Details of the Drug Combination

General Information of Drug Combination (ID: DCBLUSP)

• Drug Combination Name: 10-hydroxycamptothecin + Valrubicin
• Indication: Amelanotic melanoma; Status: Investigative [1]
• Component Drugs:
  10-hydroxycamptothecin (DM9WLN4): Small molecular drug
  Valrubicin (DMOYJFK): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: M14
  Zero Interaction Potency (ZIP) Score: 2.62
  Bliss Independence Score: 3.07
  Loewe Additivity Score: 4.46
  LHighest Single Agent (HSA) Score: 4.7

Molecular Interaction Atlas of This Drug Combination

Indication(s) of 10-hydroxycamptothecin

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[2]

10-hydroxycamptothecin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase I (TOP1)	TTGTQHC	TOP1_HUMAN	Inhibitor	[2]

10-hydroxycamptothecin Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[6]

10-hydroxycamptothecin Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Response To Substance	[7]
E3 ubiquitin-protein ligase Mdm2 (MDM2)	OTOVXARF	MDM2_HUMAN	Affects Response To Substance	[8]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Response To Substance	[7]

Indication(s) of Valrubicin

Disease Entry	ICD 11	Status	REF
Bladder cancer	2C94	Approved	[3]
In situ carcinoma	N.A.	Approved	[4]
Urinary bladder cancer	N.A.	Approved	[4]
Psoriasis vulgaris	EA90	Phase 2	[5]

Valrubicin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN; TOP2B_HUMAN	Inhibitor	[9]

Valrubicin Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[10]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Anaplastic large cell lymphoma	DCGUQTH	SR	Investigative	[11]
Childhood T acute lymphoblastic leukemia	DCAOWUL	CCRF-CEM	Investigative	[11]
Clear cell renal cell carcinoma	DC3PF9Q	A498	Investigative	[11]
Papillary renal cell carcinoma	DCIK4TW	ACHN	Investigative	[11]
Adenocarcinoma	DC9F6QD	NCIH23	Investigative	[1]
Adenocarcinoma	DC3BDSK	HCT-15	Investigative	[1]
Amelanotic melanoma	DCYD840	MDA-MB-435	Investigative	[1]
Lung adenocarcinoma	DCVLE7W	HOP-62	Investigative	[1]
Non-small cell lung carcinoma	DCKJTRS	HOP-92	Investigative	[1]
Ovarian serous cystadenocarcinoma	DC8R9Q2	SK-OV-3	Investigative	[1]

References

• [1] 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.
• [2] Upregulation of p21WAF1/CIP1 in human breast cancer cell lines MCF-7 and MDA-MB-468 undergoing apoptosis induced by natural product anticancer drugs 10-hydroxycamptothecin and camptothecin through p53-dependent and independent pathways. Int J Oncol. 1998 Apr;12(4):793-804.
• [3] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [4] Valrubicin FDA Label
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [6] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [7] siRNA-mediated Bcl-2 and Bcl-xl gene silencing sensitizes human hepatoblastoma cells to chemotherapeutic drugs. Clin Exp Pharmacol Physiol. 2007 May-Jun;34(5-6):450-6. doi: 10.1111/j.1440-1681.2007.04593.x.
• [8] Antisense therapy targeting MDM2 oncogene in prostate cancer: Effects on proliferation, apoptosis, multiple gene expression, and chemotherapy. Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11636-41. doi: 10.1073/pnas.1934692100. Epub 2003 Sep 16.
• [9] Metabolic activation of N-acylanthracyclines precedes their interaction with DNA topoisomerase II. NCI Monogr. 1987;(4):111-5.
• [10] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [11] 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.