not considered to be sufficient enough to fully contribute to the cytotoxicity in cancer cells [2].

TargetActionsOrganism
AThymidylate synthase
inhibitor
Human
ADNA
other/unknown
Human
Absorption

Systemic absorption of trifluridine following therapeutic dosing with ophthalmic trifluridine appears to be negligible [6].

At least 57% of the orally-administered trifluridine is absorbed [5]. Following twice daily oral dosing of trifluridine in combination with tipiracil, systemic exposure of trifluridine increased more than dose-proportionally over the dose range of 15 to 35 mg/m^2. Trifluridine accumulation was 3-fold for AUC0-last and 2-fold for peak plasma concentration (Cmax) at steady state [Label]. The time to reach the peak plasma concentrations (Cmax) was 2 hours [Label]. Tipiracil increases the AUC and Cmax of trifluridine. Food intake was shown to decrease the Cmax and AUC compared to those in a fasting state [5].

Volume of distribution

Following a single dose of Lonsurf (35 mg/m2) in patients with advanced solid tumours, the apparent volume of distribution (Vd/F) for trifluridine was 21 L [5].

Protein binding

In vitro findings suggest that the protein binding of trifluridine in human plasma is greater than 96%, where it is mainly bound to human serum albumin. Protein binding of trifluridine is independent of drug concentration and presence of tipiracil [Label].

Metabolism

One major metabolite, 5-carboxy-2'-deoxyuridine found on the endothelial side of the cornea, indicating localized metabolism [4, 6].

Trifluridine is mainly eliminated by metabolism via thymidine phosphorylase (TPase) to form an inactive metabolite, 5-(trifluoromethyl) uracil (FTY) [Label].

Route of elimination

About 55% of the total recovered radio-labelled trifluridine was detected in the urine within 24 hours [5]. Following oral administration of trifluridine in combination with tipiracil, only 3% of the total dose was excreted into faeces and expired air [5]. Administration of a 60mg single oral dose of the combination product resulted in the mean urinary recovery of 1.5% of unchanged trifluridine and 19.2% for the inactive metabolite FTY after the 48-hour cumulative excretion [5].

Half life

The half life is 12 to 18 minutes following ophthalmic administration [6].

After administration of trifluridine with tipiracil at oral doses 35 mg/m^2 twice daily, the mean elimination half-life (t1/2) of trifluridine was 1.4 hours following a single dose [Label]. At steady state, the mean elimination half-life was 2.1 hours [Label].

Clearance

Following a single dose of Lonsurf (35 mg/m^2) in patients with advanced solid tumours, the oral clearance (CL/F) for trifluridine was 10.5 L/hr.

Toxicity

Intravenous LD50 in rat was 2946 mg/kg [MSDS]. Oral LD50 in rat and mouse were > 4379mg/kg [MSDS]. Overdosage via ocular instillation is unlikely. The highest dose of orally-administered Lonsurf, trifluridine in combination with tipiracil, administered in clinical studies was 180 mg/m^2 per day. The primary anticipated complication of an overdose is bone marrow suppression. There is no known antidote for trifluridine overdose: in case of an overdose, management should include customary therapeutic and supportive medical intervention aimed at correcting the presenting clinical manifestations and preventing their possible complications [5]. Based on the findings from animal studies, trifluridine may cause fetal toxicity when administered to pregnant patients [5].

Affected organisms
  • Human Herpes Virus
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2-MethoxyethanolThe risk or severity of adverse effects can be increased when Trifluridine is combined with 2-Methoxyethanol.
9-(N-methyl-L-isoleucine)-cyclosporin AThe risk or severity of adverse effects can be increased when Trifluridine is combined with 9-(N-methyl-L-isoleucine)-cyclosporin A.
AbacavirTrifluridine may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbataceptThe risk or severity of adverse effects can be increased when Trifluridine is combined with Abatacept.
AbetimusThe risk or severity of adverse effects can be increased when Trifluridine is combined with Abetimus.
AcarboseAcarbose may decrease the excretion rate of Trifluridine which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Trifluridine which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Trifluridine which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Trifluridine which could result in a higher serum level.
AcetazolamideThe excretion of Trifluridine can be decreased when combined with Acetazolamide.
Food Interactions
Not Available

