Details of the Drug Combination

General Information of Drug Combination (ID: DCWXLZZ)

• Drug Combination Name: Thioguanine + Bleomycin
• Indication: Childhood T acute lymphoblastic leukemia; Status: Investigative [1]
• Component Drugs:
  Thioguanine (DM7NKEV): Small molecular drug
  Bleomycin (DMNER5S): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: CCRF-CEM
  Zero Interaction Potency (ZIP) Score: 7.83
  Bliss Independence Score: 9.13
  Loewe Additivity Score: 6.27
  LHighest Single Agent (HSA) Score: 8.84

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 Bleomycin

Disease Entry	ICD 11	Status	REF
Cervical cancer	2C77.0	Approved	[6]
Head and neck cancer	2D42	Approved	[6]
Hodgkin lymphoma	2B30	Approved	[7]
Penile cancer	N.A.	Approved	[6]
Testicular germ cell tumor	N.A.	Approved	[6]
Classic Hodgkin lymphoma	N.A.	Investigative	[6]
Follicular lymphoma	2A80	Investigative	[6]

Bleomycin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Breaker	[21]

Bleomycin Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Bleomycin hydrolase (BLMH)	DECH1VP	BLMH_HUMAN	Metabolism	[22]

Bleomycin Interacts with 23 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[23]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Increases Expression	[24]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[24]
Mucin-5AC (MUC5AC)	OTJV8O04	MUC5A_HUMAN	Increases Expression	[24]
Transmembrane protein 250 (TMEM250)	OTLJ4G5G	TM250_HUMAN	Increases Expression	[17]
Serine/threonine-protein kinase Chk2 (CHEK2)	OT8ZPCNS	CHK2_HUMAN	Increases Phosphorylation	[25]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[18]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[26]
Max-interacting protein 1 (MXI1)	OTUQ9E0D	MXI1_HUMAN	Decreases Expression	[17]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Increases Expression	[18]
Unconventional myosin-Ie (MYO1E)	OTM9YSIZ	MYO1E_HUMAN	Decreases Expression	[17]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Increases Phosphorylation	[25]
Structural maintenance of chromosomes protein 1A (SMC1A)	OT9ZMRK9	SMC1A_HUMAN	Increases Phosphorylation	[25]
7SK snRNA methylphosphate capping enzyme (MEPCE)	OTRBQEYP	MEPCE_HUMAN	Increases Expression	[17]
Transmembrane protein 87A (TMEM87A)	OT8ATDVX	TM87A_HUMAN	Increases Expression	[17]
Lipase member H (LIPH)	OTRGYLKL	LIPH_HUMAN	Decreases Expression	[17]
Abasic site processing protein HMCES (HMCES)	OTVRDL6U	HMCES_HUMAN	Decreases Expression	[17]
Small integral membrane protein 14 (SMIM14)	OT47IF19	SIM14_HUMAN	Decreases Expression	[17]
Kelch-like protein 42 (KLHL42)	OTK6WARI	KLH42_HUMAN	Increases Expression	[17]
Inactive cell surface hyaluronidase CEMIP2 (CEMIP2)	OT9I1XUO	CEIP2_HUMAN	Decreases Expression	[17]
ERBB receptor feedback inhibitor 1 (ERRFI1)	OT7VZ2IZ	ERRFI_HUMAN	Decreases Expression	[17]
Transmembrane and coiled-coil domain protein 3 (TMCC3)	OTAIQ6V6	TMCC3_HUMAN	Decreases Expression	[17]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Response To Substance	[16]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult acute myeloid leukemia	DCB1S7W	HL-60(TB)	Investigative	[1]
Adult T acute lymphoblastic leukemia	DCUCX77	MOLT-4	Investigative	[1]
Astrocytoma	DCVG1Y0	U251	Investigative	[1]
Chronic myelogenous leukemia	DCO497D	K-562	Investigative	[1]
Clear cell renal cell carcinoma	DCT7QZS	786-0	Investigative	[1]
Glioblastoma	DCTNR2E	SNB-75	Investigative	[1]
Glioma	DCXA8OV	SF-268	Investigative	[1]
Papillary renal cell carcinoma	DCNU84W	ACHN	Investigative	[1]
Plasma cell myeloma	DCP66T0	RPMI-8226	Investigative	[1]
Breast adenocarcinoma	DCUF4Q1	MDA-MB-468	Investigative	[27]
Carcinoma	DCHY3XY	MCF7	Investigative	[27]
Colon adenocarcinoma	DCULA3B	COLO 205	Investigative	[27]
Adenocarcinoma	DC7UKFJ	DU-145	Investigative	[28]
Adenocarcinoma	DCDFWO9	OVCAR3	Investigative	[28]
Adenocarcinoma	DCSBA0G	HCC-2998	Investigative	[28]
Adenocarcinoma	DC1QN5C	SW-620	Investigative	[28]
Adenocarcinoma	DC2ZSQ2	HT29	Investigative	[28]
Large cell lung carcinoma	DCK8G02	NCI-H460	Investigative	[28]
Melanoma	DCRGTTJ	MALME-3M	Investigative	[28]
Melanoma	DCUAXJL	UACC-257	Investigative	[28]
Melanoma	DCG67TU	SK-MEL-2	Investigative	[28]
Non-small cell lung carcinoma	DCD7ES7	HOP-92	Investigative	[28]

References

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• [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).
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• [6] Bleomycin FDA Label
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• [21] Bleomycin and talisomycin sequence-specific strand scission of DNA: a mechanism of double-strand cleavage. Cancer Res. 1982 Jul;42(7):2779-85.
• [22] The C-terminus of human bleomycin hydrolase is required for protection against bleomycin-induced chromosomal damage. Mutat Res. 1998 Oct 12;421(1):1-7.
• [23] Age-dependent basal level and induction capacity of copper-zinc and manganese superoxide dismutase and other scavenging enzyme activities in leukocytes from young and elderly adults. Am J Pathol. 1993 Jul;143(1):312-20.
• [24] Agents associated with lung inflammation induce similar responses in NCI-H292 lung epithelial cells. Toxicol In Vitro. 2008 Oct;22(7):1782-8.
• [25] Direct activation of ATM by resveratrol under oxidizing conditions. PLoS One. 2014 Jun 16;9(6):e97969. doi: 10.1371/journal.pone.0097969. eCollection 2014.
• [26] Distinct mechanisms of cell-kill by triapine and its terminally dimethylated derivative Dp44mT due to a loss or gain of activity of their copper(II) complexes. Biochem Pharmacol. 2014 Oct 1;91(3):312-22. doi: 10.1016/j.bcp.2014.08.006. Epub 2014 Aug 15.
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