Details of the Drug Combination

General Information of Drug Combination (ID: DCOH6WD)

• Drug Combination Name: Dacarbazine + Bleomycin
• Indication: Carcinoma; Status: Investigative [1]
• Component Drugs:
  Dacarbazine (DMNPZL4): Small molecular drug
  Bleomycin (DMNER5S): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: MCF7
  Zero Interaction Potency (ZIP) Score: 3.5
  Bliss Independence Score: 6.63
  Loewe Additivity Score: 3.96
  LHighest Single Agent (HSA) Score: 4.28

Molecular Interaction Atlas of This Drug Combination

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	[7]

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	[8]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[9]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[10]

Dacarbazine Interacts with 12 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	[11]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[6]
Interferon regulatory factor 1 (IRF1)	OT43DI6J	IRF1_HUMAN	Increases Expression	[12]
Methylated-DNA--protein-cysteine methyltransferase (MGMT)	OT40A9WH	MGMT_HUMAN	Decreases Activity	[13]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Response To Substance	[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]
Clusterin (CLU)	OTQGG0JM	CLUS_HUMAN	Affects Response To Substance	[18]
Mitogen-activated protein kinase kinase kinase 1 (MAP3K1)	OTS3FVTY	M3K1_HUMAN	Decreases Response To Substance	[17]
Erythropoietin (EPO)	OTZ90CN4	EPO_HUMAN	Decreases Response To Substance	[19]

Indication(s) of Bleomycin

Disease Entry	ICD 11	Status	REF
Cervical cancer	2C77.0	Approved	[4]
Head and neck cancer	2D42	Approved	[4]
Hodgkin lymphoma	2B30	Approved	[5]
Penile cancer	N.A.	Approved	[4]
Testicular germ cell tumor	N.A.	Approved	[4]
Classic Hodgkin lymphoma	N.A.	Investigative	[4]
Follicular lymphoma	2A80	Investigative	[4]

Bleomycin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Breaker	[24]

Bleomycin Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Bleomycin hydrolase (BLMH)	DECH1VP	BLMH_HUMAN	Metabolism	[25]

Bleomycin Interacts with 41 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bleomycin hydrolase (BLMH)	OT2QPWQJ	BLMH_HUMAN	Affects Response To Substance	[26]
Superoxide dismutase (SOD1)	OT39TA1L	SODC_HUMAN	Increases Expression	[27]
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Increases Expression	[27]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[27]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Increases Expression	[28]
Granulocyte-macrophage colony-stimulating factor (CSF2)	OT1M7D28	CSF2_HUMAN	Increases Expression	[28]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[28]
C-X-C motif chemokine 2 (CXCL2)	OTEJCYMY	CXCL2_HUMAN	Increases Expression	[28]
Mucin-5AC (MUC5AC)	OTJV8O04	MUC5A_HUMAN	Increases Expression	[28]
Proheparin-binding EGF-like growth factor (HBEGF)	OTLU00JS	HBEGF_HUMAN	Increases Expression	[28]
Transmembrane protein 250 (TMEM250)	OTLJ4G5G	TM250_HUMAN	Increases Expression	[20]
Suppressor of cytokine signaling 1 (SOCS1)	OTWA9KFU	SOCS1_HUMAN	Decreases Expression	[29]
Serine/threonine-protein kinase Chk2 (CHEK2)	OT8ZPCNS	CHK2_HUMAN	Increases Phosphorylation	[30]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[21]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Expression	[31]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[21]
Fibronectin (FN1)	OTB5ZN4Q	FINC_HUMAN	Increases Expression	[21]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[32]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Expression	[21]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[33]
Cathepsin S (CTSS)	OT3PXIPM	CATS_HUMAN	Increases Expression	[34]
Glycogen synthase kinase-3 beta (GSK3B)	OTL3L14B	GSK3B_HUMAN	Increases Phosphorylation	[35]
Max-interacting protein 1 (MXI1)	OTUQ9E0D	MXI1_HUMAN	Decreases Expression	[20]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Increases Expression	[21]
Unconventional myosin-Ie (MYO1E)	OTM9YSIZ	MYO1E_HUMAN	Decreases Expression	[20]
Transcription intermediary factor 1-beta (TRIM28)	OTE38OBF	TIF1B_HUMAN	Increases Phosphorylation	[30]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Increases Phosphorylation	[30]
Structural maintenance of chromosomes protein 1A (SMC1A)	OT9ZMRK9	SMC1A_HUMAN	Increases Phosphorylation	[30]
7SK snRNA methylphosphate capping enzyme (MEPCE)	OTRBQEYP	MEPCE_HUMAN	Increases Expression	[20]
Transmembrane protein 87A (TMEM87A)	OT8ATDVX	TM87A_HUMAN	Increases Expression	[20]
Terminal nucleotidyltransferase 4B (TENT4B)	OTUF6FWW	PAPD5_HUMAN	Decreases Expression	[20]
Lipase member H (LIPH)	OTRGYLKL	LIPH_HUMAN	Decreases Expression	[20]
Abasic site processing protein HMCES (HMCES)	OTVRDL6U	HMCES_HUMAN	Decreases Expression	[20]
Small integral membrane protein 14 (SMIM14)	OT47IF19	SIM14_HUMAN	Decreases Expression	[20]
Kelch-like protein 42 (KLHL42)	OTK6WARI	KLH42_HUMAN	Increases Expression	[20]
Inactive cell surface hyaluronidase CEMIP2 (CEMIP2)	OT9I1XUO	CEIP2_HUMAN	Decreases Expression	[20]
ERBB receptor feedback inhibitor 1 (ERRFI1)	OT7VZ2IZ	ERRFI_HUMAN	Decreases Expression	[20]
Transmembrane and coiled-coil domain protein 3 (TMCC3)	OTAIQ6V6	TMCC3_HUMAN	Decreases Expression	[20]
Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5)	OT27CCUF	SIAT9_HUMAN	Decreases Expression	[20]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Response To Substance	[36]
DNA cytosine-5)-methyltransferase 1 (DNMT1)	OTM2DGTK	DNMT1_HUMAN	Affects Response To Substance	[37]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Amelanotic melanoma	DC24OFM	MDA-MB-435	Investigative	[38]
Anaplastic large cell lymphoma	DCFZ3K6	SR	Investigative	[38]
Clear cell renal cell carcinoma	DCSAS1E	786-0	Investigative	[38]
Cutaneous melanoma	DCF5LZ6	SK-MEL-28	Investigative	[38]
Melanoma	DC78WCC	SK-MEL-2	Investigative	[38]
Plasma cell myeloma	DCFUBW8	RPMI-8226	Investigative	[38]
Invasive ductal carcinoma	DCA9FVR	BT-549	Investigative	[1]

