Details of the Drug Combination

General Information of Drug Combination (ID: DCV5SNH)

• Drug Combination Name: Thioguanine + Vincristine
• Indication: Childhood T acute lymphoblastic leukemia; Status: Investigative [1]
• Component Drugs:
  Thioguanine (DM7NKEV): Small molecular drug
  Vincristine (DMINOX3): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: CCRF-CEM
  Zero Interaction Potency (ZIP) Score: 10.87
  Bliss Independence Score: 11.82
  Loewe Additivity Score: 8.47
  LHighest Single Agent (HSA) Score: 10.98

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Thioguanine

Disease Entry	ICD 11	Status	REF
Acute lymphocytic leukaemia	2B33.3	Approved	[2]
Acute myelogenous leukaemia	2A41	Approved	[3]
Acute myeloid leukaemia	2A60	Approved	[4]
Middle East Respiratory Syndrome (MERS)	1D64	Preclinical	[5]
Severe acute respiratory syndrome (SARS)	1D65	Preclinical	[5]

Thioguanine Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
MERS-CoV papain-like proteinase (PL-PRO)	TTYJOLE	R1AB_CVEMC (854-2740)	Inhibitor	[5]
Inosine-5'-monophosphate dehydrogenase (IMPDH)	TTCAQMW	NOUNIPROTAC	Intercalator	[8]
SARS-CoV papain-like proteinase (PL-PRO)	TTRGHB2	R1AB_CVHSA (819-2740)	Inhibitor	[5]

Thioguanine 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	[9]
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[10]
Concentrative Na(+)-nucleoside cotransporter 3 (SLC28A3)	DT4YL5R	S28A3_HUMAN	Substrate	[11]

Thioguanine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Thiopurine methyltransferase (TPMT)	DEFQ8VO	TPMT_HUMAN	Metabolism	[12]
Hypoxanthine phosphoribosyltransferase (HPRT1)	DEVXTP5	HPRT_HUMAN	Metabolism	[13]

Thioguanine Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Occludin (OCLN)	OTSUTVWL	OCLN_HUMAN	Decreases Activity	[14]
ATP-binding cassette sub-family C member 5 (ABCC5)	OT34G4US	MRP5_HUMAN	Decreases Response To Substance	[15]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Response To Substance	[16]

Indication(s) of Vincristine

Disease Entry	ICD 11	Status	REF
Acute lymphoblastic leukaemia	2A85	Approved	[6]
Adult kidney Wilms tumor	N.A.	Approved	[7]
Beckwith-Wiedemann syndrome	N.A.	Approved	[7]
Burkitt lymphoma	N.A.	Approved	[7]
Central nervous system neoplasm	N.A.	Approved	[7]
Childhood acute lymphoblastic leukemia	N.A.	Approved	[7]
Childhood kidney Wilms tumor	N.A.	Approved	[7]
Hamartoma	N.A.	Approved	[7]
Kidney neoplasm	N.A.	Approved	[7]
Leukemia	N.A.	Approved	[7]
MALT lymphoma	N.A.	Approved	[7]
Nodal marginal zone lymphoma	2A85.0	Approved	[7]
Plasma cell myeloma	2A83.1	Approved	[7]
Primitive neuroectodermal tumor	N.A.	Approved	[7]
Splenic marginal zone lymphoma	N.A.	Approved	[7]
Testicular lymphoma	N.A.	Approved	[7]
Wilms tumor	N.A.	Approved	[7]
Classic Hodgkin lymphoma	N.A.	Investigative	[7]
Follicular lymphoma	2A80	Investigative	[7]
Neuroblastoma	2D11.2	Investigative	[7]

Vincristine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tubulin beta (TUBB)	TTYFKSZ	NOUNIPROTAC	Modulator	[17]

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	[18]
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[19]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[20]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[21]

