Details of the Drug Combination

General Information of Drug Combination (ID: DC3118Q)

• Drug Combination Name: Raloxifene + Valrubicin
• Indication: Invasive ductal carcinoma; Status: Investigative [1]
• Component Drugs:
  Raloxifene (DMDKF3M): Small molecular drug
  Valrubicin (DMOYJFK): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: BT-549
  Zero Interaction Potency (ZIP) Score: 1.98
  Bliss Independence Score: 5.28
  Loewe Additivity Score: 2.18
  LHighest Single Agent (HSA) Score: 2.96

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 Valrubicin

Disease Entry	ICD 11	Status	REF
Bladder cancer	2C94	Approved	[3]
In situ carcinoma	N.A.	Approved	[4]
Urinary bladder cancer	N.A.	Approved	[4]
Psoriasis vulgaris	EA90	Phase 2	[2]

Valrubicin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN; TOP2B_HUMAN	Inhibitor	[10]

Valrubicin Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[11]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult acute myeloid leukemia	DCG9RGZ	HL-60(TB)	Investigative	[12]
Anaplastic large cell lymphoma	DCXV013	SR	Investigative	[12]
Childhood T acute lymphoblastic leukemia	DCPWVVP	CCRF-CEM	Investigative	[12]
Glioblastoma	DCKRW8Z	SNB-75	Investigative	[12]
Papillary renal cell carcinoma	DCBAU5T	ACHN	Investigative	[12]
Plasma cell myeloma	DC1I160	RPMI-8226	Investigative	[12]
Breast adenocarcinoma	DCJIP3U	MDA-MB-468	Investigative	[1]
Adenocarcinoma	DC4U32T	DU-145	Investigative	[13]
Adenocarcinoma	DCBH3W9	NCIH23	Investigative	[13]
Adenocarcinoma	DCB9HVG	HCT116	Investigative	[13]
Amelanotic melanoma	DCTXJB4	M14	Investigative	[13]
Cutaneous melanoma	DC0ZEVL	SK-MEL-28	Investigative	[13]
High grade ovarian serous adenocarcinoma	DC4I2F5	OVCAR-5	Investigative	[13]
Lung adenocarcinoma	DCUI8I6	EKVX	Investigative	[13]
Lung adenocarcinoma	DCPCSPW	HOP-62	Investigative	[13]
Malignant melanoma	DC2YD9F	UACC62	Investigative	[13]
Melanoma	DC0TDVV	MALME-3M	Investigative	[13]
Melanoma	DCNN0YK	SK-MEL-2	Investigative	[13]

References

• [1] Biologically active neutrophil chemokine pattern in tonsillitis.Clin Exp Immunol. 2004 Mar;135(3):511-8. doi: 10.1111/j.1365-2249.2003.02390.x.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [4] Valrubicin 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. (Target id: 620).
• [6] Influence of hepatic and intestinal efflux transporters and their genetic variants on the pharmacokinetics and pharmacodynamics of raloxifene in osteoporosis treatment. Transl Res. 2012 Oct;160(4):298-308.
• [7] The role of P-glycoprotein in the bioactivation of raloxifene. Drug Metab Dispos. 2006 Dec;34(12):2073-8.
• [8] Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201-8.
• [9] Characterization of raloxifene glucuronidation: potential role of UGT1A8 genotype on raloxifene metabolism in vivo. Cancer Prev Res (Phila). 2013 Jul;6(7):719-30.
• [10] Metabolic activation of N-acylanthracyclines precedes their interaction with DNA topoisomerase II. NCI Monogr. 1987;(4):111-5.
• [11] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [12] 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.
• [13] 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.