Details of the Drug Combination

General Information of Drug Combination (ID: DCE6P1Q)

• Drug Combination Name: Dexrazoxane + Plicamycin
• Indication: Colon carcinoma; Status: Investigative [1]
• Component Drugs:
  Dexrazoxane (DMD7X1O): Small molecular drug
  Plicamycin (DM7C8YV): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KM12
  Zero Interaction Potency (ZIP) Score: 8.02
  Bliss Independence Score: 9.27
  Loewe Additivity Score: 13.62
  LHighest Single Agent (HSA) Score: 12.68

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Dexrazoxane

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[2]
Chemoprotection	N.A.	Approved	[3]
Inflammatory breast cancer	2C62	Approved	[4]
Respiratory tract disease	CB7Z	Investigative	[5]

Dexrazoxane Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase II beta (TOP2B)	TT4NVEM	TOP2B_HUMAN	Inhibitor	[8]
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN; TOP2B_HUMAN	Modulator	[9]

Dexrazoxane Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Dihydropyrimidinase-related protein 1 (DRP1)	DE0EUXB	DPYL1_HUMAN	Metabolism	[10]

Dexrazoxane Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase 2-alpha (TOP2A)	OT6LPS08	TOP2A_HUMAN	Decreases Activity	[11]

Indication(s) of Plicamycin

Disease Entry	ICD 11	Status	REF
Hypercalcaemia	5B91.0	Approved	[3]
Testicular cancer	2C80	Approved	[3]
Solid tumour/cancer	2A00-2F9Z	Withdrawn from market	[6]
Lung cancer	2C25.0	Investigative	[7]
Ovarian cancer	2C73	Investigative	[7]

Plicamycin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
RNA synthesis (hRNA synth)	TTX2AYW	NOUNIPROTAC	Modulator	[13]

Plicamycin Interacts with 16 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
17-beta-hydroxysteroid dehydrogenase type 2 (HSD17B2)	OT3K7HY5	DHB2_HUMAN	Decreases Expression	[14]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Expression	[15]
Aryl hydrocarbon receptor (AHR)	OTFE4EYE	AHR_HUMAN	Decreases Expression	[15]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Expression	[15]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[16]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Activity	[16]
Epoxide hydrolase 1 (EPHX1)	OTBKWQER	HYEP_HUMAN	Decreases Expression	[17]
Transcription factor Sp1 (SP1)	OTISPT4X	SP1_HUMAN	Decreases Expression	[12]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Decreases Expression	[18]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Decreases Expression	[19]
Tyrosine-protein kinase receptor UFO (AXL)	OTKA2SUX	UFO_HUMAN	Decreases Expression	[20]
Transcription factor Sp3 (SP3)	OTYDQZ1T	SP3_HUMAN	Decreases Expression	[12]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[21]
Epidermal growth factor receptor kinase substrate 8 (EPS8)	OTZ6ES6V	EPS8_HUMAN	Decreases Expression	[18]
TNFAIP3-interacting protein 1 (TNIP1)	OTRAOTEW	TNIP1_HUMAN	Decreases Expression	[22]
Sphingomyelin phosphodiesterase 3 (SMPD3)	OTHQBETH	NSMA2_HUMAN	Decreases Expression	[23]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult acute myeloid leukemia	DCIFVCJ	HL-60(TB)	Investigative	[24]
Adult T acute lymphoblastic leukemia	DC1CXSU	MOLT-4	Investigative	[24]
Anaplastic large cell lymphoma	DCSZUSY	SR	Investigative	[24]
Childhood T acute lymphoblastic leukemia	DC3V7JA	CCRF-CEM	Investigative	[24]
Chronic myelogenous leukemia	DC6W5PQ	K-562	Investigative	[24]
Clear cell renal cell carcinoma	DCMA5UE	A498	Investigative	[24]
Glioma	DCIADZ5	SF-539	Investigative	[24]
Plasma cell myeloma	DCI81IH	RPMI-8226	Investigative	[24]
Carcinoma	DCAFZRW	RXF 393	Investigative	[1]
Colon adenocarcinoma	DCQQ6D4	COLO 205	Investigative	[1]
Invasive ductal carcinoma	DCMDXSC	BT-549	Investigative	[1]
Invasive ductal carcinoma	DCZE2RW	T-47D	Investigative	[1]
Invasive ductal carcinoma	DCZBKKJ	HS 578T	Investigative	[1]
Adenocarcinoma	DCPYEDW	SW-620	Investigative	[25]
Adenocarcinoma	DC9GSPC	HCT116	Investigative	[25]
High grade ovarian serous adenocarcinoma	DCBKGCV	OVCAR-5	Investigative	[25]
Large cell lung carcinoma	DCR9ZVA	NCI-H460	Investigative	[25]
Lung adenocarcinoma	DC2WA1C	NCI-H522	Investigative	[25]
Melanoma	DCO661E	MALME-3M	Investigative	[25]

