Details of the Drug Combination

General Information of Drug Combination (ID: DCHGZZ8)

• Drug Combination Name: Pemetrexed + Oxaliplatin
• Indication: Lung Cancer; Status: Phase 1 [1]
• Component Drugs:
  Pemetrexed (DMMX2E6): Small molecular drug
  Oxaliplatin (DMQNWRD): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Pemetrexed

Disease Entry	ICD 11	Status	REF
Central nervous system lymphoma	2B33.5	Approved	[2]
Epithelioid mesothelioma	2F10	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Malignant pleural mesothelioma	2C26.0	Approved	[3]
Non-small-cell lung cancer	2C25.Y	Approved	[2]
Sarcomatoid mesothelioma	N.A.	Approved	[2]
Small-cell lung cancer	2C25.Y	Approved	[2]
Lung neoplasm	N.A.	Investigative	[2]

Pemetrexed 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	[8]

Pemetrexed Interacts with 6 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[9]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[10]
Multidrug resistance-associated protein 5 (ABCC5)	DTYVM24	MRP5_HUMAN	Substrate	[11]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[12]
Folate transporter 1 (SLC19A1)	DTOSN46	S19A1_HUMAN	Substrate	[13]
Proton-coupled folate transporter (SLC46A1)	DTDJEMI	PCFT_HUMAN	Substrate	[14]

Pemetrexed Interacts with 18 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proton-coupled folate transporter (SLC46A1)	OT049V7Y	PCFT_HUMAN	Increases Activity	[15]
Reduced folate transporter (SLC19A1)	OTWB0BTO	S19A1_HUMAN	Increases Response To Substance	[16]
ATP-binding cassette sub-family C member 5 (ABCC5)	OT34G4US	MRP5_HUMAN	Decreases Response To Substance	[17]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[18]
DNA excision repair protein ERCC-1 (ERCC1)	OTNPYQHI	ERCC1_HUMAN	Decreases Expression	[19]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[20]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[21]
Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial (MTHFD2)	OT1LQSGX	MTDC_HUMAN	Increases Response To Substance	[22]
GTPase KRas (KRAS)	OT78QCN8	RASK_HUMAN	Increases Response To Substance	[22]
Splicing factor 45 (RBM17)	OT9ROJCL	SPF45_HUMAN	Decreases Response To Substance	[23]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Response To Substance	[6]
Gamma-glutamyl hydrolase (GGH)	OTL71J7T	GGH_HUMAN	Affects Response To Substance	[7]
Nucleophosmin (NPM1)	OTTBYYT0	NPM_HUMAN	Decreases Response To Substance	[24]
ALK tyrosine kinase receptor (ALK)	OTV3P4V8	ALK_HUMAN	Affects Response To Substance	[25]
ATP-binding cassette sub-family C member 11 (ABCC11)	OTVHL7OR	MRP8_HUMAN	Decreases Response To Substance	[26]
GTPase NRas (NRAS)	OTVQ1DG3	RASN_HUMAN	Increases Response To Substance	[22]
Folylpolyglutamate synthase, mitochondrial (FPGS)	OTW3F1ZE	FOLC_HUMAN	Increases Response To Substance	[7]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Response To Substance	[18]

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	[27]

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	[28]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[29]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[30]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[31]
High affinity copper uptake protein 1 (SLC31A1)	DTP8L4F	COPT1_HUMAN	Substrate	[32]

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	[33]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[33]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[33]
Cytochrome P450 1B1 (CYP1B1)	DE9QHP6	CP1B1_HUMAN	Metabolism	[33]
Glutathione S-transferase pi (GSTP1)	DEK6079	GSTP1_HUMAN	Metabolism	[34]
Glutathione S-transferase theta-1 (GSTT1)	DE3PKUG	GSTT1_HUMAN	Metabolism	[34]
Metallothionein-1A (MT1A)	DE5ME8A	MT1A_HUMAN	Metabolism	[34]
Metallothionein-2A (MT2A)	DEFKGT7	MT2_HUMAN	Metabolism	[34]
Myeloperoxidase (MPO)	DEA3U9Y	PERM_HUMAN	Metabolism	[34]
Quinone reductase 1 (NQO1)	DENP5RY	NQO1_HUMAN	Metabolism	[34]
Superoxide dismutase 1 (SOD1)	DEUTDON	SODC_HUMAN	Metabolism	[34]
Glutathione S-transferase mu-1 (GSTM1)	DEYZEJA	GSTM1_HUMAN	Metabolism	[34]

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	[35]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Esophagogastric Cancer	DCOJZ0H	N. A.	Phase 2	[36]
Lymphoma	DCVMNXK	N. A.	Phase 1	[37]

