Details of the Drug Combination

General Information of Drug Combination (ID: DC1RM97)

Drug Combination Name

Dactinomycin Fludarabine

Indication

Disease Entry	Status	REF
Adenocarcinoma	Investigative	[1]

Component Drugs

Dactinomycin DM2YGNW

Fludarabine DMVRLT7

Small molecular drug

2D MOL

3D MOL is unavailable

3D MOL

High-throughput Screening Result

Testing Cell Line: DU-145

Zero Interaction Potency (ZIP) Score: 1.02

Bliss Independence Score: 5.03

Loewe Additivity Score: 2.7

LHighest Single Agent (HSA) Score: 5.48

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)

Indication(s) of Dactinomycin

Disease Entry	ICD 11	Status	REF
Adult kidney Wilms tumor	N.A.	Approved	[2]
Advanced cancer	2A00-2F9Z	Approved	[2]
Beckwith-Wiedemann syndrome	N.A.	Approved	[2]
Childhood kidney Wilms tumor	N.A.	Approved	[2]
Gestational trophoblastic neoplasia	2F33-2F76	Approved	[2]
Hamartoma	N.A.	Approved	[2]
Solid tumour/cancer	2A00-2F9Z	Approved	[3]
Wilms tumor	N.A.	Approved	[2]

Dactinomycin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Breaker	[9]
------------------------------------------------------------------------------------

Dactinomycin Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 1 (ABCC1)	DTSYQGK	MRP1_HUMAN	Substrate	[10]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[11]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[12]
------------------------------------------------------------------------------------

