General Information of Drug Combination (ID: DCEDCHE)

Drug Combination Name
Thiotepa Fludarabine
Indication
Disease Entry Status REF
Acute Myeloid Leukaemia Phase 2 [1]
Component Drugs Thiotepa   DMIZKOP Fludarabine   DMVRLT7
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Thiotepa
Disease Entry ICD 11 Status REF
Breast cancer 2C60-2C65 Approved [2]
Immunodeficiency 4A00-4A85 Approved [3]
Leukemia N.A. Approved [3]
Urinary bladder cancer N.A. Approved [3]
Classic Hodgkin lymphoma N.A. Investigative [3]
Neuroblastoma 2D11.2 Investigative [3]
Thiotepa Interacts with 2 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [7]
Glutathione S-transferase alpha-1 (GSTA1) DE4ZHS1 GSTA1_HUMAN Metabolism [8]
------------------------------------------------------------------------------------
Thiotepa Interacts with 17 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) OTQGYY83 CP3A4_HUMAN Affects Export [9]
Glutathione S-transferase A1 (GSTA1) OTA7K5XA GSTA1_HUMAN Affects Export [9]
Cytochrome P450 2B6 (CYP2B6) OTOYO4S7 CP2B6_HUMAN Decreases Activity [10]
Apoptosis regulator Bcl-2 (BCL2) OT9DVHC0 BCL2_HUMAN Decreases Expression [6]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [6]
Apoptosis regulator BAX (BAX) OTAW0V4V BAX_HUMAN Increases Expression [6]
Bcl-2-like protein 1 (BCL2L1) OTRC5K9O B2CL1_HUMAN Increases Expression [6]
Bcl-2 homologous antagonist/killer (BAK1) OTDP6ILW BAK_HUMAN Increases Expression [6]
Bcl2-associated agonist of cell death (BAD) OT63ERYM BAD_HUMAN Increases Expression [6]
DNA repair nuclease/redox regulator APEX1 (APEX1) OT53OI14 APEX1_HUMAN Increases Response To Substance [11]
Aldehyde dehydrogenase, dimeric NADP-preferring (ALDH3A1) OTAYZZE6 AL3A1_HUMAN Affects Response To Substance [12]
Aldehyde dehydrogenase 1A1 (ALDH1A1) OTCUWZKB AL1A1_HUMAN Affects Response To Substance [12]
Multidrug resistance-associated protein 1 (ABCC1) OTGUN89S MRP1_HUMAN Decreases Response To Substance [13]
N-glycosylase/DNA lyase (OGG1) OTJ97TF3 OGG1_HUMAN Decreases Response To Substance [14]
Glutathione S-transferase P (GSTP1) OTLP0A0Y GSTP1_HUMAN Decreases Response To Substance [8]
Receptor tyrosine-protein kinase erbB-2 (ERBB2) OTOAUNCK ERBB2_HUMAN Affects Response To Substance [15]
Cytochrome P450 3A5 (CYP3A5) OTSXFBXB CP3A5_HUMAN Affects Export [9]
------------------------------------------------------------------------------------
⏷ Show the Full List of 17 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 [19]
------------------------------------------------------------------------------------
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 [20]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B) OTA1CPBV TR10B_HUMAN Increases Expression [21]
Cellular tumor antigen p53 (TP53) OTIE1VH3 P53_HUMAN Increases Expression [21]
Proliferating cell nuclear antigen (PCNA) OTHZ1RIA PCNA_HUMAN Increases Expression [22]
Matrix metalloproteinase-9 (MMP9) OTB2QDAV MMP9_HUMAN Increases Expression [23]
Histone H2AX (H2AX) OT18UX57 H2AX_HUMAN Increases Expression [16]
Tumor necrosis factor receptor superfamily member 6 (FAS) OTP9XG86 TNR6_HUMAN Increases Expression [24]
DNA cytosine-5)-methyltransferase 1 (DNMT1) OTM2DGTK DNMT1_HUMAN Decreases Expression [25]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Decreases Phosphorylation [17]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Decreases Phosphorylation [17]
RAC-alpha serine/threonine-protein kinase (AKT1) OT8H2YY7 AKT1_HUMAN Increases Activity [26]
Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2) OTUE7Z91 MP2K2_HUMAN Increases Activity [26]
Cyclin-dependent kinase inhibitor 1 (CDKN1A) OTQWHCZE CDN1A_HUMAN Increases Expression [22]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [24]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN) OTOWDUNT PTEN_HUMAN Increases Expression [25]
Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1) OT4Y9NQI MP2K1_HUMAN Increases Activity [26]
Bcl-2-like protein 1 (BCL2L1) OTRC5K9O B2CL1_HUMAN Decreases Expression [23]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) OT2YYI1A MCL1_HUMAN Decreases Expression [23]
Caspase-8 (CASP8) OTA8TVI8 CASP8_HUMAN Increases Activity [24]
Hypoxia-inducible factor 1-alpha (HIF1A) OTADSC03 HIF1A_HUMAN Decreases Expression [17]
Bcl-2-binding component 3, isoforms 3/4 (BBC3) OTUAXDAY BBC3B_HUMAN Increases Expression [18]
Growth/differentiation factor 15 (GDF15) OTWQN50N GDF15_HUMAN Increases Expression [22]
------------------------------------------------------------------------------------
⏷ Show the Full List of 22 DOT(s)

Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
Leukemia DCFXMSL N. A. Phase 1 [27]
------------------------------------------------------------------------------------

References

1 ClinicalTrials.gov (NCT04217278) A Trial of Treatments to Assess the Effects on Outcome of Adults With AML and MDS Undergoing Allogeneic SCT
2 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: 7622).
3 Thiotepa FDA Label
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 Susceptibility to drug-induced apoptosis correlates with differential modulation of Bad, Bcl-2 and Bcl-xL protein levels. Cell Death Differ. 2000 Jun;7(6):574-86. doi: 10.1038/sj.cdd.4400688.
7 Cytochrome P450 isozymes 3A4 and 2B6 are involved in the in vitro human metabolism of thiotepa to TEPA. Cancer Chemother Pharmacol. 2002 Jun;49(6):461-7.
8 Differential catalytic efficiency of allelic variants of human glutathione S-transferase Pi in catalyzing the glutathione conjugation of thiotepa. Arch Biochem Biophys. 1999 Jun 1;366(1):89-94.
9 Polymorphisms of drug-metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa. Br J Clin Pharmacol. 2009 Jan;67(1):50-60. doi: 10.1111/j.1365-2125.2008.03321.x. Epub 2008 Nov 17.
10 The naturally occurring cytochrome P450 (P450) 2B6 K262R mutant of P450 2B6 exhibits alterations in substrate metabolism and inactivation. Drug Metab Dispos. 2005 Jun;33(6):795-802.
11 Impairment of APE1 function enhances cellular sensitivity to clinically relevant alkylators and antimetabolites. Mol Cancer Res. 2009 Jun;7(6):897-906. doi: 10.1158/1541-7786.MCR-08-0519. Epub 2009 May 26.
12 Relations between polymorphisms in drug-metabolising enzymes and toxicity of chemotherapy with cyclophosphamide, thiotepa and carboplatin. Pharmacogenet Genomics. 2008 Nov;18(11):1009-15. doi: 10.1097/FPC.0b013e328313aaa4.
13 [Establishment of MRP-overexpression subline of bladder carcinoma and its MDR phenotype]. Zhonghua Zhong Liu Za Zhi. 2000 Jul;22(4):273-5.
14 Protection of mammalian cells against chemotherapeutic agents thiotepa, 1,3-N,N'-bis(2-chloroethyl)-N-nitrosourea, and mafosfamide using the DNA base excision repair genes Fpg and alpha-hOgg1: implications for protective gene therapy applications. J Pharmacol Exp Ther. 2001 Mar;296(3):825-31.
15 Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene. 1999 Apr 1;18(13):2241-51. doi: 10.1038/sj.onc.1202526.
16 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.
17 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.
18 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.
19 Purine nucleoside analogs in indolent non-Hodgkin's lymphoma. Oncology (Williston Park). 2000 Jun;14(6 Suppl 2):13-5.
20 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.
21 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.
22 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.
23 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.
24 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.
25 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.
26 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.
27 ClinicalTrials.gov (NCT00392782) Donor Stem Cell Transplant in Treating Patients With Myeloid Cancer or Other Disease