References

General References
  1. Carmine AA, Brogden RN, Heel RC, Speight TM, Avery GS: Trifluridine: a review of its antiviral activity and therapeutic use in the topical treatment of viral eye infections. Drugs. 1982 May;23(5):329-53. [PubMed:6284470]
  2. Burness CB, Duggan ST: Trifluridine/Tipiracil: A Review in Metastatic Colorectal Cancer. Drugs. 2016 Sep;76(14):1393-402. doi: 10.1007/s40265-016-0633-9. [PubMed:27568360]
  3. Matsuoka K, Nakagawa F, Kobunai T, Takechi T: Trifluridine/tipiracil overcomes the resistance of human gastric 5-fluorouracil-refractory cells with high thymidylate synthase expression. Oncotarget. 2018 Feb 5;9(17):13438-13450. doi: 10.18632/oncotarget.24412. eCollection 2018 Mar 2. [PubMed:29568368]
  4. Pavan-Langston D, Nelson DJ: Intraocular penetration of trifluridine. Am J Ophthalmol. 1979 Jun;87(6):814-8. [PubMed:110152]
  5. Lonsurf Summary of Product Characteristics- European Medicines Agency - Europa EU [File]
  6. DailyMed Label: VIROPTIC® Ophthalmic Solution, 1% Sterile (trifluridine ophthalmic solution) [File]
External Links
Human Metabolome Database
HMDB0014576
KEGG Drug
D00391
PubChem Compound
6256
PubChem Substance
46506192
ChemSpider
6020
BindingDB
50132298
ChEBI
75179
ChEMBL
CHEMBL1129
Therapeutic Targets Database
DAP000760
PharmGKB
PA451775
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Trifluridine
ATC Codes
L01BC59 — Trifluridine, combinationsS01AD02 — Trifluridine
AHFS Codes
  • 52:04.20 — Antivirals
FDA label
Download (490 KB)
MSDS
Download (50.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentNeoplasms Malignant1
1CompletedTreatmentAdvanced Solid Tumors1
1CompletedTreatmentMetastatic Colorectal Cancers1
1Not Yet RecruitingTreatmentAdvanced or Metastatic Colorectal Cancer (mCRC) / Advanced or Metastatic Solid Tumors1
1RecruitingTreatmentHepatic Metastases / Malignant Neoplasm of Colon / Rectal Carcinoma1
1RecruitingTreatmentPretreated Metastatic Colorectal Cancer1
1RecruitingTreatmentRAS Family Gene Mutation / Stage III Colon Cancer AJCC v7 / Stage III Colorectal Cancer AJCC v7 / Stage III Rectal Cancer AJCC v7 / Stage IIIA Colon Cancer AJCC v7 / Stage IIIA Colorectal Cancer AJCC v7 / Stage IIIA Rectal Cancer AJCC v7 / Stage IIIB Colon Cancer AJCC v7 / Stage IIIB Colorectal Cancer AJCC v7 / Stage IIIB Rectal Cancer AJCC v7 / Stage IIIC Colon Cancer AJCC v7 / Stage IIIC Colorectal Cancer AJCC v7 / Stage IIIC Rectal Cancer AJCC v7 / Stage IV Colon Cancer AJCC v7 / Stage IV Colorectal Cancer AJCC v7 / Stage IV Rectal Cancer AJCC v7 / Stage IVA Colon Cancer AJCC v7 / Stage IVA Colorectal Cancer AJCC v7 / Stage IVA Rectal Cancer AJCC v7 / Stage IVB Colon Cancer AJCC v7 / Stage IVB Colorectal Cancer AJCC v7 / Stage IVB Rectal Cancer AJCC v71
1RecruitingTreatmentRectal Adenocarcinoma / Recurrent Rectal Carcinoma / Stage IV Rectal Cancer AJCC v7 / Stage IVA Rectal Cancer AJCC v7 / Stage IVB Rectal Cancer AJCC v71
1, 2RecruitingTreatmentAdvanced Gastric Cancer / Colorectal Adenocarcinoma / Gastric Adenocarcinoma / Non-Resectable Cholangiocarcinoma / Pancreatic Adenocarcinoma Metastatic / Stage IV Colorectal Cancer / Stage IV Pancreatic Cancer / Stage IVA Colorectal Cancer / Stage IVB Colorectal Cancer / Unresectable Pancreatic Carcinoma1
1, 2RecruitingTreatmentColorectal Cancers1
2CompletedTreatmentRefractory, metastatic Colorectal cancer1
2Not Yet RecruitingTreatmentAdenocarcinomas of the Gastroesophageal Junction / Gastric Adenocarcinoma / Malignant Neoplasm of Stomach1
2RecruitingTreatmentMalignant Neoplasm of Pancreas1
2RecruitingTreatmentPreviously Treated Metastatic Colorectal Cancer1
2RecruitingTreatmentSquamous Cell Lung Carcinoma1
2SuspendedTreatmentCholangiocarcinomas / Stage III Gallbladder Cancer AJCC V7 / Stage IIIA Gallbladder Cancer AJCC v7 / Stage IIIB Gallbladder Cancer AJCC v7 / Stage IV Gallbladder Cancer AJCC v7 / Stage IVA Gallbladder Cancer AJCC v7 / Stage IVB Gallbladder Cancer AJCC v71
2TerminatedTreatmentMetastatic Colorectal Cancers1
3Not Yet RecruitingTreatmentCarcinoma NOS / Metastatic Colorectal Cancers1
Not AvailableCompletedTreatmentHerpes Simplex / Human Immunodeficiency Virus (HIV) Infections1
Not AvailableCompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Infection, Mycobacterium Avium-Intracellulare1
Not AvailableRecruitingNot AvailableMetastatic Colorectal Cancers1

