Details of the Drug Combination

General Information of Drug Combination (ID: DC8EB5I)

• Drug Combination Name: 10-hydroxycamptothecin + Bendamustine hydrochloride
• Indication: Adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  10-hydroxycamptothecin (DM9WLN4): Small molecular drug
  Bendamustine hydrochloride (DMFH15Z): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HCT-15
  Zero Interaction Potency (ZIP) Score: 5.96
  Bliss Independence Score: 7.24
  Loewe Additivity Score: 4.61
  LHighest Single Agent (HSA) Score: 6.52

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	[4]

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	[5]
E3 ubiquitin-protein ligase Mdm2 (MDM2)	OTOVXARF	MDM2_HUMAN	Affects Response To Substance	[6]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Response To Substance	[5]

Indication(s) of Bendamustine hydrochloride

Disease Entry	ICD 11	Status	REF
leukaemia	2A60-2B33	Approved	[3]

Bendamustine hydrochloride Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Modulator	[3]

Bendamustine hydrochloride Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[8]

Bendamustine hydrochloride Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[7]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[7]
Beta-galactosidase (GLB1)	OTB0TKAG	BGAL_HUMAN	Increases Expression	[9]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[7]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[7]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[7]
Caspase-6 (CASP6)	OTXLD3EC	CASP6_HUMAN	Increases Activity	[7]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[7]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Expression	[10]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[7]
PRKC apoptosis WT1 regulator protein (PAWR)	OTKY7W52	PAWR_HUMAN	Decreases Expression	[7]
Diablo IAP-binding mitochondrial protein (DIABLO)	OTHJ9MCZ	DBLOH_HUMAN	Increases Localization	[7]
Death domain-associated protein 6 (DAXX)	OTX6O7PL	DAXX_HUMAN	Decreases Expression	[7]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Invasive ductal carcinoma	DCNYJIL	BT-549	Investigative	[11]
Adenocarcinoma	DCQI67T	HCT116	Investigative	[1]
Adenocarcinoma	DC8O1K0	SW-620	Investigative	[1]
Pleural epithelioid mesothelioma	DCDF2GH	NCI-H226	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] 2008 FDA drug approvals. Nat Rev Drug Discov. 2009 Feb;8(2):93-6.
• [4] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [5] 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.
• [6] 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.
• [7] Synergistic effects of chemotherapeutic drugs in lymphoma cells are associated with down-regulation of inhibitor of apoptosis proteins (IAPs), prostate-apoptosis-response-gene 4 (Par-4), death-associated protein (Daxx) and with enforced caspase activation. Biochem Pharmacol. 2003 Sep 1;66(5):711-24. doi: 10.1016/s0006-2952(03)00410-6.
• [8] Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites. Cancer Chemother Pharmacol. 2015 Jun;75(6):1143-54.
• [9] Chronic senescent human mesenchymal stem cells as possible contributor to the wound healing disorder after exposure to the alkylating agent sulfur mustard. Arch Toxicol. 2021 Feb;95(2):727-747. doi: 10.1007/s00204-020-02946-5. Epub 2021 Jan 25.
• [10] Upon drug-induced apoptosis in lymphoma cells X-linked inhibitor of apoptosis (XIAP) translocates from the cytosol to the nucleus. Leuk Lymphoma. 2004 Jul;45(7):1429-36. doi: 10.1080/1042819042000198858.
• [11] 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.