Details of the Drug Combination

General Information of Drug Combination (ID: DCQ7ESX)

• Drug Combination Name: Dacarbazine + Vincristine
• Indication: Adult T acute lymphoblastic leukemia; Status: Investigative [1]
• Component Drugs:
  Dacarbazine (DMNPZL4): Small molecular drug
  Vincristine (DMINOX3): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: MOLT-4
  Zero Interaction Potency (ZIP) Score: 4.68
  Bliss Independence Score: 4.85
  Loewe Additivity Score: 1.13
  LHighest Single Agent (HSA) Score: 4.22

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 Vincristine

Disease Entry	ICD 11	Status	REF
Acute lymphoblastic leukaemia	2A85	Approved	[4]
Adult kidney Wilms tumor	N.A.	Approved	[5]
Beckwith-Wiedemann syndrome	N.A.	Approved	[5]
Burkitt lymphoma	N.A.	Approved	[5]
Central nervous system neoplasm	N.A.	Approved	[5]
Childhood acute lymphoblastic leukemia	N.A.	Approved	[5]
Childhood kidney Wilms tumor	N.A.	Approved	[5]
Hamartoma	N.A.	Approved	[5]
Kidney neoplasm	N.A.	Approved	[5]
Leukemia	N.A.	Approved	[5]
MALT lymphoma	N.A.	Approved	[5]
Nodal marginal zone lymphoma	2A85.0	Approved	[5]
Plasma cell myeloma	2A83.1	Approved	[5]
Primitive neuroectodermal tumor	N.A.	Approved	[5]
Splenic marginal zone lymphoma	N.A.	Approved	[5]
Testicular lymphoma	N.A.	Approved	[5]
Wilms tumor	N.A.	Approved	[5]
Classic Hodgkin lymphoma	N.A.	Investigative	[5]
Follicular lymphoma	2A80	Investigative	[5]
Neuroblastoma	2D11.2	Investigative	[5]

Vincristine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tubulin beta (TUBB)	TTYFKSZ	NOUNIPROTAC	Modulator	[20]

Vincristine Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 1 (ABCC1)	DTSYQGK	MRP1_HUMAN	Substrate	[21]
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[22]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[23]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[24]

Vincristine Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[25]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[25]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[26]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DCJ1ZIR	HCT-15	Investigative	[1]
Adult acute myeloid leukemia	DCPO0CF	HL-60(TB)	Investigative	[1]
Anaplastic large cell lymphoma	DCW8CA2	SR	Investigative	[1]
Childhood T acute lymphoblastic leukemia	DCX39CA	CCRF-CEM	Investigative	[1]
Clear cell renal cell carcinoma	DC5EE5S	786-0	Investigative	[1]
Glioma	DCYPJFB	SF-295	Investigative	[1]
High grade ovarian serous adenocarcinoma	DC7SCZR	NCI\\/ADR-RES	Investigative	[1]
Large cell lung carcinoma	DC54IJ7	NCI-H460	Investigative	[1]
Invasive ductal carcinoma	DCXV6UL	BT-549	Investigative	[27]

References

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• [3] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 075259.
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• [5] Vincristine FDA Label
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• [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.
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• [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] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [21] Interaction of plant cannabinoids with the multidrug transporter ABCC1 (MRP1). Eur J Pharmacol. 2008 Sep 4;591(1-3):128-31.
• [22] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [23] L-type calcium channel blockers reverse docetaxel and vincristine-induced multidrug resistance independent of ABCB1 expression in human lung cancer cell lines. Toxicol Lett. 2010 Feb 15;192(3):408-18.
• [24] Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates. Cancer Chemother Pharmacol. 2006 Dec;58(6):826-34.
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