Pharmacoeconomics

Manufacturers
  • Alcon laboratories inc
  • Monarch pharmaceuticals inc
Packagers
  • Alcon Laboratories
  • DSM Corp.
  • Falcon Pharmaceuticals Ltd.
  • Monarch Pharmacy
  • Pharmedix
  • Physicians Total Care Inc.
  • Professional Compounding Centers America LLC
  • Watson Pharmaceuticals
Dosage forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
SolutionOphthalmic10 mg/1mL
Solution / dropsOphthalmic10 mg/1mL
SolutionOphthalmic1 %
SolutionOphthalmic1 g/100mL
Prices
Unit descriptionCostUnit
Viroptic 1% Solution 7.5ml Bottle160.07USD bottle
Trifluridine 1% Solution 7.5ml Bottle153.4USD bottle
Trifluridine 1% eye drops19.69USD ml
Viroptic 1% eye drops18.63USD ml
Trifluridine 1 % opth soln15.21USD ml
Sandoz Trifluridine 1 % Solution3.41USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7799783No2006-12-162026-12-16Us
US5744475No1996-03-282016-03-28Us
US6479500No2000-03-162020-03-16Us
US9527833No2014-06-172034-06-17Us
USRE46284No2006-12-162026-12-16Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)186-189PhysProp
water solubilitySolubleMSDS
logP-0.46HANSCH,C ET AL. (1995)
pKa7.95SANGSTER (1994)
Predicted Properties
PropertyValueSource
Water Solubility6.69 mg/mLALOGPS
logP-0.45ALOGPS
logP-0.75ChemAxon
logS-1.6ALOGPS
pKa (Strongest Acidic)7.6ChemAxon
pKa (Strongest Basic)-3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area99.1 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity56.34 m3·mol-1ChemAxon
Polarizability23.07 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9636
Blood Brain Barrier+0.7348
Caco-2 permeable-0.8782
P-glycoprotein substrateNon-substrate0.7103
P-glycoprotein inhibitor INon-inhibitor0.8788
P-glycoprotein inhibitor IINon-inhibitor0.8078
Renal organic cation transporterNon-inhibitor0.9088
CYP450 2C9 substrateNon-substrate0.7706
CYP450 2D6 substrateNon-substrate0.8588
CYP450 3A4 substrateNon-substrate0.5276
CYP450 1A2 substrateNon-inhibitor0.9046
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8903
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8652
Ames testAMES toxic0.9108
CarcinogenicityNon-carcinogens0.7552
BiodegradationNot ready biodegradable0.9698
Rat acute toxicity2.4696 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9897
hERG inhibition (predictor II)Non-inhibitor0.7454
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as pyrimidine 2'-deoxyribonucleosides. These are compounds consisting of a pyrimidine linked to a ribose which lacks a hydroxyl group at position 2.
Kingdom
Organic compounds
Super Class
Nucleosides, nucleotides, and analogues
Class
Pyrimidine nucleosides
Sub Class
Pyrimidine 2'-deoxyribonucleosides
Direct Parent
Pyrimidine 2'-deoxyribonucleosides
Alternative Parents
Pyrimidones / Hydroxypyrimidines / Hydropyrimidines / Tetrahydrofurans / Heteroaromatic compounds / Secondary alcohols / Oxacyclic compounds / Azacyclic compounds / Primary alcohols / Organopnictogen compounds
show 5 more
Substituents
Pyrimidine 2'-deoxyribonucleoside / Pyrimidone / Hydroxypyrimidine / Hydropyrimidine / Pyrimidine / Tetrahydrofuran / Heteroaromatic compound / Secondary alcohol / Oxacycle / Azacycle
