General Information of Drug Combination (ID: DCTYD32)

Drug Combination Name
Dexrazoxane Mechlorethamine
Indication
Disease Entry Status REF
Adenocarcinoma Investigative [1]
Component Drugs Dexrazoxane   DMD7X1O Mechlorethamine   DM0CVXA
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: OVCAR3
Zero Interaction Potency (ZIP) Score: 1.32
Bliss Independence Score: 8.83
Loewe Additivity Score: 4.01
LHighest Single Agent (HSA) Score: 8.54

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Dexrazoxane
Disease Entry ICD 11 Status REF
Breast cancer 2C60-2C65 Approved [2]
Chemoprotection N.A. Approved [3]
Inflammatory breast cancer 2C62 Approved [4]
Respiratory tract disease CB7Z Investigative [5]
Dexrazoxane Interacts with 2 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
DNA topoisomerase II beta (TOP2B) TT4NVEM TOP2B_HUMAN Inhibitor [8]
DNA topoisomerase II (TOP2) TT0IHXV TOP2A_HUMAN; TOP2B_HUMAN Modulator [9]
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Dexrazoxane Interacts with 1 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Dihydropyrimidinase-related protein 1 (DRP1) DE0EUXB DPYL1_HUMAN Metabolism [10]
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Dexrazoxane Interacts with 1 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
DNA topoisomerase 2-alpha (TOP2A) OT6LPS08 TOP2A_HUMAN Decreases Activity [11]
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Indication(s) of Mechlorethamine
Disease Entry ICD 11 Status REF
Chronic myelogenous leukaemia 2A20.0 Approved [6]
Lung cancer 2C25.0 Approved [6]
Mycosis fungoides 2B01 Approved [6]
Primary cutaneous T-cell lymphoma N.A. Approved [6]
Small lymphocytic lymphoma 2A82.0 Approved [6]
T-cell lymphoma 2A90 Approved [3]
Hodgkin lymphoma 2B30 Phase 3 [7]
Classic Hodgkin lymphoma N.A. Investigative [6]
Mechlorethamine Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Human Deoxyribonucleic acid (hDNA) TTUTN1I NOUNIPROTAC Intercalator [14]
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Mechlorethamine Interacts with 19 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Receptor tyrosine-protein kinase erbB-2 (ERBB2) OTOAUNCK ERBB2_HUMAN Decreases Expression [15]
Cellular tumor antigen p53 (TP53) OTIE1VH3 P53_HUMAN Decreases Activity [16]
Transcription factor Jun (JUN) OTCYBO6X JUN_HUMAN Increases Expression [17]
Cyclin-dependent kinase 1 (CDK1) OTW1SC2N CDK1_HUMAN Decreases Activity [18]
Glutathione S-transferase A2 (GSTA2) OTW7UB1H GSTA2_HUMAN Increases Expression [19]
Interleukin-8 (CXCL8) OTS7T5VH IL8_HUMAN Increases Expression [17]
Apoptosis regulator Bcl-2 (BCL2) OT9DVHC0 BCL2_HUMAN Decreases Expression [20]
G2/mitotic-specific cyclin-B1 (CCNB1) OT19S7E5 CCNB1_HUMAN Decreases Activity [18]
Transcription factor JunB (JUNB) OTG2JXV5 JUNB_HUMAN Increases Expression [17]
Transcription factor JunD (JUND) OTNKACJD JUND_HUMAN Increases Expression [17]
Cyclin-A2 (CCNA2) OTPHHYZJ CCNA2_HUMAN Increases Stability [18]
Cyclin-dependent kinase 2 (CDK2) OTB5DYYZ CDK2_HUMAN Increases Activity [18]
Protein S100-P (S100P) OTJCXNJG S100P_HUMAN Increases Expression [21]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [22]
Caspase-2 (CASP2) OTUDYSPP CASP2_HUMAN Increases Activity [20]
Caspase-9 (CASP9) OTD4RFFG CASP9_HUMAN Increases Activity [20]
Laminin subunit gamma-2 (LAMC2) OTJMTM72 LAMC2_HUMAN Decreases Expression [23]
Bcl-2 homologous antagonist/killer (BAK1) OTDP6ILW BAK_HUMAN Increases Expression [24]
Transient receptor potential cation channel subfamily A member 1 (TRPA1) OTRDIR5M TRPA1_HUMAN Increases Response To Substance [25]
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⏷ Show the Full List of 19 DOT(s)

Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
Adult acute myeloid leukemia DC6DF7D HL-60(TB) Investigative [26]
Chronic myelogenous leukemia DCWG9CN K-562 Investigative [26]
Glioma DCF6K8B SF-268 Investigative [26]
Glioma DC5A2ZB SF-539 Investigative [26]
Papillary renal cell carcinoma DCQI14E ACHN Investigative [26]
Colon adenocarcinoma DCTE1X3 COLO 205 Investigative [27]
High grade ovarian serous adenocarcinoma DCPC4UF OVCAR-8 Investigative [1]
Large cell lung carcinoma DCHWF7E NCI-H460 Investigative [1]
Melanoma DCF2FWX UACC-257 Investigative [1]
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⏷ Show the Full List of 9 DrugCom(s)

References

1 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.
2 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: 7330).
3 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
4 Dexrazoxane FDA Label
5 Design and development of antisense drugs. Expert Opin. Drug Discov. 2008 3(10):1189-1207.
6 Mechlorethamine FDA Label
7 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: 7218).
8 How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
9 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
10 Metabolism of the cardioprotective drug dexrazoxane and one of its metabolites by isolated rat myocytes, hepatocytes, and blood. Drug Metab Dispos. 2005 Jun;33(6):719-25.
11 Investigation of novel dexrazoxane analogue JR-311 shows significant cardioprotective effects through topoisomerase IIbeta but not its iron chelating metabolite. Toxicology. 2017 Dec 1;392:1-10. doi: 10.1016/j.tox.2017.09.012. Epub 2017 Sep 21.
12 Thioredoxin Cross-Linking by Nitrogen Mustard in Lung Epithelial Cells: Formation of Multimeric Thioredoxin/Thioredoxin Reductase Complexes and Inhibition of Disulfide Reduction. Chem Res Toxicol. 2015 Nov 16;28(11):2091-103. doi: 10.1021/acs.chemrestox.5b00194. Epub 2015 Oct 19.
13 Cross-linking of thioredoxin reductase by the sulfur mustard analogue mechlorethamine (methylbis(2-chloroethyl)amine) in human lung epithelial cells and rat lung: selective inhibition of disulfide reduction but not redox cycling. Chem Res Toxicol. 2014 Jan 21;27(1):61-75. doi: 10.1021/tx400329a. Epub 2013 Dec 9.
14 Proteomic analysis of DNA-protein cross-linking by antitumor nitrogen mustards. Chem Res Toxicol. 2009 Jun;22(6):1151-62.
15 Down-regulation of HER-2 expression in human breast cancer cell HBC-4 and ZR75-1 by nitrogen-mustard-N-oxide. Kobe J Med Sci. 2007;53(4):135-42.
16 Nitrogen Mustard Alkylates and Cross-Links p53 in Human Keratinocytes. Chem Res Toxicol. 2022 Apr 18;35(4):636-650. doi: 10.1021/acs.chemrestox.1c00420. Epub 2022 Mar 21.
17 Nitrogen mustard prevents transport of Fra-1 into the nucleus to promote c-Fos- and FosB-dependent IL-8 induction in injured mouse epidermis. Toxicol Lett. 2020 Feb 1;319:256-263. doi: 10.1016/j.toxlet.2019.10.006. Epub 2019 Oct 19.
18 G2 delay induced by nitrogen mustard in human cells affects cyclin A/cdk2 and cyclin B1/cdc2-kinase complexes differently. J Biol Chem. 1993 Apr 15;268(11):8298-308.
19 Overexpression of GSTA2 protects against cell cycle arrest and apoptosis induced by the DNA inter-strand crosslinking nitrogen mustard, mechlorethamine. J Cell Biochem. 2005 May 15;95(2):339-51. doi: 10.1002/jcb.20440.
20 Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis. Apoptosis. 2006 Sep;11(9):1545-59. doi: 10.1007/s10495-006-8764-1.
21 S100P is selectively upregulated in tumor cell lines challenged with DNA cross-linking agents. Leuk Res. 2005 Oct;29(10):1181-90. doi: 10.1016/j.leukres.2005.03.012.
22 Ebselen reduces the toxicity of mechlorethamine in A-431 cells via inhibition of apoptosis. J Biochem Mol Toxicol. 2013 Jun;27(6):313-22. doi: 10.1002/jbt.21490. Epub 2013 May 6.
23 Histopathologic and immunohistochemical features in human skin after exposure to nitrogen and sulfur mustard. Am J Dermatopathol. 1998 Feb;20(1):22-8. doi: 10.1097/00000372-199802000-00005.
24 Increased expression of VDAC1 sensitizes carcinoma cells to apoptosis induced by DNA cross-linking agents. Biochem Pharmacol. 2012 May 1;83(9):1172-82. doi: 10.1016/j.bcp.2012.01.017. Epub 2012 Jan 21.
25 Activation of the human TRPA1 channel by different alkylating sulfur and nitrogen mustards and structurally related chemotherapeutic drugs. Toxicol Lett. 2023 Mar 1;376:51-59. doi: 10.1016/j.toxlet.2023.01.007. Epub 2023 Jan 21.
26 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.
27 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.