Details of the Drug Combination

General Information of Drug Combination (ID: DCCR03I)

• Drug Combination Name: ABIRATERONE + Vincristine
• Indication: Clear cell renal cell carcinoma; Status: Investigative [1]
• Component Drugs:
  ABIRATERONE (DM8V75C): Small molecular drug
  Vincristine (DMINOX3): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: CAKI-1
  Zero Interaction Potency (ZIP) Score: 2.03
  Bliss Independence Score: 8.91
  Loewe Additivity Score: 11.5
  LHighest Single Agent (HSA) Score: 10.78

Molecular Interaction Atlas of This Drug Combination

Indication(s) of ABIRATERONE

Disease Entry	ICD 11	Status	REF
Prostate cancer	2C82.0	Approved	[2]

ABIRATERONE Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Steroid 17-alpha-monooxygenase (S17AH)	TTRA5BZ	CP17A_HUMAN	Modulator	[5]

ABIRATERONE Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1)	OTZKVLVJ	CP17A_HUMAN	Decreases Activity	[6]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Increases Expression	[7]
Membrane cofactor protein (CD46)	OTQ8NWJD	MCP_HUMAN	Increases Expression	[8]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Decreases Response To Substance	[9]

Indication(s) of Vincristine

Disease Entry	ICD 11	Status	REF
Acute lymphoblastic leukaemia	2A85	Approved	[3]
Adult kidney Wilms tumor	N.A.	Approved	[4]
Beckwith-Wiedemann syndrome	N.A.	Approved	[4]
Burkitt lymphoma	N.A.	Approved	[4]
Central nervous system neoplasm	N.A.	Approved	[4]
Childhood acute lymphoblastic leukemia	N.A.	Approved	[4]
Childhood kidney Wilms tumor	N.A.	Approved	[4]
Hamartoma	N.A.	Approved	[4]
Kidney neoplasm	N.A.	Approved	[4]
Leukemia	N.A.	Approved	[4]
MALT lymphoma	N.A.	Approved	[4]
Nodal marginal zone lymphoma	2A85.0	Approved	[4]
Plasma cell myeloma	2A83.1	Approved	[4]
Primitive neuroectodermal tumor	N.A.	Approved	[4]
Splenic marginal zone lymphoma	N.A.	Approved	[4]
Testicular lymphoma	N.A.	Approved	[4]
Wilms tumor	N.A.	Approved	[4]
Classic Hodgkin lymphoma	N.A.	Investigative	[4]
Follicular lymphoma	2A80	Investigative	[4]
Neuroblastoma	2D11.2	Investigative	[4]

Vincristine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tubulin beta (TUBB)	TTYFKSZ	NOUNIPROTAC	Modulator	[10]

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	[11]
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[12]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[13]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[14]

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	[15]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[15]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[16]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult T acute lymphoblastic leukemia	DC9HHV9	MOLT-4	Investigative	[1]
Anaplastic large cell lymphoma	DC95AF7	SR	Investigative	[1]
Chronic myelogenous leukemia	DCN8WVN	K-562	Investigative	[1]
Papillary renal cell carcinoma	DCGKC3Z	ACHN	Investigative	[1]
Renal cell carcinoma	DCV4KGM	UO-31	Investigative	[1]
Renal cell carcinoma	DCYJ5J5	SN12C	Investigative	[1]
Breast adenocarcinoma	DCL1IZW	MDA-MB-468	Investigative	[17]
Carcinoma	DCFOMSM	MCF7	Investigative	[17]
Adenocarcinoma	DCF5WWX	OVCAR3	Investigative	[18]
Adenocarcinoma	DC2IF08	HCT-15	Investigative	[18]
Amelanotic melanoma	DC5KYNC	MDA-MB-435	Investigative	[18]
High grade ovarian serous adenocarcinoma	DC90QTP	OVCAR-5	Investigative	[18]
Large cell lung carcinoma	DCQMPZK	NCI-H460	Investigative	[18]
Lung adenocarcinoma	DC0NX5E	NCI-H522	Investigative	[18]
Malignant melanoma	DCNZ7PF	LOX IMVI	Investigative	[18]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [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: 6745).
• [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: 6785).
• [4] Vincristine FDA Label
• [5] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [6] A fission yeast-based test system for the determination of IC50 values of anti-prostate tumor drugs acting on CYP21. J Enzyme Inhib Med Chem. 2006 Oct;21(5):547-56.
• [7] Elucidating mechanisms of toxicity using phenotypic data from primary human cell systems--a chemical biology approach for thrombosis-related side effects. Int J Mol Sci. 2015 Jan 5;16(1):1008-29. doi: 10.3390/ijms16011008.
• [8] Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer. JCI Insight. 2018 Sep 6;3(17):e121497. doi: 10.1172/jci.insight.121497. eCollection 2018 Sep 6.
• [9] Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies. Nucleic Acids Res. 2015 Jul 13;43(12):5880-97. doi: 10.1093/nar/gkv262. Epub 2015 Apr 23.
• [10] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [11] Interaction of plant cannabinoids with the multidrug transporter ABCC1 (MRP1). Eur J Pharmacol. 2008 Sep 4;591(1-3):128-31.
• [12] 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.
• [13] 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.
• [14] Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates. Cancer Chemother Pharmacol. 2006 Dec;58(6):826-34.
• [15] Association of CYP3A5 expression and vincristine neurotoxicity in pediatric malignancies in Turkish population. J Pediatr Hematol Oncol. 2017 Aug;39(6):458-462.
• [16] Drug Interactions Flockhart Table
• [17] Biologically active neutrophil chemokine pattern in tonsillitis.Clin Exp Immunol. 2004 Mar;135(3):511-8. doi: 10.1111/j.1365-2249.2003.02390.x.
• [18] Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy.Hum Genet. 2018 Apr;137(4):293-303. doi: 10.1007/s00439-018-1882-3. Epub 2018 Apr 24.