show 15 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
organofluorine compound, nucleoside analogue, pyrimidine 2'-deoxyribonucleoside (CHEBI:75179)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Thymidylate synthase activity
Specific Function
Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.
Gene Name
TYMS
Uniprot ID
P04818
Uniprot Name
Thymidylate synthase
Molecular Weight
35715.65 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. De Clercq E: Antiviral drugs in current clinical use. J Clin Virol. 2004 Jun;30(2):115-33. [PubMed:15125867]
  3. Bijnsdorp IV, Kruyt FA, Fukushima M, Smid K, Gokoel S, Peters GJ: Molecular mechanism underlying the synergistic interaction between trifluorothymidine and the epidermal growth factor receptor inhibitor erlotinib in human colorectal cancer cell lines. Cancer Sci. 2010 Feb;101(2):440-7. doi: 10.1111/j.1349-7006.2009.01375.x. Epub 2009 Sep 29. [PubMed:19886911]
  4. Bijnsdorp IV, Peters GJ, Temmink OH, Fukushima M, Kruyt FA: Differential activation of cell death and autophagy results in an increased cytotoxic potential for trifluorothymidine compared to 5-fluorouracil in colon cancer cells. Int J Cancer. 2010 May 15;126(10):2457-68. doi: 10.1002/ijc.24943. [PubMed:19816940]
  5. Bijnsdorp IV, Kruyt FA, Fukushima M, Peters GJ: Trifluorothymidine induces cell death independently of p53. Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):699-703. doi: 10.1080/15257770802145017. [PubMed:18600528]
  6. Madeira VM, Antunes-Madeira MC: Chemical composition of sarcolemma isolated from rabbit skeletal muscle. Biochim Biophys Acta. 1973 Mar 16;298(2):230-8. [PubMed:4719131]
  7. Temmink OH, Hoogeland MF, Fukushima M, Peters GJ: Low folate conditions may enhance the interaction of trifluorothymidine with antifolates in colon cancer cells. Cancer Chemother Pharmacol. 2006 Jan;57(2):171-9. Epub 2005 Jul 12. [PubMed:16010590]
  8. Oberg B, Johansson NG: The relative merits and drawbacks of new nucleoside analogues with clinical potential. J Antimicrob Chemother. 1984 Aug;14 Suppl A:5-26. [PubMed:6436227]
  9. Temmink OH, Comijn EM, Fukushima M, Peters GJ: Intracellular thymidylate synthase inhibition by trifluorothymidine in FM3A cells. Nucleosides Nucleotides Nucleic Acids. 2004 Oct;23(8-9):1491-4. [PubMed:15571283]
  10. Shintani M, Urano M, Takakuwa Y, Kuroda M, Kamoshida S: Immunohistochemical characterization of pyrimidine synthetic enzymes, thymidine kinase-1 and thymidylate synthase, in various types of cancer. Oncol Rep. 2010 May;23(5):1345-50. [PubMed:20372850]
  11. Emura T, Nakagawa F, Fujioka A, Ohshimo H, Kitazato K: Thymidine kinase and thymidine phosphorylase level as the main predictive parameter for sensitivity to TAS-102 in a mouse model. Oncol Rep. 2004 Feb;11(2):381-7. [PubMed:14719072]
  12. Overman MJ, Kopetz S, Varadhachary G, Fukushima M, Kuwata K, Mita A, Wolff RA, Hoff P, Xiong H, Abbruzzese JL: Phase I clinical study of three times a day oral administration of TAS-102 in patients with solid tumors. Cancer Invest. 2008 Oct;26(8):794-9. doi: 10.1080/07357900802087242. [PubMed:18798063]