Dactinomycin Interacts with 58 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Response To Substance	[13]
Dihydropyrimidinase-related protein 4 (DPYSL4)	OT3SBS2S	DPYL4_HUMAN	Increases Expression	[6]
Integral membrane protein GPR137B (GPR137B)	OT1CINQQ	G137B_HUMAN	Increases Expression	[6]
Integrin alpha-IIb (ITGA2B)	OT4Y17PY	ITA2B_HUMAN	Increases Expression	[6]
Ras-related protein R-Ras (RRAS)	OTBBF28C	RRAS_HUMAN	Increases Expression	[6]
Growth arrest and DNA damage-inducible protein GADD45 alpha (GADD45A)	OTDRV63V	GA45A_HUMAN	Increases Expression	[6]
Stomatin (STOM)	OTC8R6EH	STOM_HUMAN	Increases Expression	[6]
Cellular retinoic acid-binding protein 2 (CRABP2)	OTY01V9G	RABP2_HUMAN	Increases Expression	[6]
Tyrosine-protein kinase receptor UFO (AXL)	OTKA2SUX	UFO_HUMAN	Increases Expression	[6]
14-3-3 protein sigma (SFN)	OTLJCZ1U	1433S_HUMAN	Increases Expression	[6]
Tumor necrosis factor ligand superfamily member 9 (TNFSF9)	OTV9L89D	TNFL9_HUMAN	Increases Expression	[6]
Galectin-7 (LGALS7)	OTMSVI7R	LEG7_HUMAN	Increases Expression	[6]
Large ribosomal subunit protein eL34 (RPL34)	OT0U9VMQ	RL34_HUMAN	Increases Expression	[6]
Rho GDP-dissociation inhibitor 2 (ARHGDIB)	OT9PD6CS	GDIR2_HUMAN	Increases Expression	[6]
Epithelial membrane protein 1 (EMP1)	OTSZHUHQ	EMP1_HUMAN	Increases Expression	[6]
Epithelial membrane protein 3 (EMP3)	OTODMJ1D	EMP3_HUMAN	Increases Expression	[6]
Protein ripply3 (RIPPLY3)	OT1HK35I	DSCR6_HUMAN	Increases Expression	[6]
Endonuclease III-like protein 1 (NTHL1)	OTPQXPT1	NTH_HUMAN	Decreases Expression	[6]
Kinesin-like protein KIF1A (KIF1A)	OT3JVEGV	KIF1A_HUMAN	Increases Expression	[6]
Protein AF1q (MLLT11)	OTG5RVHC	AF1Q_HUMAN	Increases Expression	[6]
Laminin subunit gamma-2 (LAMC2)	OTJMTM72	LAMC2_HUMAN	Increases Expression	[6]
Filamin-C (FLNC)	OT3F8J6Y	FLNC_HUMAN	Increases Expression	[6]
Immediate early response gene 5 protein (IER5)	OTJPTXMD	IER5_HUMAN	Increases Expression	[6]
Keratin, type II cytoskeletal 80 (KRT80)	OTAU54U3	K2C80_HUMAN	Increases Expression	[6]
All-trans-retinol 13,14-reductase (RETSAT)	OTC3AOPX	RETST_HUMAN	Increases Expression	[6]
Interleukin-27 receptor subunit alpha (IL27RA)	OTSQBAKI	I27RA_HUMAN	Increases Expression	[6]
Neuropilin and tolloid-like protein 2 (NETO2)	OT0YAMC0	NETO2_HUMAN	Increases Expression	[6]
Mitochondria-eating protein (SPATA18)	OTOEHTHU	MIEAP_HUMAN	Increases Expression	[6]
Phospholipase ABHD3 (ABHD3)	OTH8P977	ABHD3_HUMAN	Increases Expression	[6]
Homer protein homolog 3 (HOMER3)	OTQ6D9X1	HOME3_HUMAN	Increases Expression	[6]
BSD domain-containing protein 1 (BSDC1)	OT853CP9	BSDC1_HUMAN	Increases Expression	[6]
Stathmin-3 (STMN3)	OT20F289	STMN3_HUMAN	Increases Expression	[6]
Endothelial protein C receptor (PROCR)	OTRHED17	EPCR_HUMAN	Increases Expression	[6]
Fatty acid desaturase 3 (FADS3)	OT9RVXGE	FADS3_HUMAN	Increases Expression	[6]
Protein O-mannosyl-transferase 1 (POMT1)	OTGQSHL5	POMT1_HUMAN	Increases Expression	[6]
Tumor protein p53-inducible protein 11 (TP53I11)	OTFPDYZU	P5I11_HUMAN	Decreases Expression	[14]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Decreases Expression	[15]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Expression	[16]
Mitogen-activated protein kinase kinase kinase 7 (MAP3K7)	OTUXEASC	M3K7_HUMAN	Decreases Expression	[17]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[17]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Decreases Expression	[18]
Proto-oncogene tyrosine-protein kinase ROS (ROS1)	OTDSKUGE	ROS1_HUMAN	Increases Expression	[17]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[19]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[20]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Decreases Expression	[17]
Lamin-B1 (LMNB1)	OT100T3P	LMNB1_HUMAN	Decreases Expression	[17]
rRNA 2'-O-methyltransferase fibrillarin (FBL)	OTRODIE5	FBRL_HUMAN	Affects Localization	[21]
DNA-directed RNA polymerase II subunit RPB1 (POLR2A)	OTHJQ1DZ	RPB1_HUMAN	Decreases Phosphorylation	[22]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Decreases Expression	[23]
Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4)	OTZPZX11	MP2K4_HUMAN	Decreases Expression	[17]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[24]
Son of sevenless homolog 1 (SOS1)	OTTCWXC3	SOS1_HUMAN	Decreases Expression	[17]
FAS-associated death domain protein (FADD)	OTV7GFHH	FADD_HUMAN	Decreases Expression	[17]
Growth arrest-specific protein 6 (GAS6)	OTPOPUUE	GAS6_HUMAN	Increases Degradation	[25]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[26]
Transcription factor SOX-17 (SOX17)	OT9H4WWE	SOX17_HUMAN	Decreases Localization	[27]
Hyaluronidase-1 (HYAL1)	OT2SJN0X	HYAL1_HUMAN	Increases ADR	[28]
Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP)	OTPYQX3K	C1QBP_HUMAN	Decreases Response To Substance	[29]
------------------------------------------------------------------------------------


⏷ Show the Full List of 58 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	[33]
------------------------------------------------------------------------------------

Fludarabine Interacts with 10 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	[34]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[35]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[30]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[36]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[31]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[31]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[37]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Expression	[38]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[39]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[32]
------------------------------------------------------------------------------------


⏷ Show the Full List of 10 DOT(s)

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult T acute lymphoblastic leukemia	DC8APIG	MOLT-4	Investigative	[1]
Pleural epithelioid mesothelioma	DCYJ8EF	NCI-H226	Investigative	[1]
------------------------------------------------------------------------------------

