Details of the Drug Combination

General Information of Drug Combination (ID: DCKEY5C)

• Drug Combination Name: Oxaliplatin + Raltitrexed
• Indication: Colorectal Cancer; Status: Phase 1 [1]
• Component Drugs:
  Oxaliplatin (DMQNWRD): Small molecular drug
  Raltitrexed (DMT9K8G): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Oxaliplatin

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

Oxaliplatin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Modulator	[5]

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	[6]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[7]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[8]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[9]
High affinity copper uptake protein 1 (SLC31A1)	DTP8L4F	COPT1_HUMAN	Substrate	[10]

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	[11]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[11]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[11]
Cytochrome P450 1B1 (CYP1B1)	DE9QHP6	CP1B1_HUMAN	Metabolism	[11]
Glutathione S-transferase pi (GSTP1)	DEK6079	GSTP1_HUMAN	Metabolism	[12]
Glutathione S-transferase theta-1 (GSTT1)	DE3PKUG	GSTT1_HUMAN	Metabolism	[12]
Metallothionein-1A (MT1A)	DE5ME8A	MT1A_HUMAN	Metabolism	[12]
Metallothionein-2A (MT2A)	DEFKGT7	MT2_HUMAN	Metabolism	[12]
Myeloperoxidase (MPO)	DEA3U9Y	PERM_HUMAN	Metabolism	[12]
Quinone reductase 1 (NQO1)	DENP5RY	NQO1_HUMAN	Metabolism	[12]
Superoxide dismutase 1 (SOD1)	DEUTDON	SODC_HUMAN	Metabolism	[12]
Glutathione S-transferase mu-1 (GSTM1)	DEYZEJA	GSTM1_HUMAN	Metabolism	[12]

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	[13]

Indication(s) of Raltitrexed

Disease Entry	ICD 11	Status	REF
Rectal adenocarcinoma	2B92	Approved	[4]

Raltitrexed Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Candida Thymidylate synthase (Candi TMP1)	TTU6BFZ	TYSY_CANAL	Inhibitor	[15]

Raltitrexed Interacts with 2 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]

Raltitrexed Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Annexin A2 (ANXA2)	OTFNS0CC	ANXA2_HUMAN	Increases Expression	[18]
Diamine acetyltransferase 1 (SAT1)	OT52AU22	SAT1_HUMAN	Increases Expression	[18]
10 kDa heat shock protein, mitochondrial (HSPE1)	OT7JSZLB	CH10_HUMAN	Increases Expression	[18]
Thymosin beta-10 (TMSB10)	OTLVZ13T	TYB10_HUMAN	Increases Expression	[18]
FXYD domain-containing ion transport regulator 3 (FXYD3)	OT9PPRHE	FXYD3_HUMAN	Increases Expression	[18]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[19]
Signal transducer and activator of transcription 1-alpha/beta (STAT1)	OTLMBUZ6	STAT1_HUMAN	Increases Phosphorylation	[19]
Proton-coupled folate transporter (SLC46A1)	OT049V7Y	PCFT_HUMAN	Increases Response To Substance	[20]
Folate receptor alpha (FOLR1)	OT0QZ0H6	FOLR1_HUMAN	Increases Response To Substance	[20]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Response To Substance	[14]
Reduced folate transporter (SLC19A1)	OTWB0BTO	S19A1_HUMAN	Decreases Response To Substance	[21]

References

• [1] ClinicalTrials.gov (NCT01348412) Hepatic Arterial Chemotherapy With Raltitrexed and Oxaliplatin Versus Standard Chemotherapy in Unresectable Liver Metastases From Colorectal Cancer After Conventional Chemotherapy Failure
• [2] Oxaliplatin FDA Label
• [3] 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).
• [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: 7403).
• [5] Structures of oxaliplatin-oligonucleotide adducts from DNA.J Mass Spectrom.2012 Oct;47(10):1282-93.
• [6] Multidrug Resistance-Associated Protein 2 (MRP2) Mediated Transport of Oxaliplatin-Derived Platinum in Membrane Vesicles. PLoS One. 2015 Jul 1;10(7):e0130727.
• [7] Effect of ABCG2 on cytotoxicity of platinum drugs: interference of EGFP. Toxicol In Vitro. 2008 Dec;22(8):1846-52.
• [8] 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.
• [9] Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res. 2006 Sep 1;66(17):8847-57.
• [10] Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs. Crit Rev Oncol Hematol. 2005 Jan;53(1):13-23.
• [11] 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.
• [12] PharmGKB: A worldwide resource for pharmacogenomic information. Wiley Interdiscip Rev Syst Biol Med. 2018 Jul;10(4):e1417. (ID: PA150642262)
• [13] 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.
• [14] Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels. Br J Cancer. 2007 Mar 12;96(5):769-75.
• [15] DNA damage and homologous recombination signaling induced by thymidylate deprivation. Biochem Pharmacol. 2008 Oct 15;76(8):987-96.
• [16] Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Res. 1999 Jun 1;59(11):2532-5.
• [17] Pharmacogenomic importance of ABCG2. Pharmacogenomics. 2008 Aug;9(8):1005-9.
• [18] 5-Fluorouracil: identification of novel downstream mediators of tumour response. Anticancer Res. 2004 Mar-Apr;24(2A):417-23.
• [19] Effect of p53 status and STAT1 on chemotherapy-induced, Fas-mediated apoptosis in colorectal cancer. Cancer Res. 2005 Oct 1;65(19):8951-60. doi: 10.1158/0008-5472.CAN-05-0961.
• [20] Synthesis, biological, and antitumor activity of a highly potent 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitor with proton-coupled folate transporter and folate receptor selectivity over the reduced folate carrier that inhibits -glycinamide ribonucleotide formyltransferase. J Med Chem. 2011 Oct 27;54(20):7150-64.
• [21] The inverse relationship between reduced folate carrier function and pemetrexed activity in a human colon cancer cell line. Mol Cancer Ther. 2006 Feb;5(2):438-49. doi: 10.1158/1535-7163.MCT-05-0243.