Details of the Drug Combination

General Information of Drug Combination (ID: DCMZ702)

• Drug Combination Name: Tolcapone + Oxaliplatin
• Indication: Neuroblastoma; Status: Phase 1 [1]
• Component Drugs:
  Tolcapone (DM8MNVO): Small molecular drug
  Oxaliplatin (DMQNWRD): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Tolcapone

Disease Entry	ICD 11	Status	REF
Parkinson disease	8A00.0	Approved	[2]

Tolcapone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Catechol-O-methyl-transferase (COMT)	TTKWFB8	COMT_HUMAN	Inhibitor	[6]

Tolcapone Interacts with 22 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[7]
Superoxide dismutase (SOD1)	OT39TA1L	SODC_HUMAN	Decreases Expression	[8]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Decreases Expression	[8]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Decreases Expression	[8]
Lipid transferase CIDEA (CIDEA)	OTDUTSOV	CIDEA_HUMAN	Increases Expression	[9]
Apolipoprotein B-100 (APOB)	OTH0UOCZ	APOB_HUMAN	Decreases Expression	[9]
Platelet glycoprotein 4 (CD36)	OT5CZWKY	CD36_HUMAN	Increases Expression	[9]
Long-chain-fatty-acid--CoA ligase 1 (ACSL1)	OTB06ESI	ACSL1_HUMAN	Decreases Expression	[9]
Microsomal triglyceride transfer protein large subunit (MTTP)	OTNUVSDT	MTP_HUMAN	Increases Expression	[9]
Long-chain-fatty-acid--CoA ligase 5 (ACSL5)	OT3L9XO3	ACSL5_HUMAN	Decreases Expression	[9]
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Decreases Expression	[10]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Decreases Expression	[10]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[11]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[10]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[10]
Catechol O-methyltransferase (COMT)	OTPWKTQG	COMT_HUMAN	Decreases Activity	[12]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Increases Expression	[10]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[13]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Decreases Expression	[10]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[11]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Decreases Expression	[10]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Response To Substance	[14]

Indication(s) of Oxaliplatin

Disease Entry	ICD 11	Status	REF
Adenocarcinoma	2D40	Approved	[3]
Appendiceal neoplasm	N.A.	Approved	[3]
Cholangiocarcinoma	2C12.10	Approved	[3]
Colon adenocarcinoma	N.A.	Approved	[3]
Colorectal cancer	2B91.Z	Approved	[4]
Colorectal carcinoma	N.A.	Approved	[3]
Endocrine gland neoplasm	N.A.	Approved	[3]
Gallbladder carcinoma	N.A.	Approved	[3]
Metastasis from malignant tumor of colon	N.A.	Approved	[3]
Nasopharyngeal carcinoma	2B6B	Approved	[3]
Peritoneal neoplasm	N.A.	Approved	[3]
Rectal adenocarcinoma	2B92	Approved	[3]
Rectal neoplasm	N.A.	Approved	[3]
Rectum mucinous adenocarcinoma	N.A.	Approved	[3]
Colon cancer	2B90.Z	Investigative	[3]
Gastric cancer	2B72	Investigative	[3]

Oxaliplatin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Modulator	[15]

Oxaliplatin Interacts with 5 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[16]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[17]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[18]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[19]
High affinity copper uptake protein 1 (SLC31A1)	DTP8L4F	COPT1_HUMAN	Substrate	[20]

Oxaliplatin Interacts with 12 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[21]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[21]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[21]
Cytochrome P450 1B1 (CYP1B1)	DE9QHP6	CP1B1_HUMAN	Metabolism	[21]
Glutathione S-transferase pi (GSTP1)	DEK6079	GSTP1_HUMAN	Metabolism	[22]
Glutathione S-transferase theta-1 (GSTT1)	DE3PKUG	GSTT1_HUMAN	Metabolism	[22]
Metallothionein-1A (MT1A)	DE5ME8A	MT1A_HUMAN	Metabolism	[22]
Metallothionein-2A (MT2A)	DEFKGT7	MT2_HUMAN	Metabolism	[22]
Myeloperoxidase (MPO)	DEA3U9Y	PERM_HUMAN	Metabolism	[22]
Quinone reductase 1 (NQO1)	DENP5RY	NQO1_HUMAN	Metabolism	[22]
Superoxide dismutase 1 (SOD1)	DEUTDON	SODC_HUMAN	Metabolism	[22]
Glutathione S-transferase mu-1 (GSTM1)	DEYZEJA	GSTM1_HUMAN	Metabolism	[22]