References

1	CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125976
2	Dactinomycin FDA Label
3	FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 050682.
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	Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
7	Synergy is achieved by complementation with Apo2L/TRAIL and actinomycin D in Apo2L/TRAIL-mediated apoptosis of prostate cancer cells: role of XIAP in resistance. Prostate. 2002 Dec 1;53(4):286-99. doi: 10.1002/pros.10155.
8	Endocrine disruptors fludioxonil and fenhexamid stimulate miR-21 expression in breast cancer cells. Toxicol Sci. 2013 Jan;131(1):71-83. doi: 10.1093/toxsci/kfs290. Epub 2012 Oct 10.
9	Structural studies of atom-specific anticancer drugs acting on DNA. Pharmacol Ther. 1999 Sep;83(3):181-215.
10	Expression of multidrug resistance-associated protein in NIH/3T3 cells confers multidrug resistance associated with increased drug efflux and altered intracellular drug distribution. Cancer Res. 1995 Nov 15;55(22):5342-7.
11	Potential role of drug transporters in the pathogenesis of medically intractable epilepsy. Epilepsia. 2005 Feb;46(2):224-35.
12	Breast cancer resistance protein (BCRP/ABCG2) induces cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors. Mol Pharmacol. 2003 Jan;63(1):65-72.
13	Establishment and characterization of new cellular lymphoma model expressing transgenic human MDR1. Leuk Res. 2005 Apr;29(4):407-14. doi: 10.1016/j.leukres.2004.09.001.
14	Possible roles of a tumor suppressor gene PIG11 in hepatocarcinogenesis and As2O3-induced apoptosis in liver cancer cells. J Gastroenterol. 2009;44(5):460-9. doi: 10.1007/s00535-009-0030-1. Epub 2009 Apr 1.
15	Death receptor regulation and celecoxib-induced apoptosis in human lung cancer cells. J Natl Cancer Inst. 2004 Dec 1;96(23):1769-80. doi: 10.1093/jnci/djh322.
16	Combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and actinomycin D induces apoptosis even in TRAIL-resistant human pancreatic cancer cells. Clin Cancer Res. 2001 Feb;7(2):407-14.
17	Response rate of fibrosarcoma cells to cytotoxic drugs on the expression level correlates to the therapeutic response rate of fibrosarcomas and is mediated by regulation of apoptotic pathways. BMC Cancer. 2005 Jul 7;5:74. doi: 10.1186/1471-2407-5-74.
18	The effects of particulate wear debris, cytokines, and growth factors on the functions of MG-63 osteoblasts. J Bone Joint Surg Am. 2001 Feb;83(2):201-11. doi: 10.2106/00004623-200102000-00007.
19	Profiling the immunotoxicity of chemicals based on in vitro evaluation by a combination of the Multi-ImmunoTox assay and the IL-8 Luc assay. Arch Toxicol. 2018 Jun;92(6):2043-2054. doi: 10.1007/s00204-018-2199-7. Epub 2018 Mar 29.
20	Actinomycin D inhibits the expression of the cystine/glutamate transporter xCT via attenuation of CD133 synthesis in CD133(+) HCC. Chem Biol Interact. 2019 Aug 25;309:108713. doi: 10.1016/j.cbi.2019.06.026. Epub 2019 Jun 19.
21	Specific inhibition of rRNA transcription and dynamic relocation of fibrillarin induced by mercury. Exp Cell Res. 2000 Aug 25;259(1):225-38. doi: 10.1006/excr.2000.4923.
22	Phosphorylation of the RNA polymerase II largest subunit during heat shock and inhibition of transcription in HeLa cells. J Cell Physiol. 1994 Mar;158(3):417-26. doi: 10.1002/jcp.1041580305.
23	Selective and nonselective toxicity of TRAIL/Apo2L combined with chemotherapy in human bone tumour cells vs. normal human cells. Int J Cancer. 2003 Dec 20;107(6):929-40. doi: 10.1002/ijc.11503.
24	Mechanisms of thymidine kinase/ganciclovir and cytosine deaminase/ 5-fluorocytosine suicide gene therapy-induced cell death in glioma cells. Oncogene. 2005 Feb 10;24(7):1231-43. doi: 10.1038/sj.onc.1208290.
25	Androgen receptor-dependent transactivation of growth arrest-specific gene 6 mediates inhibitory effects of testosterone on vascular calcification. J Biol Chem. 2010 Mar 5;285(10):7537-44. doi: 10.1074/jbc.M109.055087. Epub 2010 Jan 4.
26	Actinomycin D upregulates proapoptotic protein Puma and downregulates Bcl-2 mRNA in normal peripheral blood lymphocytes. Anticancer Drugs. 2007 Aug;18(7):763-72. doi: 10.1097/CAD.0b013e3280adc905.
27	A high-throughput screen for teratogens using human pluripotent stem cells. Toxicol Sci. 2014 Jan;137(1):76-90. doi: 10.1093/toxsci/kft239. Epub 2013 Oct 23.
28	ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
29	[Expression of C1QBP gene and its correlation with drug resistance in human resistance choriocarcinoma cell line]. Zhonghua Fu Chan Ke Za Zhi. 2014 Aug;49(8):616-20.
30	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.
31	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.
32	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.
33	Purine nucleoside analogs in indolent non-Hodgkin's lymphoma. Oncology (Williston Park). 2000 Jun;14(6 Suppl 2):13-5.
34	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.
35	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.
36	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.
37	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.
38	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.
39	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.