Details of the Drug Combination

General Information of Drug Combination (ID: DCHPNYE)

• Drug Combination Name: Mechlorethamine + Busulfan
• Indication: High grade ovarian serous adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  Mechlorethamine (DM0CVXA): Small molecular drug
  Busulfan (DMXYJ9C): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: OVCAR-4
  Zero Interaction Potency (ZIP) Score: 5.35
  Bliss Independence Score: 3.49
  Loewe Additivity Score: 1.79
  LHighest Single Agent (HSA) Score: 2.48

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Mechlorethamine

Disease Entry	ICD 11	Status	REF
Chronic myelogenous leukaemia	2A20.0	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Mycosis fungoides	2B01	Approved	[2]
Primary cutaneous T-cell lymphoma	N.A.	Approved	[2]
Small lymphocytic lymphoma	2A82.0	Approved	[2]
T-cell lymphoma	2A90	Approved	[3]
Hodgkin lymphoma	2B30	Phase 3	[4]
Classic Hodgkin lymphoma	N.A.	Investigative	[2]

Mechlorethamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Intercalator	[9]

Mechlorethamine Interacts with 9 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	[10]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Expression	[11]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[11]
Transcription factor JunB (JUNB)	OTG2JXV5	JUNB_HUMAN	Increases Expression	[11]
Transcription factor JunD (JUND)	OTNKACJD	JUND_HUMAN	Increases Expression	[11]
Protein S100-P (S100P)	OTJCXNJG	S100P_HUMAN	Increases Expression	[12]
Laminin subunit gamma-2 (LAMC2)	OTJMTM72	LAMC2_HUMAN	Decreases Expression	[13]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[14]
Transient receptor potential cation channel subfamily A member 1 (TRPA1)	OTRDIR5M	TRPA1_HUMAN	Increases Response To Substance	[15]

Indication(s) of Busulfan

Disease Entry	ICD 11	Status	REF
Chronic myelogenous leukaemia	2A20.0	Approved	[5]
Hematologic disease	3C0Z	Approved	[5]
Immunodeficiency	4A00-4A85	Approved	[5]
Leukemia	N.A.	Approved	[5]
Myeloproliferative syndrome	2A22	Approved	[6]
Systemic lupus erythematosus	4A40.0	Approved	[5]
Systemic sclerosis	4A42	Approved	[5]
Neuroblastoma	2D11.2	Investigative	[5]
Retinoblastoma	2D02.2	Investigative	[5]

Busulfan Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Modulator	[17]

Busulfan Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[18]
Glutathione S-transferase alpha-1 (GSTA1)	DE4ZHS1	GSTA1_HUMAN	Metabolism	[19]
Glutathione S-transferase alpha-2 (GSTA2)	DEH49YS	GSTA2_HUMAN	Metabolism	[20]
Glutathione S-transferase pi (GSTP1)	DEK6079	GSTP1_HUMAN	Metabolism	[21]
Microsomal glutathione S-transferase 2 (MGST2)	DE31KMQ	MGST2_HUMAN	Metabolism	[22]
Glutathione S-transferase mu-1 (GSTM1)	DEYZEJA	GSTM1_HUMAN	Metabolism	[21]

Busulfan Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Serotransferrin (TF)	OT41PEMS	TRFE_HUMAN	Increases Expression	[23]
Antithrombin-III (SERPINC1)	OTDFATG0	ANT3_HUMAN	Affects Expression	[24]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[25]
Plasminogen activator inhibitor 1 (SERPINE1)	OTT0MPQ3	PAI1_HUMAN	Increases Expression	[25]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[26]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[26]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[16]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Increases Expression	[16]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Activity	[27]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Activity	[27]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[27]
Signal transducer and activator of transcription 2 (STAT2)	OTO9G2RZ	STAT2_HUMAN	Decreases Expression	[16]
Pseudouridylate synthase 7 homolog (PUS7)	OTE5AQHJ	PUS7_HUMAN	Increases Expression	[28]
DNA repair nuclease/redox regulator APEX1 (APEX1)	OT53OI14	APEX1_HUMAN	Increases Response To Substance	[29]
Rho GDP-dissociation inhibitor 1 (ARHGDIA)	OTEXWJDO	GDIR1_HUMAN	Affects Response To Substance	[30]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Childhood T acute lymphoblastic leukemia	DCMUQV7	CCRF-CEM	Investigative	[31]
Cutaneous melanoma	DCCH36P	SK-MEL-28	Investigative	[1]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125976
• [2] Mechlorethamine FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [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: 7218).
• [5] Busulfan FDA Label
• [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: 7136).
• [7] 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.
• [8] 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.
• [9] Proteomic analysis of DNA-protein cross-linking by antitumor nitrogen mustards. Chem Res Toxicol. 2009 Jun;22(6):1151-62.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Direct transcriptomic comparison of xenobiotic metabolism and toxicity pathway induction of airway epithelium models at an air-liquid interface generated from induced pluripotent stem cells and primary bronchial epithelial cells. Cell Biol Toxicol. 2023 Feb;39(1):1-18. doi: 10.1007/s10565-022-09726-0. Epub 2022 May 31.
• [17] DNA intrastrand cross-link at the 5'-GA-3' sequence formed by busulfan and its role in the cytotoxic effect. Cancer Sci. 2004 May;95(5):454-8.
• [18] Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy. 1998 Jan-Feb;18(1):84-112.
• [19] Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation. Blood. 2004 Sep 1;104(5):1574-7.
• [20] Endothelial cells do not express GSTA1: potential relevance to busulfan-mediated endothelial damage during haematopoietic stem cell transplantation. Eur J Haematol. 2008 Apr;80(4):299-302.
• [21] Busulfan conjugation by glutathione S-transferases alpha, mu, and pi. Drug Metab Dispos. 1996 Sep;24(9):1015-9.
• [22] Overexpression of glutathione-S-transferase, MGSTII, confers resistance to busulfan and melphalan. Cancer Invest. 2005;23(1):19-25.
• [23] Busulfan induces activin A expression in vitro and in vivo: a possible link to venous occlusive disease. Clin Pharmacol Ther. 2003 Sep;74(3):264-74.
• [24] Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation. Ann Hematol. 2005 May;84(5):321-30. doi: 10.1007/s00277-004-0982-4. Epub 2004 Dec 4.
• [25] Antineoplastic agent busulfan regulates a network of genes related to coagulation and fibrinolysis. Eur J Clin Pharmacol. 2012 Jun;68(6):923-35. doi: 10.1007/s00228-011-1209-y.
• [26] Altered gene expression in busulfan-resistant human myeloid leukemia. Leuk Res. 2008 Nov;32(11):1684-97. doi: 10.1016/j.leukres.2008.01.016. Epub 2008 Mar 12.
• [27] Busulfan selectively induces cellular senescence but not apoptosis in WI38 fibroblasts via a p53-independent but extracellular signal-regulated kinase-p38 mitogen-activated protein kinase-dependent mechanism. J Pharmacol Exp Ther. 2006 Nov;319(2):551-60. doi: 10.1124/jpet.106.107771. Epub 2006 Aug 1.
• [28] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [29] 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.
• [30] Reduced expression of Rho guanine nucleotide dissociation inhibitor-alpha modulates the cytotoxic effect of busulfan in HEK293 cells. Anticancer Drugs. 2007 Mar;18(3):333-40. doi: 10.1097/CAD.0b013e328011fd7f.
• [31] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966