Details of the Drug Combination

General Information of Drug Combination (ID: DCSDF09)

• Drug Combination Name: Pralatrexate + Oxaliplatin
• Indication: Adenocarcinoma of the Gastroesophageal Junction; Status: Phase 1 [1]
• Component Drugs:
  Pralatrexate (DMAO80I): Small molecular drug
  Oxaliplatin (DMQNWRD): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Pralatrexate

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[2]
Peripheral T-cell lymphoma	2A90.C	Approved	[2]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	N.A.	Approved	[3]

Pralatrexate Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Polypeptide deformylase (PDF)	TT9SL3Q	DEFM_HUMAN	Inhibitor	[6]

Pralatrexate Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Folate transporter 1 (SLC19A1)	DTOSN46	S19A1_HUMAN	Substrate	[7]
Proton-coupled folate transporter (SLC46A1)	DTDJEMI	PCFT_HUMAN	Substrate	[7]

Pralatrexate Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Folylpolyglutamate synthase (FPGS)	DECWT2V	FOLC_HUMAN	Metabolism	[8]

Indication(s) of Oxaliplatin

Disease Entry	ICD 11	Status	REF
Adenocarcinoma	2D40	Approved	[4]
Appendiceal neoplasm	N.A.	Approved	[4]
Cholangiocarcinoma	2C12.10	Approved	[4]
Colon adenocarcinoma	N.A.	Approved	[4]
Colorectal cancer	2B91.Z	Approved	[5]
Colorectal carcinoma	N.A.	Approved	[4]
Endocrine gland neoplasm	N.A.	Approved	[4]
Gallbladder carcinoma	N.A.	Approved	[4]
Metastasis from malignant tumor of colon	N.A.	Approved	[4]
Nasopharyngeal carcinoma	2B6B	Approved	[4]
Peritoneal neoplasm	N.A.	Approved	[4]
Rectal adenocarcinoma	2B92	Approved	[4]
Rectal neoplasm	N.A.	Approved	[4]
Rectum mucinous adenocarcinoma	N.A.	Approved	[4]
Colon cancer	2B90.Z	Investigative	[4]
Gastric cancer	2B72	Investigative	[4]

Oxaliplatin Interacts with 1 DTT Molecule(s)

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

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	[10]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[11]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[12]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[13]
High affinity copper uptake protein 1 (SLC31A1)	DTP8L4F	COPT1_HUMAN	Substrate	[14]

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	[15]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[15]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[15]
Cytochrome P450 1B1 (CYP1B1)	DE9QHP6	CP1B1_HUMAN	Metabolism	[15]
Glutathione S-transferase pi (GSTP1)	DEK6079	GSTP1_HUMAN	Metabolism	[16]
Glutathione S-transferase theta-1 (GSTT1)	DE3PKUG	GSTT1_HUMAN	Metabolism	[16]
Metallothionein-1A (MT1A)	DE5ME8A	MT1A_HUMAN	Metabolism	[16]
Metallothionein-2A (MT2A)	DEFKGT7	MT2_HUMAN	Metabolism	[16]
Myeloperoxidase (MPO)	DEA3U9Y	PERM_HUMAN	Metabolism	[16]
Quinone reductase 1 (NQO1)	DENP5RY	NQO1_HUMAN	Metabolism	[16]
Superoxide dismutase 1 (SOD1)	DEUTDON	SODC_HUMAN	Metabolism	[16]
Glutathione S-transferase mu-1 (GSTM1)	DEYZEJA	GSTM1_HUMAN	Metabolism	[16]

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	[17]

References

• [1] ClinicalTrials.gov (NCT01178944) Pralatrexate and Oxaliplatin in Treating Patients With Unresectable or Metastatic Esophageal, Stomach, or Gastroesophageal Junction Cancer
• [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: 6840).
• [3] Pralatrexate FDA Label
• [4] Oxaliplatin FDA Label
• [5] 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).
• [6] Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
• [7] Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012 Aug;15(4):183-210.
• [8] Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23.
• [9] Structures of oxaliplatin-oligonucleotide adducts from DNA.J Mass Spectrom.2012 Oct;47(10):1282-93.
• [10] Multidrug Resistance-Associated Protein 2 (MRP2) Mediated Transport of Oxaliplatin-Derived Platinum in Membrane Vesicles. PLoS One. 2015 Jul 1;10(7):e0130727.
• [11] Effect of ABCG2 on cytotoxicity of platinum drugs: interference of EGFP. Toxicol In Vitro. 2008 Dec;22(8):1846-52.
• [12] 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.
• [13] Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res. 2006 Sep 1;66(17):8847-57.
• [14] Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs. Crit Rev Oncol Hematol. 2005 Jan;53(1):13-23.
• [15] 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.
• [16] PharmGKB: A worldwide resource for pharmacogenomic information. Wiley Interdiscip Rev Syst Biol Med. 2018 Jul;10(4):e1417. (ID: PA150642262)
• [17] 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.