References

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• [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: 7330).
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] Dexrazoxane FDA Label
• [5] Design and development of antisense drugs. Expert Opin. Drug Discov. 2008 3(10):1189-1207.
• [6] 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: 8394).
• [7] The Pluripotency Factor Musashi-2 Is a Novel Target for Lung Cancer Therapy.Ann Am Thorac Soc. 2018 Apr;15(Supplement_2):S124.
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• [11] Investigation of novel dexrazoxane analogue JR-311 shows significant cardioprotective effects through topoisomerase IIbeta but not its iron chelating metabolite. Toxicology. 2017 Dec 1;392:1-10. doi: 10.1016/j.tox.2017.09.012. Epub 2017 Sep 21.
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• [13] Role of magnesium ion in mithramycin-DNA interaction: binding of mithramycin-Mg2+ complexes with DNA. Biochemistry. 1995 Jan 31;34(4):1376-85.
• [14] SP1 and SP3 mediate progesterone-dependent induction of the 17beta hydroxysteroid dehydrogenase type 2 gene in human endometrium. Biol Reprod. 2006 Oct;75(4):605-14.
• [15] Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression. Toxicol Appl Pharmacol. 2014 Oct 1;280(1):138-48.
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• [17] Sp1 and Sp3 transcription factors regulate the basal expression of human microsomal epoxide hydrolase (EPHX1) through interaction with the E1b far upstream promoter. Gene. 2014 Feb 15;536(1):135-44. doi: 10.1016/j.gene.2013.11.053. Epub 2013 Dec 4.
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• [19] Asbestos induces tissue factor in Beas-2B human lung bronchial epithelial cells in vitro. Lung. 2004;182(4):251-64. doi: 10.1007/s00408-004-2507-2.
• [20] The human receptor tyrosine kinase Axl gene--promoter characterization and regulation of constitutive expression by Sp1, Sp3 and CpG methylation. Biosci Rep. 2008 Jun;28(3):161-76. doi: 10.1042/BSR20080046.
• [21] CREB/Sp1-mediated MCL1 expression and NFB-mediated ABCB1 expression modulate the cytotoxicity of daunorubicin in chronic myeloid leukemia cells. Toxicol Appl Pharmacol. 2022 Jan 15;435:115847. doi: 10.1016/j.taap.2021.115847. Epub 2021 Dec 25.
• [22] Sp sites contribute to basal and inducible expression of the human TNIP1 (TNF-inducible protein 3-interacting protein 1) promoter. Biochem J. 2013 Jun 15;452(3):519-29. doi: 10.1042/BJ20121666.
• [23] Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin. Biochim Biophys Acta. 2009 Nov-Dec;1789(11-12):681-90. doi: 10.1016/j.bbagrm.2009.08.006. Epub 2009 Aug 19.
• [24] 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.
• [25] Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy.Hum Genet. 2018 Apr;137(4):293-303. doi: 10.1007/s00439-018-1882-3. Epub 2018 Apr 24.