Details of the Drug Combination

General Information of Drug Combination (ID: DCO1LRA)

• Drug Combination Name: Vandetanib + Raloxifene
• Indication: Melanoma; Status: Investigative [1]
• Component Drugs:
  Vandetanib (DMRICNP): Small molecular drug
  Raloxifene (DMDKF3M): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: SK-MEL-2
  Zero Interaction Potency (ZIP) Score: 5.18
  Bliss Independence Score: 10.03
  Loewe Additivity Score: 7.12
  LHighest Single Agent (HSA) Score: 6.82

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Vandetanib

Disease Entry	ICD 11	Status	REF
Solid tumour/cancer	2A00-2F9Z	Approved	[2]

Vandetanib Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[4]
Proto-oncogene c-Ret (RET)	TT4DXQT	RET_HUMAN	Inhibitor	[4]
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Inhibitor	[4]

Vandetanib Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[5]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[6]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[6]

Vandetanib Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]

Vandetanib Interacts with 34 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proto-oncogene tyrosine-protein kinase receptor Ret (RET)	OTLU040A	RET_HUMAN	Decreases Phosphorylation	[8]
Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2)	OTKOZRZP	PLOD2_HUMAN	Increases Expression	[9]
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Increases Expression	[9]
Insulin-induced gene 1 protein (INSIG1)	OTZF5X1D	INSI1_HUMAN	Increases Expression	[9]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L)	OTJKOMXE	BNI3L_HUMAN	Increases Expression	[9]
Protein FAM13A (FAM13A)	OTZ6GN0Q	FA13A_HUMAN	Increases Expression	[9]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Activity	[10]
Phosphoglycerate kinase 1 (PGK1)	OT6V1ICH	PGK1_HUMAN	Increases Expression	[9]
Calbindin (CALB1)	OTM7IXDG	CALB1_HUMAN	Increases Expression	[9]
Prothymosin alpha (PTMA)	OT2W4T1M	PTMA_HUMAN	Decreases Expression	[9]
Trypsin-2 (PRSS2)	OTOMVUWL	TRY2_HUMAN	Increases Expression	[9]
Insulin-like growth factor-binding protein 1 (IGFBP1)	OT6UQV2K	IBP1_HUMAN	Increases Expression	[9]
Gamma-enolase (ENO2)	OTRODL0T	ENOG_HUMAN	Increases Expression	[9]
Solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3)	OT2HZK5M	GTR3_HUMAN	Increases Expression	[9]
Mucin-1 (MUC1)	OTHQI7IY	MUC1_HUMAN	Increases Expression	[9]
Histone H1.2 (H1-2)	OT0AVI4M	H12_HUMAN	Increases Expression	[9]
Insulin-like growth factor-binding protein 3 (IGFBP3)	OTIX63TX	IBP3_HUMAN	Increases Expression	[9]
DNA mismatch repair protein Msh3 (MSH3)	OTD3YPVL	MSH3_HUMAN	Decreases Expression	[9]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Secretion	[11]
Dual specificity protein phosphatase 1 (DUSP1)	OTN6BR75	DUS1_HUMAN	Increases Expression	[9]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[12]
Pro-adrenomedullin (ADM)	OT7T0TA4	ADML_HUMAN	Increases Expression	[9]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[12]
Collagen alpha-3(IV) chain (COL4A3)	OT6SB8X5	CO4A3_HUMAN	Increases Expression	[9]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Expression	[13]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1)	OTHBQVD5	4EBP1_HUMAN	Decreases Phosphorylation	[12]
Solute carrier family 2, facilitated glucose transporter member 14 (SLC2A14)	OTBFIOVY	GTR14_HUMAN	Increases Expression	[9]
Protein NDRG1 (NDRG1)	OTVO66BO	NDRG1_HUMAN	Increases Expression	[9]
TSC22 domain family protein 3 (TSC22D3)	OT03UM03	T22D3_HUMAN	Increases Expression	[9]
Angiopoietin-related protein 4 (ANGPTL4)	OTQL5SPX	ANGL4_HUMAN	Increases Expression	[9]
Transcription factor SOX-17 (SOX17)	OT9H4WWE	SOX17_HUMAN	Decreases Localization	[14]
Lysine-specific demethylase 3A (KDM3A)	OTZYJ8VN	KDM3A_HUMAN	Increases Expression	[9]
Hypoxia-inducible lipid droplet-associated protein (HILPDA)	OTEID3ZM	HLPDA_HUMAN	Increases Expression	[9]
Insulin-induced gene 2 protein (INSIG2)	OTX4VY51	INSI2_HUMAN	Increases Expression	[9]

Indication(s) of Raloxifene

Disease Entry	ICD 11	Status	REF
Osteoporosis	FB83.0	Approved	[3]

