General Information of Drug Combination (ID: DCHME68)

Drug Combination Name
Trifluridine Fludarabine
Indication
Disease Entry Status REF
Papillary renal cell carcinoma Investigative [1]
Component Drugs Trifluridine   DMG2YBD Fludarabine   DMVRLT7
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: ACHN
Zero Interaction Potency (ZIP) Score: 0.7
Bliss Independence Score: 3.35
Loewe Additivity Score: 6.5
LHighest Single Agent (HSA) Score: 8.99

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Trifluridine
Disease Entry ICD 11 Status REF
Herpetic keratitis 1F00.10 Approved [2]
Virus infection 1A24-1D9Z Approved [3]
Colon cancer 2B90.Z Investigative [2]
Trifluridine Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Candida Thymidylate synthase (Candi TMP1) TTU6BFZ TYSY_CANAL Inhibitor [6]
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Trifluridine Interacts with 4 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
Organic anion transporter 1 (SLC22A6) DTQ23VB S22A6_HUMAN Substrate [7]
Concentrative nucleoside transporter 1 (SLC28A1) DT0EQPW S28A1_HUMAN Substrate [8]
Equilibrative nucleoside transporter 1 (SLC29A1) DTXD1TQ S29A1_HUMAN Substrate [8]
Equilibrative nucleoside transporter 2 (SLC29A2) DTW78DQ S29A2_HUMAN Substrate [8]
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Trifluridine Interacts with 1 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Thymidine phosphorylase (TYMP) DE4HCYL TYPH_HUMAN Metabolism [9]
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Trifluridine Interacts with 7 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Nuclear receptor subfamily 1 group I member 2 (NR1I2) OTC5U0N5 NR1I2_HUMAN Increases Activity [10]
Cellular tumor antigen p53 (TP53) OTIE1VH3 P53_HUMAN Affects Activity [11]
Cathepsin B (CTSB) OTP9G5QB CATB_HUMAN Increases Cleavage [12]
Poly polymerase 1 (PARP1) OT310QSG PARP1_HUMAN Increases Cleavage [12]
Caspase-9 (CASP9) OTD4RFFG CASP9_HUMAN Increases Cleavage [12]
Caspase-8 (CASP8) OTA8TVI8 CASP8_HUMAN Increases Cleavage [12]
Nuclear factor erythroid 2-related factor 2 (NFE2L2) OT0HENJ5 NF2L2_HUMAN Increases Activity [13]
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⏷ Show the Full List of 7 DOT(s)
Indication(s) of Fludarabine
Disease Entry ICD 11 Status REF
Acute myelogenous leukaemia 2A41 Approved [4]
Cutaneous melanoma 2C30 Approved [4]
Haematological malignancy 2B33.Y Approved [5]
Hematologic disease 3C0Z Approved [4]
Hepatosplenic T-cell lymphoma N.A. Approved [4]
Immunodeficiency 4A00-4A85 Approved [4]
Large granular lymphocytic leukemia 2A90.1 Approved [4]
Lung cancer 2C25.0 Approved [4]
MALT lymphoma N.A. Approved [4]
Multiple sclerosis 8A40 Approved [4]
Myeloproliferative neoplasm 2A20 Approved [4]
Nodal marginal zone lymphoma 2A85.0 Approved [4]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified N.A. Approved [4]
Recurrent adult burkitt lymphoma 2A85.6 Approved [4]
Small intestine lymphoma N.A. Approved [4]
Splenic marginal zone lymphoma N.A. Approved [4]
Systemic lupus erythematosus 4A40.0 Approved [4]
Systemic sclerosis 4A42 Approved [4]
Testicular lymphoma N.A. Approved [4]
Classic Hodgkin lymphoma N.A. Investigative [4]
Colon cancer 2B90.Z Investigative [4]
Gastric cancer 2B72 Investigative [4]
Neuroblastoma 2D11.2 Investigative [4]
Fludarabine Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Adenosine deaminase (ADA) TTLP57V ADA_HUMAN Inhibitor [17]
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Fludarabine Interacts with 22 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A) OTBPCU2O TR10A_HUMAN Affects Expression [18]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B) OTA1CPBV TR10B_HUMAN Increases Expression [19]
Cellular tumor antigen p53 (TP53) OTIE1VH3 P53_HUMAN Increases Expression [19]
Proliferating cell nuclear antigen (PCNA) OTHZ1RIA PCNA_HUMAN Increases Expression [20]
Matrix metalloproteinase-9 (MMP9) OTB2QDAV MMP9_HUMAN Increases Expression [21]
Histone H2AX (H2AX) OT18UX57 H2AX_HUMAN Increases Expression [14]
Tumor necrosis factor receptor superfamily member 6 (FAS) OTP9XG86 TNR6_HUMAN Increases Expression [22]
DNA cytosine-5)-methyltransferase 1 (DNMT1) OTM2DGTK DNMT1_HUMAN Decreases Expression [23]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Decreases Phosphorylation [15]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Decreases Phosphorylation [15]
RAC-alpha serine/threonine-protein kinase (AKT1) OT8H2YY7 AKT1_HUMAN Increases Activity [24]
Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2) OTUE7Z91 MP2K2_HUMAN Increases Activity [24]
Cyclin-dependent kinase inhibitor 1 (CDKN1A) OTQWHCZE CDN1A_HUMAN Increases Expression [20]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [22]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN) OTOWDUNT PTEN_HUMAN Increases Expression [23]
Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1) OT4Y9NQI MP2K1_HUMAN Increases Activity [24]
Bcl-2-like protein 1 (BCL2L1) OTRC5K9O B2CL1_HUMAN Decreases Expression [21]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) OT2YYI1A MCL1_HUMAN Decreases Expression [21]
Caspase-8 (CASP8) OTA8TVI8 CASP8_HUMAN Increases Activity [22]
Hypoxia-inducible factor 1-alpha (HIF1A) OTADSC03 HIF1A_HUMAN Decreases Expression [15]
Bcl-2-binding component 3, isoforms 3/4 (BBC3) OTUAXDAY BBC3B_HUMAN Increases Expression [16]
Growth/differentiation factor 15 (GDF15) OTWQN50N GDF15_HUMAN Increases Expression [20]
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⏷ Show the Full List of 22 DOT(s)

