Details of the Drug Combination

General Information of Drug Combination (ID: DCF0T6F)

• Drug Combination Name: Fludarabine + Taxol
• Indication: Adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  Fludarabine (DMVRLT7): Small molecular drug
  Taxol (DMUOT9V): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HT29
  Zero Interaction Potency (ZIP) Score: 1.77
  Bliss Independence Score: 0.63
  Loewe Additivity Score: 3.57
  LHighest Single Agent (HSA) Score: 5.74

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Fludarabine

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[2]
Cutaneous melanoma	2C30	Approved	[2]
Haematological malignancy	2B33.Y	Approved	[3]
Hematologic disease	3C0Z	Approved	[2]
Hepatosplenic T-cell lymphoma	N.A.	Approved	[2]
Immunodeficiency	4A00-4A85	Approved	[2]
Large granular lymphocytic leukemia	2A90.1	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
MALT lymphoma	N.A.	Approved	[2]
Multiple sclerosis	8A40	Approved	[2]
Myeloproliferative neoplasm	2A20	Approved	[2]
Nodal marginal zone lymphoma	2A85.0	Approved	[2]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	N.A.	Approved	[2]
Recurrent adult burkitt lymphoma	2A85.6	Approved	[2]
Small intestine lymphoma	N.A.	Approved	[2]
Splenic marginal zone lymphoma	N.A.	Approved	[2]
Systemic lupus erythematosus	4A40.0	Approved	[2]
Systemic sclerosis	4A42	Approved	[2]
Testicular lymphoma	N.A.	Approved	[2]
Classic Hodgkin lymphoma	N.A.	Investigative	[2]
Colon cancer	2B90.Z	Investigative	[2]
Gastric cancer	2B72	Investigative	[2]
Neuroblastoma	2D11.2	Investigative	[2]

Fludarabine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adenosine deaminase (ADA)	TTLP57V	ADA_HUMAN	Inhibitor	[11]

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	[12]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[13]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[13]
Proliferating cell nuclear antigen (PCNA)	OTHZ1RIA	PCNA_HUMAN	Increases Expression	[14]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Increases Expression	[15]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[8]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[16]
DNA cytosine-5)-methyltransferase 1 (DNMT1)	OTM2DGTK	DNMT1_HUMAN	Decreases Expression	[17]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[9]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[9]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Increases Activity	[18]
Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2)	OTUE7Z91	MP2K2_HUMAN	Increases Activity	[18]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[14]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[16]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Expression	[17]
Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1)	OT4Y9NQI	MP2K1_HUMAN	Increases Activity	[18]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[15]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[15]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[16]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Decreases Expression	[9]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[10]
Growth/differentiation factor 15 (GDF15)	OTWQN50N	GDF15_HUMAN	Increases Expression	[14]

Indication(s) of Taxol

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[4]
Solid tumour/cancer	2A00-2F9Z	Approved	[5]
Pancreatic cancer	2C10	Phase 3	[6]
Gastric adenocarcinoma	2B72	Phase 2	[7]
Ovarian cancer	2C73	Phase 2	[7]

Taxol Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Apoptosis regulator Bcl-2 (BCL-2)	TTJGNVC	BCL2_HUMAN	Modulator	[4]
Tubulin beta (TUBB)	TTYFKSZ	NOUNIPROTAC	Modulator	[4]

References

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• [2] Fludarabine 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: 4802).
• [4] Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77. Cancer Res. 2009 Sep 1;69(17):6906-14.
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
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• [9] 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.
• [10] 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.
• [11] Purine nucleoside analogs in indolent non-Hodgkin's lymphoma. Oncology (Williston Park). 2000 Jun;14(6 Suppl 2):13-5.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.