SN-38

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Biological Activity

Description	SN-38 is an active metabolite of CPT-11, inhibits DNA topoisomerase I, DNA synthesis and causes frequent DNA single-strand breaks.
Targets
IC50
In vitro	SN-38, a biological active metabolite of irinotecan hydrochloride (CPT-11). SN-38 causes the strongest inhibition of DNA topoisomerase I, followed by CPT and then CPT-11. CPT-11 dose dependently shifts the position of relaxed DNA in the direction of nicked DNA, but SN-38 and CPT shows no effect on the position of relaxed DNA. SN-38 dose-dependently and time-dependently inhibit DNA synthesis. Respective IC50 values of SN-38, in DNA synthesis is 0.077 μM. The inhibitory effect of SN-38 on RNA synthesis is less than that on DNA synthesis and it does not inhibit protein synthesis. SN-38 caused frequent DNA single-strand breaks in P388 cells. [1]
In vivo	After oral dosing, peak SN-38 concentrations occurrs within 1 h, and the The percent unbound SN-38 lactone in murine plasma at 1000 ng/mL is 3.4 +/- 0.67%, whereas at 100 ng/mL the percent unbound is 1.18 +/- 0.14%. SN-38 lactone AUCs in micebearing human neuroblastoma xenografts are greater than in nontumor-bearing animals. [2]
Features

Protocol(Only for Reference)

Kinase Assay: ^[1]

Topoisomerase I Assay

One unit (the minimum amount for full relaxation of 0.5 μg SV40 DNA under the conditions of this study) of topoisomerase I, 0.5 μL of the test compounds, and 0.5μg SV40 DNA are added sequentially to the reaction buffer, which is composed of 25 mM Tris-HCl (pH 7.5), 50 mM KC1, 5 mM MgCl2, 0.25 mM EDTA disodium salt, 0.25 mM dithiothreitol, 15μg /mL bovine serum albumin, and 5% glycerol. Then, the reaction mixture (50 μL) is incubated for 10 min at 37 °C, and the reaction is terminated by treatment with 7.5 μL of a solution consisting of 1% sodium dodecyl sulfate, 20 mM EDTA disodium salt, and 0.5 mg/mL proteinase K for an additional 30 min at 37°C. The samples are mixed with 5 μL of the loading buffer containing 10 mM Na2HPO4, 31.3% sucrose, and 0.3% bromophenol blue. Relaxed (form Ir) DNA is separated from supercoiled (form I) and nicked (form II) DNA by electrophoresis on 0.8% agarose gel at 50 mA and 20 V for 17 h in the presence of 2 μg/mL chloroquine, 10 mM EDTA, 30 mM NaH2PO4, and 36 Mm Tris-HCl (pH 7.8). After electrophoresis, the gel is stained with 0.05% ethidium bromide and photographed with UV light (302 nm). The amount of DNA is quantified using a densitometer.

Cell Assay: ^[3]

Cell lines	A-172, U-87, and LA-567
Concentrations	0 -1000 nM
Incubation Time	48 h
Method	MTT assay

1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT01822613	Not yet recruiting	Esophageal Squamous Cell Carcinoma	Novartis|Novartis Pharmaceuticals	2013-06	Phase 1|Phase 2
NCT01859858	Not yet recruiting	Advanced Colorectal Cancer	UNC Lineberger Comprehensive Cancer Center	2013-06	Phase 1
NCT01876446	Not yet recruiting	Recurrent Small Cell Lung Cancer	Roswell Park Cancer Institute|National Cancer Institute (NCI)	2013-06	Phase 2
NCT01467986	Not yet recruiting	Neuroblastoma Recurrent	University of Regensburg	2013-07	Phase 2
NCT01862003	Not yet recruiting	Metastatic Colorectal Cancer|Recurrent Colorectal Cancer	University College, London|Cancer Research UK|AstraZeneca|UCL Biomedical Research Centre	2013-08	Phase 1

Chemical Information

Download SN-38 SDF

Chemical Name	1H-Pyrano[3’,4’:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione, 4,11-diethyl-4,9-dihydroxy-, (4S)-

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.3924	3.924	7.848	11.772

Customer Reviews (1)

Click to enlarge	Rating
	Source	J Pharmacol Exp Ther, 2014, 348(3):432-41. SN-38 purchased from Selleck
	Method	Western blot
	Cell Lines	HCT116 cells
	Concentrations	1 uM
	Incubation Time	2 h
	Results	HCT116 cells displayed a robust increase of γ-H2AX after treatment with SN-38 (1 μM).

Product Citations (1)

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  DW09849, a Selective Phosphatidylinositol 3-Kinase (PI3K) Inhibitor, Prevents PI3K Signaling and Preferentially Inhibits Proliferation of Cells Containing the Oncogenic Mutation p110α (H1047R). [Liu JL, et al. J Pharmacol Exp Ther 2014;348(3):432-41]