References

1 Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
2 Trifluridine FDA Label
3 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8697).
4 Fludarabine FDA Label
5 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4802).
6 Trifluorothymidine induces cell death independently of p53. Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):699-703.
7 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.
8 Lonsurf, INN-trifluridine/tipiracil.
9 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.
10 Screening of a chemical library reveals novel PXR-activating pharmacologic compounds. Toxicol Lett. 2015 Jan 5;232(1):193-202. doi: 10.1016/j.toxlet.2014.10.009. Epub 2014 Oct 16.
11 Identification of environmental chemicals that activate p53 signaling after in vitro metabolic activation. Arch Toxicol. 2022 Jul;96(7):1975-1987. doi: 10.1007/s00204-022-03291-5. Epub 2022 Apr 18.
12 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.
13 Identification of Compounds That Inhibit Estrogen-Related Receptor Alpha Signaling Using High-Throughput Screening Assays. Molecules. 2019 Feb 27;24(5):841. doi: 10.3390/molecules24050841.
14 Role of histone deacetylase inhibitor-induced reactive oxygen species and DNA damage in LAQ-824/fludarabine antileukemic interactions. Mol Cancer Ther. 2008 Oct;7(10):3285-97. doi: 10.1158/1535-7163.MCT-08-0385.
15 9-beta-D-arabinofuranosyl-2-fluoroadenine inhibits expression of vascular endothelial growth factor through hypoxia-inducible factor-1 in human ovarian cancer cells. Mol Pharmacol. 2004 Jul;66(1):178-86. doi: 10.1124/mol.66.1.178.
16 MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells. Blood. 2006 May 15;107(10):4109-14. doi: 10.1182/blood-2005-08-3273. Epub 2006 Jan 26.
17 Purine nucleoside analogs in indolent non-Hodgkin's lymphoma. Oncology (Williston Park). 2000 Jun;14(6 Suppl 2):13-5.
18 Role of the TRAIL/APO2-L death receptors in chlorambucil- and fludarabine-induced apoptosis in chronic lymphocytic leukemia. Oncogene. 2003 Nov 13;22(51):8356-69. doi: 10.1038/sj.onc.1207004.
19 Differential effects of chemotherapeutic drugs versus the MDM-2 antagonist nutlin-3 on cell cycle progression and induction of apoptosis in SKW6.4 lymphoblastoid B-cells. J Cell Biochem. 2008 May 15;104(2):595-605. doi: 10.1002/jcb.21649.
20 Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL). Blood. 2006 May 15;107(10):4122-9. doi: 10.1182/blood-2005-11-4465. Epub 2006 Jan 26.
21 Matrix metalloproteinase-9 is involved in chronic lymphocytic leukemia cell response to fludarabine and arsenic trioxide. PLoS One. 2014 Jun 23;9(6):e99993. doi: 10.1371/journal.pone.0099993. eCollection 2014.
22 Caspase 8 activation independent of Fas (CD95/APO-1) signaling may mediate killing of B-chronic lymphocytic leukemia cells by cytotoxic drugs or gamma radiation. Blood. 2001 Nov 1;98(9):2800-7. doi: 10.1182/blood.v98.9.2800.
23 Comparative effects of retinoic acid, vitamin D and resveratrol alone and in combination with adenosine analogues on methylation and expression of phosphatase and tensin homologue tumour suppressor gene in breast cancer cells. Br J Nutr. 2012 Mar;107(6):781-90. doi: 10.1017/S0007114511003631. Epub 2011 Aug 1.
24 The histone deacetylase inhibitor MS-275 interacts synergistically with fludarabine to induce apoptosis in human leukemia cells. Cancer Res. 2004 Apr 1;64(7):2590-600. doi: 10.1158/0008-5472.can-03-2631.