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	[22]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[22]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[23]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult acute myeloid leukemia	DC6GEYF	HL-60(TB)	Investigative	[1]
Adult T acute lymphoblastic leukemia	DCVBM2B	MOLT-4	Investigative	[1]
Anaplastic large cell lymphoma	DCUMSR6	SR	Investigative	[1]
Clear cell renal cell carcinoma	DC5QG4P	786-0	Investigative	[1]
Clear cell renal cell carcinoma	DC784KE	A498	Investigative	[1]
Clear cell renal cell carcinoma	DCQ2JU8	CAKI-1	Investigative	[1]
Glioma	DCGHNZD	SF-295	Investigative	[1]
Papillary renal cell carcinoma	DCAEDRB	ACHN	Investigative	[1]
Renal cell carcinoma	DC6LHLZ	SN12C	Investigative	[1]
Adenocarcinoma	DC2BBEM	DU-145	Investigative	[24]
Adenocarcinoma	DCUUJMY	OVCAR3	Investigative	[24]
Adenocarcinoma	DC2XM9J	A549	Investigative	[24]
Adenocarcinoma	DCL81ZA	HCT-15	Investigative	[24]
Amelanotic melanoma	DCJJ0K2	M14	Investigative	[24]
Cutaneous melanoma	DCDZ06U	SK-MEL-5	Investigative	[24]
High grade ovarian serous adenocarcinoma	DCDKOS1	NCI\\/ADR-RES	Investigative	[24]
Large cell lung carcinoma	DCZJBJ8	NCI-H460	Investigative	[24]
Malignant melanoma	DCE9Z4Y	LOX IMVI	Investigative	[24]
Minimally invasive lung adenocarcinoma	DCMSZFP	NCI-H322M	Investigative	[24]
Mixed endometrioid and clear cell carcinoma	DCBJ9XD	IGROV1	Investigative	[24]
Non-small cell lung carcinoma	DC8PHJA	HOP-92	Investigative	[24]
Ovarian serous cystadenocarcinoma	DCSJBCD	SK-OV-3	Investigative	[24]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Thioguanine FDA Label
• [4] 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: 6845).
• [5] Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. Antiviral Res. 2015 Mar;115:9-16.
• [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: 6785).
• [7] Vincristine FDA Label
• [8] Immune effector cells produce lethal DNA damage in cells treated with a thiopurine. Cancer Res. 2009 Mar 15;69(6):2393-9.
• [9] ABC transporters and their role in nucleoside and nucleotide drug resistance. Biochem Pharmacol. 2012 Apr 15;83(8):1073-83.
• [10] Multidrug resistance protein 4 (MRP4/ABCC4) mediates efflux of bimane-glutathione. Int J Biochem Cell Biol. 2004 Feb;36(2):247-57.
• [11] Involvement of the concentrative nucleoside transporter 3 and equilibrative nucleoside transporter 2 in the resistance of T-lymphoblastic cell lines to thiopurines. Biochem Biophys Res Commun. 2006 Apr 28;343(1):208-15.
• [12] Usefulness of thiopurine methyltransferase and thiopurine metabolite analysis in clinical practice in patients with inflammatory bowel diseases. Acta Gastroenterol Belg. 2010 Jul-Sep;73(3):331-5.
• [13] Qualitative and quantitative difference in mutation induction between carbon- and neon-ion beams in normal human cells. Biol Sci Space. 2003 Dec;17(4):302-6.
• [14] The thiopurine methyltransferase genetic polymorphism is associated with thioguanine-related veno-occlusive disease of the liver in children with acute lymphoblastic leukemia. Clin Pharmacol Ther. 2006 Oct;80(4):375-83. doi: 10.1016/j.clpt.2006.07.002.
• [15] The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolites. Mol Cancer Ther. 2005 May;4(5):855-63.
• [16] Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res. 2000 May;6(5):1796-803.
• [17] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [18] Interaction of plant cannabinoids with the multidrug transporter ABCC1 (MRP1). Eur J Pharmacol. 2008 Sep 4;591(1-3):128-31.
• [19] 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.
• [20] 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.
• [21] Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates. Cancer Chemother Pharmacol. 2006 Dec;58(6):826-34.
• [22] Association of CYP3A5 expression and vincristine neurotoxicity in pediatric malignancies in Turkish population. J Pediatr Hematol Oncol. 2017 Aug;39(6):458-462.
• [23] Drug Interactions Flockhart Table
• [24] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125976