  13. Hong DS, Abbruzzese JL, Bogaard K, Lassere Y, Fukushima M, Mita A, Kuwata K, Hoff PM: Phase I study to determine the safety and pharmacokinetics of oral administration of TAS-102 in patients with solid tumors. Cancer. 2006 Sep 15;107(6):1383-90. [PubMed:16902987]
  14. Temmink OH, Prins HJ, van Gelderop E, Peters GJ: The Hollow Fibre Assay as a model for in vivo pharmacodynamics of fluoropyrimidines in colon cancer cells. Br J Cancer. 2007 Jan 15;96(1):61-6. Epub 2006 Dec 19. [PubMed:17179993]
  15. Bassler R, Buchwald W: [Experimental inflammation and fibrosis of the lung framework caused by ionizing rays. Light and electron microscopic studies]. Fortschr Geb Rontgenstr Nuklearmed. 1966 Feb;104(2):192-206. [PubMed:6010427]
2. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
Yes
Actions
Other/unknown
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
References
  1. Bijnsdorp IV, Kruyt FA, Fukushima M, Smid K, Gokoel S, Peters GJ: Molecular mechanism underlying the synergistic interaction between trifluorothymidine and the epidermal growth factor receptor inhibitor erlotinib in human colorectal cancer cell lines. Cancer Sci. 2010 Feb;101(2):440-7. doi: 10.1111/j.1349-7006.2009.01375.x. Epub 2009 Sep 29. [PubMed:19886911]
  2. Bijnsdorp IV, Peters GJ, Temmink OH, Fukushima M, Kruyt FA: Differential activation of cell death and autophagy results in an increased cytotoxic potential for trifluorothymidine compared to 5-fluorouracil in colon cancer cells. Int J Cancer. 2010 May 15;126(10):2457-68. doi: 10.1002/ijc.24943. [PubMed:19816940]
  3. Bijnsdorp IV, Kruyt FA, Fukushima M, Peters GJ: Trifluorothymidine induces cell death independently of p53. Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):699-703. doi: 10.1080/15257770802145017. [PubMed:18600528]
  4. Madeira VM, Antunes-Madeira MC: Chemical composition of sarcolemma isolated from rabbit skeletal muscle. Biochim Biophys Acta. 1973 Mar 16;298(2):230-8. [PubMed:4719131]
  5. Temmink OH, Hoogeland MF, Fukushima M, Peters GJ: Low folate conditions may enhance the interaction of trifluorothymidine with antifolates in colon cancer cells. Cancer Chemother Pharmacol. 2006 Jan;57(2):171-9. Epub 2005 Jul 12. [PubMed:16010590]
  6. Oberg B, Johansson NG: The relative merits and drawbacks of new nucleoside analogues with clinical potential. J Antimicrob Chemother. 1984 Aug;14 Suppl A:5-26. [PubMed:6436227]
  7. Emura T, Nakagawa F, Fujioka A, Ohshimo H, Kitazato K: Thymidine kinase and thymidine phosphorylase level as the main predictive parameter for sensitivity to TAS-102 in a mouse model. Oncol Rep. 2004 Feb;11(2):381-7. [PubMed:14719072]
  8. Overman MJ, Kopetz S, Varadhachary G, Fukushima M, Kuwata K, Mita A, Wolff RA, Hoff P, Xiong H, Abbruzzese JL: Phase I clinical study of three times a day oral administration of TAS-102 in patients with solid tumors. Cancer Invest. 2008 Oct;26(8):794-9. doi: 10.1080/07357900802087242. [PubMed:18798063]
