General Information of Drug Combination (ID: DC7RRB2)

Drug Combination Name
Dacarbazine Mercaptopurine
Indication
Disease Entry Status REF
Anaplastic large cell lymphoma Investigative [1]
Component Drugs Dacarbazine   DMNPZL4 Mercaptopurine   DMTM2IK
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: SR
Zero Interaction Potency (ZIP) Score: 2.27
Bliss Independence Score: 1.53
Loewe Additivity Score: 0.78
LHighest Single Agent (HSA) Score: 4.35

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Dacarbazine
Disease Entry ICD 11 Status REF
Adenocarcinoma 2D40 Approved [2]
Astrocytoma 2A00.0Y Approved [2]
Brain disease 8C70-8E61 Approved [2]
Central nervous system disease 8A04-8D87 Approved [2]
Glioblastoma 2A00 Approved [2]
Gliosarcoma N.A. Approved [2]
Melanoma 2C30 Approved [3]
Classic Hodgkin lymphoma N.A. Investigative [2]
Neuroblastoma 2D11.2 Investigative [2]
Dacarbazine Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Human Deoxyribonucleic acid (hDNA) TTUTN1I NOUNIPROTAC Breaker [9]
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Dacarbazine Interacts with 3 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 1A2 (CYP1A2) DEJGDUW CP1A2_HUMAN Metabolism [10]
Cytochrome P450 1A1 (CYP1A1) DE6OQ3W CP1A1_HUMAN Metabolism [11]
Cytochrome P450 2E1 (CYP2E1) DEVDYN7 CP2E1_HUMAN Metabolism [12]
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Dacarbazine Interacts with 8 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Baculoviral IAP repeat-containing protein 5 (BIRC5) OTILXZYL BIRC5_HUMAN Increases Expression [13]
Interleukin-8 (CXCL8) OTS7T5VH IL8_HUMAN Increases Expression [8]
Methylated-DNA--protein-cysteine methyltransferase (MGMT) OT40A9WH MGMT_HUMAN Decreases Activity [14]
DNA repair nuclease/redox regulator APEX1 (APEX1) OT53OI14 APEX1_HUMAN Increases Response To Substance [15]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1) OTA675TJ GTR1_HUMAN Decreases Response To Substance [16]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Decreases Response To Substance [17]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Decreases Response To Substance [17]
Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) OTS3FVTY M3K1_HUMAN Decreases Response To Substance [17]
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⏷ Show the Full List of 8 DOT(s)
Indication(s) of Mercaptopurine
Disease Entry ICD 11 Status REF
Acute lymphoblastic leukaemia 2A85 Approved [4]
Acute lymphocytic leukaemia 2B33.3 Approved [5]
Crohn disease DD70 Phase 4 [6]
Middle East Respiratory Syndrome (MERS) 1D64 Preclinical [7]
Severe acute respiratory syndrome (SARS) 1D65 Preclinical [7]
Mercaptopurine Interacts with 4 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 [7]
Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1) TTL7C8Q IMDH1_HUMAN Inhibitor [20]
SARS-CoV papain-like proteinase (PL-PRO) TTRGHB2 R1AB_CVHSA (819-2740) Inhibitor [7]
Amidophosphoribosyltransferase (PPAT) TTZFTY4 PUR1_HUMAN Breaker [21]
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Mercaptopurine Interacts with 9 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
Breast cancer resistance protein (ABCG2) DTI7UX6 ABCG2_HUMAN Substrate [22]
Multidrug resistance-associated protein 4 (ABCC4) DTCSGPB MRP4_HUMAN Substrate [23]
Multidrug resistance-associated protein 5 (ABCC5) DTYVM24 MRP5_HUMAN Substrate [24]
Organic anion transporter 3 (SLC22A8) DTVP67E S22A8_HUMAN Substrate [25]
Concentrative nucleoside transporter 2 (SLC28A2) DT82KPY S28A2_HUMAN Substrate [26]