Oxaliplatin Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Protachykinin-1 (TAC1)	OTM842YW	TKN1_HUMAN	Increases ADR	[23]

References

• [1] ClinicalTrials.gov (NCT02630043) Trial of Tolcapone With Oxaliplatin for Neuroblastoma
• [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: 6646).
• [3] Oxaliplatin FDA Label
• [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: 7433).
• [5] Two patients with COMT inhibitor-induced hepatic dysfunction and UGT1A9 genetic polymorphism. Neurology. 2005 Dec 13;65(11):1820-2. doi: 10.1212/01.wnl.0000187066.81162.70.
• [6] Catechol-O-methyltransferase inhibitors in the management of Parkinson's disease. Semin Neurol. 2001;21(1):15-22.
• [7] Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci. 2010 Dec; 118(2):485-500.
• [8] The catechol-O-methyltransferase inhibitors tolcapone and entacapone uncouple and inhibit the mitochondrial respiratory chain in HepaRG cells. Toxicol In Vitro. 2017 Aug;42:337-347.
• [9] Effect of the Catechol-O-Methyltransferase Inhibitors Tolcapone and Entacapone on Fatty Acid Metabolism in HepaRG Cells. Toxicol Sci. 2018 Aug 1;164(2):477-488.
• [10] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [11] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
• [12] Tolcapone increases plasma catecholamine levels in patients with Parkinson's disease. Parkinsonism Relat Disord. 2001 Apr;7(2):93-96. doi: 10.1016/s1353-8020(00)00027-4.
• [13] Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. Toxicol Sci. 2013 Dec;136(2):581-94. doi: 10.1093/toxsci/kft205. Epub 2013 Sep 19.
• [14] Development of a highly sensitive cytotoxicity assay system for CYP3A4-mediated metabolic activation. Drug Metab Dispos. 2011 Aug;39(8):1388-95. doi: 10.1124/dmd.110.037077. Epub 2011 May 3.
• [15] Structures of oxaliplatin-oligonucleotide adducts from DNA.J Mass Spectrom.2012 Oct;47(10):1282-93.
• [16] Multidrug Resistance-Associated Protein 2 (MRP2) Mediated Transport of Oxaliplatin-Derived Platinum in Membrane Vesicles. PLoS One. 2015 Jul 1;10(7):e0130727.
• [17] Effect of ABCG2 on cytotoxicity of platinum drugs: interference of EGFP. Toxicol In Vitro. 2008 Dec;22(8):1846-52.
• [18] Relevance of copper transporter 1 and organic cation transporters 1-3 for oxaliplatin uptake and drug resistance in colorectal cancer cells. Metallomics. 2018 Mar 1;10(3):414-425.
• [19] Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res. 2006 Sep 1;66(17):8847-57.
• [20] Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs. Crit Rev Oncol Hematol. 2005 Jan;53(1):13-23.
• [21] The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentrations in Chinese coke oven workers. Sci Total Environ. 2007 Aug 1;381(1-3):38-46.
• [22] PharmGKB: A worldwide resource for pharmacogenomic information. Wiley Interdiscip Rev Syst Biol Med. 2018 Jul;10(4):e1417. (ID: PA150642262)
• [23] Polymorphic markers associated with severe oxaliplatin-induced, chronic peripheral neuropathy in colon cancer patients. Cancer. 2012 Jun 1;118(11):2828-36. doi: 10.1002/cncr.26614. Epub 2011 Oct 21.