Details of the Drug Combination

General Information of Drug Combination (ID: DCFXMSL)

• Drug Combination Name: Thiotepa + Fludarabine
• Indication: Leukemia; Status: Phase 1 [1]
• Component Drugs:
  Thiotepa (DMIZKOP): Small molecular drug
  Fludarabine (DMVRLT7): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

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]

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]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Acute Myeloid Leukaemia	DCEDCHE	N. A.	Phase 2	[27]

References

• [1] ClinicalTrials.gov (NCT00392782) Donor Stem Cell Transplant in Treating Patients With Myeloid Cancer or Other Disease
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• [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 (NCT04217278) A Trial of Treatments to Assess the Effects on Outcome of Adults With AML and MDS Undergoing Allogeneic SCT