Concentrative Na(+)-nucleoside cotransporter 3 (SLC28A3) DT4YL5R S28A3_HUMAN Substrate [27]
Equilibrative nucleoside transporter 1 (SLC29A1) DTXD1TQ S29A1_HUMAN Substrate [26]
Equilibrative nucleoside transporter 2 (SLC29A2) DTW78DQ S29A2_HUMAN Substrate [26]
Equilibrative nucleobase transporter 1 (SLC43A3) DTGBPR5 S43A3_HUMAN Substrate [28]
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⏷ Show the Full List of 9 DTP(s)
Mercaptopurine Interacts with 3 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
UDP-glucuronosyltransferase 1A1 (UGT1A1) DEYGVN4 UD11_HUMAN Metabolism [29]
Cytochrome P450 1A1 (CYP1A1) DE6OQ3W CP1A1_HUMAN Metabolism [29]
Thiopurine methyltransferase (TPMT) DEFQ8VO TPMT_HUMAN Metabolism [30]
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Mercaptopurine Interacts with 10 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Nuclear receptor subfamily 4 group A member 3 (NR4A3) OTPBE9R1 NR4A3_HUMAN Increases ADR [31]
Superoxide dismutase , mitochondrial (SOD2) OTIWXGZ9 SODM_HUMAN Increases Expression [32]
Glutathione peroxidase 2 (GPX2) OTXI2NTI GPX2_HUMAN Increases Expression [32]
Glutathione peroxidase 3 (GPX3) OT6PK94R GPX3_HUMAN Increases Expression [32]
Transcription factor p65 (RELA) OTUJP9CN TF65_HUMAN Affects Localization [18]
Bcl-2-like protein 1 (BCL2L1) OTRC5K9O B2CL1_HUMAN Decreases Expression [18]
Molybdenum cofactor sulfurase (MOCOS) OT0TL3Q5 MOCOS_HUMAN Decreases Oxidation [33]
HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1) OTC6GISG DQA1_HUMAN Affects Response To Substance [34]
Major vault protein (MVP) OTJGHJRB MVP_HUMAN Decreases Response To Substance [35]
Nucleotide triphosphate diphosphatase NUDT15 (NUDT15) OTX8SZOT NUD15_HUMAN Increases Response To Substance [36]
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⏷ Show the Full List of 10 DOT(s)

Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
Large cell lung carcinoma DCZN6XX NCI-H460 Investigative [1]
Malignant melanoma DCDWL27 LOX IMVI Investigative [1]
Mixed endometrioid and clear cell carcinoma DCJPO9R IGROV1 Investigative [1]
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References

1 CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
2 Dacarbazine FDA Label
3 FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 075259.
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: 7226).
5 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
6 ClinicalTrials.gov (NCT00846703) The GD-2008 ALL Protocol for Childhood Acute Lymphoblastic Leukemia. U.S. National Institutes of Health.
7 Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. Antiviral Res. 2015 Mar;115:9-16.
8 Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy. Mol Cancer Ther. 2003 Aug;2(8):753-63.
9 Predicting the myelotoxicity of chemotherapy: the use of pretreatment O6-methylguanine-DNA methyltransferase determination in peripheral blood mono... Melanoma Res. 2011 Dec;21(6):502-8.
10 Study on mesenchymal stem cells mediated enzyme-prodrug gene CYP1A2 targeting anti-tumor effect. Zhonghua Xue Ye Xue Za Zhi. 2009 Oct;30(10):667-71.
11 Metabolic activation of dacarbazine by human cytochromes P450: the role of CYP1A1, CYP1A2, and CYP2E1. Clin Cancer Res. 1999 Aug;5(8):2192-7.
12 Role of cytochrome P450 isoenzymes in metabolism of O(6)-benzylguanine: implications for dacarbazine activation. Clin Cancer Res. 2001 Dec;7(12):4239-44.
13 Serum bcl-2 and survivin levels in melanoma. Melanoma Res. 2004 Dec;14(6):543-6. doi: 10.1097/00008390-200412000-00017.