References

• [1] 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.
• [2] Dacarbazine FDA Label
• [3] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 075259.
• [4] Bleomycin FDA Label
• [5] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Metabolic activation of dacarbazine by human cytochromes P450: the role of CYP1A1, CYP1A2, and CYP2E1. Clin Cancer Res. 1999 Aug;5(8):2192-7.
• [10] Role of cytochrome P450 isoenzymes in metabolism of O(6)-benzylguanine: implications for dacarbazine activation. Clin Cancer Res. 2001 Dec;7(12):4239-44.
• [11] Serum bcl-2 and survivin levels in melanoma. Melanoma Res. 2004 Dec;14(6):543-6. doi: 10.1097/00008390-200412000-00017.
• [12] CD69 on CD56+ NK cells and response to chemoimmunotherapy in metastatic melanoma. Eur J Clin Invest. 2007 Nov;37(11):887-96. doi: 10.1111/j.1365-2362.2007.01873.x.
• [13] 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.
• [14] Mcl-1 antisense therapy chemosensitizes human melanoma in a SCID mouse xenotransplantation model. J Invest Dermatol. 2003 Jun;120(6):1081-6. doi: 10.1046/j.1523-1747.2003.12252.x.
• [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] Clusterin regulates drug-resistance in melanoma cells. J Invest Dermatol. 2005 Jun;124(6):1300-7. doi: 10.1111/j.0022-202X.2005.23720.x.
• [19] Functional erythropoietin autocrine loop in melanoma. Am J Pathol. 2005 Mar;166(3):823-30. doi: 10.1016/S0002-9440(10)62303-6.
• [20] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [21] Pulmonary fibrosis model using micro-CT analyzable human PSC-derived alveolar organoids containing alveolar macrophage-like cells. Cell Biol Toxicol. 2022 Aug;38(4):557-575. doi: 10.1007/s10565-022-09698-1. Epub 2022 Mar 10.
• [22] An antisense oligonucleotide targeted to human Ku86 messenger RNA sensitizes M059K malignant glioma cells to ionizing radiation, bleomycin, and etoposide but not DNA cross-linking agents. Cancer Res. 2002 Oct 15;62(20):5888-96.
• [23] XRCC1 deficiency sensitizes human lung epithelial cells to genotoxicity by crocidolite asbestos and Libby amphibole. Environ Health Perspect. 2010 Dec;118(12):1707-13. doi: 10.1289/ehp.1002312. Epub 2010 Aug 11.
• [24] Bleomycin and talisomycin sequence-specific strand scission of DNA: a mechanism of double-strand cleavage. Cancer Res. 1982 Jul;42(7):2779-85.
• [25] 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.
• [26] Genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes: role in mutagen sensitivity. Carcinogenesis. 2002 Jun;23(6):1003-8. doi: 10.1093/carcin/23.6.1003.
• [27] 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.
• [28] Agents associated with lung inflammation induce similar responses in NCI-H292 lung epithelial cells. Toxicol In Vitro. 2008 Oct;22(7):1782-8.
• [29] Characterization of DNA reactive and non-DNA reactive anticancer drugs by gene expression profiling. Mutat Res. 2007 Jun 1;619(1-2):16-29. doi: 10.1016/j.mrfmmm.2006.12.007. Epub 2007 Feb 8.
• [30] 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.
• [31] Enhanced IL-1 beta and tumor necrosis factor-alpha release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure. J Immunol. 1993 May 1;150(9):4188-96.
• [32] Synergistic anticancer activity of dietary tea polyphenols and bleomycin hydrochloride in human cervical cancer cell: Caspase-dependent and independent apoptotic pathways. Chem Biol Interact. 2016 Mar 5;247:1-10. doi: 10.1016/j.cbi.2016.01.012. Epub 2016 Jan 29.
• [33] 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.
• [34] Radiation-induced cathepsin S is involved in radioresistance. Int J Cancer. 2009 Apr 15;124(8):1794-801. doi: 10.1002/ijc.24095.
• [35] Bleomycin-induced nuclear factor-kappaB activation in human bronchial epithelial cells involves the phosphorylation of glycogen synthase kinase 3beta. Toxicol Lett. 2009 Jun 22;187(3):194-200. doi: 10.1016/j.toxlet.2009.02.023. Epub 2009 Mar 13.
• [36] Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res. 2000 May;6(5):1796-803.
• [37] DNA methylation inhibitor 5-Aza-2'-deoxycytidine induces reversible genome-wide DNA damage that is distinctly influenced by DNA methyltransferases 1 and 3B. Mol Cell Biol. 2008 Jan;28(2):752-71. doi: 10.1128/MCB.01799-07. Epub 2007 Nov 8.
• [38] 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.