Details of the Drug Combination

General Information of Drug Combination (ID: DCL7IJ4)

• Drug Combination Name: Raloxifene + Vincristine
• Indication: Clear cell renal cell carcinoma; Status: Investigative [1]
• Component Drugs:
  Raloxifene (DMDKF3M): Small molecular drug
  Vincristine (DMINOX3): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TK-10
  Zero Interaction Potency (ZIP) Score: 2.35
  Bliss Independence Score: 4.95
  Loewe Additivity Score: 1.5
  LHighest Single Agent (HSA) Score: 1.35

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 Vincristine

Disease Entry	ICD 11	Status	REF
Acute lymphoblastic leukaemia	2A85	Approved	[3]
Adult kidney Wilms tumor	N.A.	Approved	[4]
Beckwith-Wiedemann syndrome	N.A.	Approved	[4]
Burkitt lymphoma	N.A.	Approved	[4]
Central nervous system neoplasm	N.A.	Approved	[4]
Childhood acute lymphoblastic leukemia	N.A.	Approved	[4]
Childhood kidney Wilms tumor	N.A.	Approved	[4]
Hamartoma	N.A.	Approved	[4]
Kidney neoplasm	N.A.	Approved	[4]
Leukemia	N.A.	Approved	[4]
MALT lymphoma	N.A.	Approved	[4]
Nodal marginal zone lymphoma	2A85.0	Approved	[4]
Plasma cell myeloma	2A83.1	Approved	[4]
Primitive neuroectodermal tumor	N.A.	Approved	[4]
Splenic marginal zone lymphoma	N.A.	Approved	[4]
Testicular lymphoma	N.A.	Approved	[4]
Wilms tumor	N.A.	Approved	[4]
Classic Hodgkin lymphoma	N.A.	Investigative	[4]
Follicular lymphoma	2A80	Investigative	[4]
Neuroblastoma	2D11.2	Investigative	[4]

Vincristine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tubulin beta (TUBB)	TTYFKSZ	NOUNIPROTAC	Modulator	[10]

Vincristine Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 1 (ABCC1)	DTSYQGK	MRP1_HUMAN	Substrate	[11]
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[12]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[13]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[14]

Vincristine Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[15]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[15]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[16]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
High grade ovarian serous adenocarcinoma	DC0NUL5	OVCAR-5	Investigative	[17]

References

• [1] 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.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] 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: 6785).
• [4] Vincristine 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] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [11] Interaction of plant cannabinoids with the multidrug transporter ABCC1 (MRP1). Eur J Pharmacol. 2008 Sep 4;591(1-3):128-31.
• [12] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [13] L-type calcium channel blockers reverse docetaxel and vincristine-induced multidrug resistance independent of ABCB1 expression in human lung cancer cell lines. Toxicol Lett. 2010 Feb 15;192(3):408-18.
• [14] Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates. Cancer Chemother Pharmacol. 2006 Dec;58(6):826-34.
• [15] Association of CYP3A5 expression and vincristine neurotoxicity in pediatric malignancies in Turkish population. J Pediatr Hematol Oncol. 2017 Aug;39(6):458-462.
• [16] Drug Interactions Flockhart Table
• [17] 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.