14 Pharmacokinetic, biochemical and clinical effects of dimethyltriazenoimidazole-4-carboxamide-bischloroethylnitrosourea combination therapy in patients with advanced breast cancer. Int J Cancer. 2003 Feb 20;103(5):686-92. doi: 10.1002/ijc.10849.
15 Impairment of APE1 function enhances cellular sensitivity to clinically relevant alkylators and antimetabolites. Mol Cancer Res. 2009 Jun;7(6):897-906. doi: 10.1158/1541-7786.MCR-08-0519. Epub 2009 May 26.
16 Glut-1 as a therapeutic target: increased chemoresistance and HIF-1-independent link with cell turnover is revealed through COMPARE analysis and metabolomic studies. Cancer Chemother Pharmacol. 2008 Mar;61(3):377-93. doi: 10.1007/s00280-007-0480-1. Epub 2007 May 23.
17 Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo. J Clin Oncol. 2004 Jun 1;22(11):2092-100. doi: 10.1200/JCO.2004.11.070. Epub 2004 May 3.
18 CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest. 2003 Apr;111(8):1133-45. doi: 10.1172/JCI16432.
19 Pharmacogenetics of outcome in children with acute lymphoblastic leukemia. Blood. 2005 Jun 15;105(12):4752-8. doi: 10.1182/blood-2004-11-4544. Epub 2005 Feb 15.
20 Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol. 2008 Aug;64(8):753-67.
21 6-mercaptopurine (6-MP) induces p53-mediated apoptosis of neural progenitor cells in the developing fetal rodent brain. Neurotoxicol Teratol. 2009 Jul-Aug;31(4):198-202.
22 ABC transporters and their role in nucleoside and nucleotide drug resistance. Biochem Pharmacol. 2012 Apr 15;83(8):1073-83.
23 Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia. Blood. 2009 Aug 13;114(7):1383-6.
24 Overexpression of MRP4 (ABCC4) and MRP5 (ABCC5) confer resistance to the nucleoside analogs cytarabine and troxacitabine, but not gemcitabine. Springerplus. 2014 Dec 13;3:732.
25 Organic anion transporter 3 is involved in the brain-to-blood efflux transport of thiopurine nucleobase analogs. J Neurochem. 2004 Aug;90(4):931-41.
26 PharmGKB: A worldwide resource for pharmacogenomic information. Wiley Interdiscip Rev Syst Biol Med. 2018 Jul;10(4):e1417. (ID: PA2040)
27 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.
28 Characterization of 6-Mercaptopurine Transport by the SLC43A3-Encoded Nucleobase Transporter. Mol Pharmacol. 2019 Jun;95(6):584-596.
29 Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy. Curr Drug Metab. 2007 Aug;8(6):554-62.
30 The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse. Leukemia. 2010 Apr;24(4):715-20.
31 ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
32 Petit E, Langouet S, Akhdar H, Nicolas-Nicolaz C, Guillouzo A, Morel F. Differential toxic effects of azathioprine, 6-mercaptopurine and 6-thioguanine on human hepatocytes. Toxicol In Vitro. 2008;22(3):632-642. [PMID: 18222062]
33 Thiopurine-induced toxicity is associated with dysfunction variant of the human molybdenum cofactor sulfurase gene (xanthinuria type II). Toxicol Appl Pharmacol. 2018 Aug 15;353:102-108. doi: 10.1016/j.taap.2018.06.015. Epub 2018 Jun 20.
34 HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants. Nat Genet. 2014 Oct;46(10):1131-4. doi: 10.1038/ng.3093. Epub 2014 Sep 14.
35 Sensitization of ABCG2-overexpressing cells to conventional chemotherapeutic agent by sunitinib was associated with inhibiting the function of ABCG2. Cancer Lett. 2009 Jun 28;279(1):74-83. doi: 10.1016/j.canlet.2009.01.027. Epub 2009 Feb 18.
36 A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014 Sep;46(9):1017-20. doi: 10.1038/ng.3060. Epub 2014 Aug 10.