References

• [1] ClinicalTrials.gov (NCT00612677) Pemetrexed &Oxaliplatin in Patients w Recurrent NSCLCa After Failure to Platinum Based Adjuvant Chem
• [2] Pemetrexed 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: 6837).
• [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] 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.
• [7] A randomized, double-blind, phase II study of two doses of pemetrexed as first-line chemotherapy for advanced breast cancer. Clin Cancer Res. 2007 Jun 15;13(12):3652-9. doi: 10.1158/1078-0432.CCR-06-2377.
• [8] Updated clinical information on multitargeted antifolates in lung cancer. Clin Lung Cancer. 2009 Mar;10 Suppl 1:S35-40.
• [9] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [10] pH-Dependent transport of pemetrexed by breast cancer resistance protein. Drug Metab Dispos. 2011 Sep;39(9):1478-85.
• [11] Kinetic validation of the use of carboxydichlorofluorescein as a drug surrogate for MRP5-mediated transport. Eur J Pharm Sci. 2006 Apr;27(5):524-32.
• [12] Substrate- and pH-specific antifolate transport mediated by organic anion-transporting polypeptide 2B1 (OATP2B1-SLCO2B1). Mol Pharmacol. 2012 Feb;81(2):134-42.
• [13] Biology of the major facilitative folate transporters SLC19A1 and SLC46A1. Curr Top Membr. 2014;73:175-204.
• [14] The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier. Mol Pharmacol. 2008 Sep;74(3):854-62.
• [15] 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.
• [16] 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.
• [17] The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolites. Mol Cancer Ther. 2005 May;4(5):855-63.
• [18] Death receptor 5 and cellular FLICE-inhibitory protein regulate pemetrexed-induced apoptosis in human lung cancer cells. Eur J Cancer. 2011 Nov;47(16):2471-8. doi: 10.1016/j.ejca.2011.06.003. Epub 2011 Jul 2.
• [19] Pemetrexed downregulates ERCC1 expression and enhances cytotoxicity effected by resveratrol in human nonsmall cell lung cancer cells. Naunyn Schmiedebergs Arch Pharmacol. 2013 Dec;386(12):1047-59. doi: 10.1007/s00210-013-0905-9. Epub 2013 Aug 3.
• [20] The roles of thymidylate synthase and p53 in regulating Fas-mediated apoptosis in response to antimetabolites. Clin Cancer Res. 2004 May 15;10(10):3562-71. doi: 10.1158/1078-0432.CCR-03-0532.
• [21] Xanthohumol inhibits non-small cell lung cancer by activating PUMA-mediated apoptosis. Toxicology. 2022 Mar 30;470:153141. doi: 10.1016/j.tox.2022.153141. Epub 2022 Mar 5.
• [22] KRAS mutation status is associated with enhanced dependency on folate metabolism pathways in non-small cell lung cancer cells. Mol Cancer Ther. 2014 Jun;13(6):1611-24. doi: 10.1158/1535-7163.MCT-13-0649. Epub 2014 Mar 31.
• [23] Human splicing factor SPF45 (RBM17) confers broad multidrug resistance to anticancer drugs when overexpressed--a phenotype partially reversed by selective estrogen receptor modulators. Cancer Res. 2005 Aug 1;65(15):6593-600. doi: 10.1158/0008-5472.CAN-03-3675.
• [24] Proteomic identification of differentially expressed proteins associated with the multiple drug resistance in methotrexate-resistant human breast cancer cells. Int J Oncol. 2014 Jul;45(1):448-58.
• [25] Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol. 2011 Apr;6(4):774-80. doi: 10.1097/JTO.0b013e31820cf053.
• [26] ABCC11/MRP8 confers pemetrexed resistance in lung cancer. Cancer Sci. 2010 Nov;101(11):2404-10.
• [27] Structures of oxaliplatin-oligonucleotide adducts from DNA.J Mass Spectrom.2012 Oct;47(10):1282-93.
• [28] Multidrug Resistance-Associated Protein 2 (MRP2) Mediated Transport of Oxaliplatin-Derived Platinum in Membrane Vesicles. PLoS One. 2015 Jul 1;10(7):e0130727.
• [29] Effect of ABCG2 on cytotoxicity of platinum drugs: interference of EGFP. Toxicol In Vitro. 2008 Dec;22(8):1846-52.
• [30] 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.
• [31] Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res. 2006 Sep 1;66(17):8847-57.
• [32] Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs. Crit Rev Oncol Hematol. 2005 Jan;53(1):13-23.
• [33] 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.
• [34] PharmGKB: A worldwide resource for pharmacogenomic information. Wiley Interdiscip Rev Syst Biol Med. 2018 Jul;10(4):e1417. (ID: PA150642262)
• [35] 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.
• [36] ClinicalTrials.gov (NCT02296671) Personalized Therapy for Esophagogastric Cancer Using Thymidylate Synthase Genetic Markers
• [37] ClinicalTrials.gov (NCT00470405) Pemetrexed and Oxaliplatin in Treating Patients With Metastatic Solid Tumors or Lymphoma