Details of the Drug Combination

General Information of Drug Combination (ID: DC0CSRM)

• Drug Combination Name: Raloxifene + Dacarbazine
• Indication: Breast adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  Raloxifene (DMDKF3M): Small molecular drug
  Dacarbazine (DMNPZL4): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: MDA-MB-468
  Zero Interaction Potency (ZIP) Score: 1.25
  Bliss Independence Score: 5.26
  Loewe Additivity Score: 4.98
  LHighest Single Agent (HSA) Score: 5.4

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Raloxifene

Disease Entry	ICD 11	Status	REF
Osteoporosis	FB83.0	Approved	[2]

Raloxifene Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR)	TTZAYWL	ESR1_HUMAN	Modulator	[5]

Raloxifene Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[6]

Raloxifene Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[8]
UDP-glucuronosyltransferase 1A10 (UGT1A10)	DEL5N6Y	UD110_HUMAN	Metabolism	[9]

Indication(s) of Dacarbazine

Disease Entry	ICD 11	Status	REF
Adenocarcinoma	2D40	Approved	[3]
Astrocytoma	2A00.0Y	Approved	[3]
Brain disease	8C70-8E61	Approved	[3]
Central nervous system disease	8A04-8D87	Approved	[3]
Glioblastoma	2A00	Approved	[3]
Gliosarcoma	N.A.	Approved	[3]
Melanoma	2C30	Approved	[4]
Classic Hodgkin lymphoma	N.A.	Investigative	[3]
Neuroblastoma	2D11.2	Investigative	[3]

Dacarbazine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Breaker	[11]

Dacarbazine Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[12]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[13]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[14]

Dacarbazine Interacts with 12 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Increases Expression	[15]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[10]
Interferon regulatory factor 1 (IRF1)	OT43DI6J	IRF1_HUMAN	Increases Expression	[16]
Methylated-DNA--protein-cysteine methyltransferase (MGMT)	OT40A9WH	MGMT_HUMAN	Decreases Activity	[17]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Response To Substance	[18]
DNA repair nuclease/redox regulator APEX1 (APEX1)	OT53OI14	APEX1_HUMAN	Increases Response To Substance	[19]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1)	OTA675TJ	GTR1_HUMAN	Decreases Response To Substance	[20]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Response To Substance	[21]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Response To Substance	[21]
Clusterin (CLU)	OTQGG0JM	CLUS_HUMAN	Affects Response To Substance	[22]
Mitogen-activated protein kinase kinase kinase 1 (MAP3K1)	OTS3FVTY	M3K1_HUMAN	Decreases Response To Substance	[21]
Erythropoietin (EPO)	OTZ90CN4	EPO_HUMAN	Decreases Response To Substance	[23]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult T acute lymphoblastic leukemia	DC56KE5	MOLT-4	Investigative	[24]
Childhood T acute lymphoblastic leukemia	DCRDW8Z	CCRF-CEM	Investigative	[24]
Chronic myelogenous leukemia	DC58BZV	K-562	Investigative	[24]
Glioma	DCX2F4M	SF-268	Investigative	[24]
Glioma	DCOKG4G	SF-539	Investigative	[24]
Colon adenocarcinoma	DCAZSPV	COLO 205	Investigative	[1]
Adenocarcinoma	DCGSX4G	SW-620	Investigative	[25]
Adenocarcinoma	DC9JOT9	HCT-15	Investigative	[25]
Adenocarcinoma	DCSC5TV	HCC-2998	Investigative	[25]
Cutaneous melanoma	DCDSB2G	SK-MEL-5	Investigative	[25]
High grade ovarian serous adenocarcinoma	DC89T1V	OVCAR-8	Investigative	[25]
High grade ovarian serous adenocarcinoma	DC0YTEI	NCI\\/ADR-RES	Investigative	[25]
Melanoma	DC5C6L8	SK-MEL-2	Investigative	[25]
Melanoma	DCI9COQ	UACC-257	Investigative	[25]

References

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• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Dacarbazine FDA Label
• [4] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 075259.
• [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. (Target id: 620).
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• [18] Mcl-1 antisense therapy chemosensitizes human melanoma in a SCID mouse xenotransplantation model. J Invest Dermatol. 2003 Jun;120(6):1081-6. doi: 10.1046/j.1523-1747.2003.12252.x.
• [19] 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.
• [20] Glut-1 as a therapeutic target: increased chemoresistance and HIF-1-independent link with cell turnover is revealed through COMPARE analysis and metabolomic studies. Cancer Chemother Pharmacol. 2008 Mar;61(3):377-93. doi: 10.1007/s00280-007-0480-1. Epub 2007 May 23.
• [21] Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo. J Clin Oncol. 2004 Jun 1;22(11):2092-100. doi: 10.1200/JCO.2004.11.070. Epub 2004 May 3.
• [22] Clusterin regulates drug-resistance in melanoma cells. J Invest Dermatol. 2005 Jun;124(6):1300-7. doi: 10.1111/j.0022-202X.2005.23720.x.
• [23] Functional erythropoietin autocrine loop in melanoma. Am J Pathol. 2005 Mar;166(3):823-30. doi: 10.1016/S0002-9440(10)62303-6.
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• [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.