Raloxifene Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR)	TTZAYWL	ESR1_HUMAN	Modulator	[15]

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	[16]

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	[17]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[18]
UDP-glucuronosyltransferase 1A10 (UGT1A10)	DEL5N6Y	UD110_HUMAN	Metabolism	[19]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Breast adenocarcinoma	DCVYXDD	MDA-MB-468	Investigative	[20]
Carcinoma	DCEE2LU	MCF7	Investigative	[20]
Colon adenocarcinoma	DCKH37N	COLO 205	Investigative	[20]
Invasive ductal carcinoma	DC64N34	HS 578T	Investigative	[20]
Invasive ductal carcinoma	DCNRGWE	BT-549	Investigative	[20]
Adenocarcinoma	DCOZNSN	NCIH23	Investigative	[1]
Adenocarcinoma	DCI11V7	HCT116	Investigative	[1]
Adenocarcinoma	DCA0K7Q	HCT-15	Investigative	[1]
Adenocarcinoma	DCJMAXD	HCC-2998	Investigative	[1]
Adenocarcinoma	DC0KNX7	HT29	Investigative	[1]
Adenocarcinoma	DCQTURI	SW-620	Investigative	[1]
Adult acute myeloid leukemia	DC2JVUW	HL-60(TB)	Investigative	[1]
Adult T acute lymphoblastic leukemia	DCUHO7R	MOLT-4	Investigative	[1]
Amelanotic melanoma	DCHZQCY	MDA-MB-435	Investigative	[1]
Amelanotic melanoma	DCSPHPX	M14	Investigative	[1]
Anaplastic large cell lymphoma	DC8C86D	SR	Investigative	[1]
Astrocytoma	DCSI7S2	SNB-19	Investigative	[1]
Childhood T acute lymphoblastic leukemia	DCDHSZV	CCRF-CEM	Investigative	[1]
Chronic myelogenous leukemia	DCFS31C	K-562	Investigative	[1]
Clear cell renal cell carcinoma	DC8P00M	A498	Investigative	[1]
Cutaneous melanoma	DCAR30Y	SK-MEL-5	Investigative	[1]
Cutaneous melanoma	DCSHOF8	SK-MEL-28	Investigative	[1]
Glioma	DCHTIKL	SF-268	Investigative	[1]
High grade ovarian serous adenocarcinoma	DC8WOE4	OVCAR-8	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCJ2A28	NCI\\/ADR-RES	Investigative	[1]
Lung adenocarcinoma	DC87WQD	HOP-62	Investigative	[1]
Melanoma	DCZ3KAU	MALME-3M	Investigative	[1]
Melanoma	DCBQVWI	UACC-257	Investigative	[1]
Non-small cell lung carcinoma	DCFS4UA	HOP-92	Investigative	[1]
Plasma cell myeloma	DCQA3ZR	RPMI-8226	Investigative	[1]
Prostate carcinoma	DC7LA5I	PC-3	Investigative	[1]

References

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• [7] FDA label of Vandetanib. The 2020 official website of the U.S. Food and Drug Administration.
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• [9] ZD6474 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model. Int J Cancer. 2006 Jan 15;118(2):483-9. doi: 10.1002/ijc.21340.
• [10] Anticancer effects of ZD6474, a VEGF receptor tyrosine kinase inhibitor, in gefitinib ("Iressa")-sensitive and resistant xenograft models. Cancer Sci. 2004 Dec;95(12):984-9. doi: 10.1111/j.1349-7006.2004.tb03187.x.
• [11] Cytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes. Toxicol Lett. 2018 Jul;291:138-148. doi: 10.1016/j.toxlet.2018.04.010. Epub 2018 Apr 12.
• [12] Autophagy inhibition induces enhanced proapoptotic effects of ZD6474 in glioblastoma. Br J Cancer. 2013 Jul 9;109(1):164-71. doi: 10.1038/bjc.2013.306. Epub 2013 Jun 25.
• [13] Downregulation of hERG channel expression by tyrosine kinase inhibitors nilotinib and vandetanib predominantly contributes to arrhythmogenesis. Toxicol Lett. 2022 Jul 15;365:11-23. doi: 10.1016/j.toxlet.2022.06.001. Epub 2022 Jun 6.
• [14] 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.
• [15] 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).
• [16] 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.
• [17] The role of P-glycoprotein in the bioactivation of raloxifene. Drug Metab Dispos. 2006 Dec;34(12):2073-8.
• [18] 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.
• [19] Characterization of raloxifene glucuronidation: potential role of UGT1A8 genotype on raloxifene metabolism in vivo. Cancer Prev Res (Phila). 2013 Jul;6(7):719-30.
• [20] 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.