  9. Hong DS, Abbruzzese JL, Bogaard K, Lassere Y, Fukushima M, Mita A, Kuwata K, Hoff PM: Phase I study to determine the safety and pharmacokinetics of oral administration of TAS-102 in patients with solid tumors. Cancer. 2006 Sep 15;107(6):1383-90. [PubMed:16902987]
  10. Temmink OH, Prins HJ, van Gelderop E, Peters GJ: The Hollow Fibre Assay as a model for in vivo pharmacodynamics of fluoropyrimidines in colon cancer cells. Br J Cancer. 2007 Jan 15;96(1):61-6. Epub 2006 Dec 19. [PubMed:17179993]
  11. Bassler R, Buchwald W: [Experimental inflammation and fibrosis of the lung framework caused by ionizing rays. Light and electron microscopic studies]. Fortschr Geb Rontgenstr Nuklearmed. 1966 Feb;104(2):192-206. [PubMed:6010427]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Zinc ion binding
Specific Function
Not Available
Gene Name
TK1
Uniprot ID
P04183
Uniprot Name
Thymidine kinase, cytosolic
Molecular Weight
25468.455 Da
References
  1. Temmink OH, Comijn EM, Fukushima M, Peters GJ: Intracellular thymidylate synthase inhibition by trifluorothymidine in FM3A cells. Nucleosides Nucleotides Nucleic Acids. 2004 Oct;23(8-9):1491-4. [PubMed:15571283]
  2. Shintani M, Urano M, Takakuwa Y, Kuroda M, Kamoshida S: Immunohistochemical characterization of pyrimidine synthetic enzymes, thymidine kinase-1 and thymidylate synthase, in various types of cancer. Oncol Rep. 2010 May;23(5):1345-50. [PubMed:20372850]
  3. Emura T, Nakagawa F, Fujioka A, Ohshimo H, Yokogawa T, Okabe H, Kitazato K: An optimal dosing schedule for a novel combination antimetabolite, TAS-102, based on its intracellular metabolism and its incorporation into DNA. Int J Mol Med. 2004 Feb;13(2):249-55. [PubMed:14719131]
  4. Emura T, Nakagawa F, Fujioka A, Ohshimo H, Kitazato K: Thymidine kinase and thymidine phosphorylase level as the main predictive parameter for sensitivity to TAS-102 in a mouse model. Oncol Rep. 2004 Feb;11(2):381-7. [PubMed:14719072]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Transferase activity, transferring pentosyl groups
Specific Function
May have a role in maintaining the integrity of the blood vessels. Has growth promoting activity on endothelial cells, angiogenic activity in vivo and chemotactic activity on endothelial cells in v...
Gene Name
TYMP
Uniprot ID
P19971
Uniprot Name
Thymidine phosphorylase
Molecular Weight
49954.965 Da
References
  1. Temmink OH, Comijn EM, Fukushima M, Peters GJ: Intracellular thymidylate synthase inhibition by trifluorothymidine in FM3A cells. Nucleosides Nucleotides Nucleic Acids. 2004 Oct;23(8-9):1491-4. [PubMed:15571283]
  2. Emura T, Nakagawa F, Fujioka A, Ohshimo H, Kitazato K: Thymidine kinase and thymidine phosphorylase level as the main predictive parameter for sensitivity to TAS-102 in a mouse model. Oncol Rep. 2004 Feb;11(2):381-7. [PubMed:14719072]
  3. Overman MJ, Kopetz S, Varadhachary G, Fukushima M, Kuwata K, Mita A, Wolff RA, Hoff P, Xiong H, Abbruzzese JL: Phase I clinical study of three times a day oral administration of TAS-102 in patients with solid tumors. Cancer Invest. 2008 Oct;26(8):794-9. doi: 10.1080/07357900802087242. [PubMed:18798063]
  4. Hong DS, Abbruzzese JL, Bogaard K, Lassere Y, Fukushima M, Mita A, Kuwata K, Hoff PM: Phase I study to determine the safety and pharmacokinetics of oral administration of TAS-102 in patients with solid tumors. Cancer. 2006 Sep 15;107(6):1383-90. [PubMed:16902987]
  5. Temmink OH, Prins HJ, van Gelderop E, Peters GJ: The Hollow Fibre Assay as a model for in vivo pharmacodynamics of fluoropyrimidines in colon cancer cells. Br J Cancer. 2007 Jan 15;96(1):61-6. Epub 2006 Dec 19. [PubMed:17179993]
  6. Bassler R, Buchwald W: [Experimental inflammation and fibrosis of the lung framework caused by ionizing rays. Light and electron microscopic studies]. Fortschr Geb Rontgenstr Nuklearmed. 1966 Feb;104(2):192-206. [PubMed:6010427]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
Substrate profile was investigated in vitro using rat OAT1 expressed on Xenopus Laevis.
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. Wada S, Tsuda M, Sekine T, Cha SH, Kimura M, Kanai Y, Endou H: Rat multispecific organic anion transporter 1 (rOAT1) transports zidovudine, acyclovir, and other antiviral nucleoside analogs. J Pharmacol Exp Ther. 2000 Sep;294(3):844-9. [PubMed:10945832]
  2. VanWert AL, Gionfriddo MR, Sweet DH: Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology. Biopharm Drug Dispos. 2010 Jan;31(1):1-71. doi: 10.1002/bdd.693. [PubMed:19953504]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Pyrimidine- and adenine-specific:sodium symporter activity
Specific Function
Sodium-dependent and pyrimidine-selective. Exhibits the transport characteristics of the nucleoside transport system cit or N2 subtype (N2/cit) (selective for pyrimidine nucleosides and adenosine)....
Gene Name
SLC28A1
Uniprot ID
O00337
Uniprot Name
Sodium/nucleoside cotransporter 1
Molecular Weight
71583.18 Da
References
  1. Lonsurf Summary of Product Characteristics- European Medicines Agency - Europa EU [File]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Nucleoside transmembrane transporter activity
Specific Function
Mediates both influx and efflux of nucleosides across the membrane (equilibrative transporter). It is sensitive (ES) to low concentrations of the inhibitor nitrobenzylmercaptopurine riboside (NBMPR...
Gene Name
SLC29A1
Uniprot ID
Q99808
Uniprot Name
Equilibrative nucleoside transporter 1
Molecular Weight
50218.805 Da
References
  1. Lonsurf Summary of Product Characteristics- European Medicines Agency - Europa EU [File]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Nucleoside transmembrane transporter activity
Specific Function
Mediates equilibrative transport of purine, pyrimidine nucleosides and the purine base hypoxanthine. Very less sensitive than SLC29A1 to inhibition by nitrobenzylthioinosine (NBMPR), dipyridamole, ...
Gene Name
SLC29A2
Uniprot ID
Q14542
Uniprot Name
Equilibrative nucleoside transporter 2
Molecular Weight
50112.335 Da
References
  1. Lonsurf Summary of Product Characteristics- European Medicines Agency - Europa EU [File]

Drug created on June 13, 2005 07:24 / Updated on November 13, 2018 07:47