Mitoxantrone

Names

[ Name ]:
Mitoxantrone

[Synonym ]:
1,4-Dihydroxy-5,8-bis({2-[(2-hydroxyethyl)amino]ethyl}amino)-9,10-anthraquinone
mitoxanthrone
1,4-Dihydroxy-5,8-bis({2-[(2-hydroxyethyl)amino]ethyl}amino)anthracen-9,10-dion
UNII-BZ114NVM5P
MFCD00242942
PharmasubstanceEP4
1,4-dihydroxy-5,8-bis({2-[(2-hydroxyéthyl)amino]éthyl}amino)anthracène-9,10-dione
DHAQ
1,4-dihydroxy-5,8-bis[[2-(2-hydroxy-ethylamino)ethyl]amino]anthraquinone
9,10-Anthracenedione, 1,4-dihydroxy-5,8-bis((2-((2-hydroxyethyl)amino)ethyl)amino)-
dihydroxyanthraquinone
1,4-dehydroxy-5,8-bis[[[2-(2-hydroxyethyl)amino]ethyl]amino]-9,19-antracenedion
9,10-Anthracenedione, 1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-
MITOXANTRONUM AND THE INTERMEDIATES
1,4-Dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9,10-anthracenedione
1,4-Dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9,10-anthraquinone
1,4-bis-[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxy-9,10-anthracenedione
1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone
Mitoxantrone
[3H]-Mitoxantrone
MITOXANTRONUM

Biological Activity

[Description]:

Mitoxantrone is a topoisomerase II inhibitor; also inhibits protein kinase C (PKC) activity with an IC50 of 8.5 μM.

[Related Catalog]:

Signaling Pathways >> Epigenetics >> PKC

Signaling Pathways >> TGF-beta/Smad >> PKC

Signaling Pathways >> Cell Cycle/DNA Damage >> Topoisomerase

Research Areas >> Cancer

[Target]

PKC:8.5 μM (IC50)

Topoisomerase II

[In Vitro]

Mitoxantrone inhibits PKC in a competitive manner with respect to histone H1, and its Ki value is 6.3 μM and in a non-competitive manner with respect to phosphatidylserine and ATP[1]. Treatment of B-CLL cells for 48 h with mitoxantrone (0.5 μg/mL) induces a decrease in cell viability. Mitoxantrone induces DNA fragmentation and the proteolytic cleavage of poly(ADP-ribose) polymerase (PARP), demonstrating that the cytotoxic effect of mitoxantrone is due to induction of apoptosis[2]. Mitoxantrone shows cytotoxicity to human breast carcinoma cell lines MDA-MB-231 and MCF-7 with IC50 values of 18 and 196 nM, respectively[3].

[In Vivo]

Mitoxantrone given IP at the optimal dose (1.6 mg/kg/day; as a free base) produces a statistically significant number of 60-day survivors (curative effect) in mice with IP implanted L1210 leukemia. In SC implanted Lewis lung carcinoma, mitoxantrone and ADM administered IV also shows effective antitumor activities and produces a 60% and a 45% ILS, respectively.[4].

[Cell Assay]

The human breast carcinoma cell lines MDA-MB-231 and MCF-7 are seeded in standard 96-well plates. One day after seeding, the culture medium is changed and replaced by medium containing different concentration of Mitoxantrone (10-5 to 5 μM) with or without DHA (30 μM) during 7 days. Viability of cells are measured as a whole by the tetrazolium salt assay[3].

[Animal admin]

Mice: Mitoxantrone is tested for antitumor activity against experimental tumors in mice and the results are compared with those of seven antitumor antibiotics. The drugs are given IP or IV, in general on days 1, 5, and 9 following tumor inoculation. Mitoxantrone is given IP at the optimal dose (1.6 mg/kg/day; as a free base)[4].

[References]

[1]. Takeuchi N, et al. Inhibitory effect of mitoxantrone on activity of protein kinase C and growth of HL60 cells. J Biochem. 1992 Dec;112(6):762-7.

[2]. Bellosillo B, et al. Mitoxantrone, a topoisomerase II inhibitor, induces apoptosis of B-chronic lymphocytic leukaemia cells. Br J Haematol. 1998 Jan;100(1):142-6.

[3]. Vibet S, et al. Differential subcellular distribution of mitoxantrone in relation to chemosensitization in two human breast cancer cell lines. Drug Metab Dispos. 2007 May;35(5):822-8.

[4]. Fujimoto S, et al. Antitumor activity of mitoxantrone against murine experimental tumors: comparative analysis against various antitumor antibiotics. Cancer Chemother Pharmacol. 1982;8(2):157-62.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.5±0.1 g/cm3

[ Boiling Point ]:
805.7±65.0 °C at 760 mmHg

[ Melting Point ]:
170-174ºC

[ Molecular Formula ]:
C₂₂H₂₈N₄O₆

[ Molecular Weight ]:
444.481

[ Flash Point ]:
441.1±34.3 °C

[ Exact Mass ]:
444.200897

[ PSA ]:
163.18000

[ LogP ]:
0.45

[ Vapour Pressure ]:
0.0±3.0 mmHg at 25°C

[ Index of Refraction ]:
1.709

[ Storage condition ]:
-20°C Freezer

Toxicological Information

CHEMICAL IDENTIFICATION

RTECS NUMBER :: CB5748500

CHEMICAL NAME :: Anthraquinone, 5,8-bis((2-((2-hydroxyethyl)amino)ethyl)amino)-1,4-di hydroxy-

CAS REGISTRY NUMBER :: 65271-80-9

LAST UPDATED :: 199612

DATA ITEMS CITED :: 22

MOLECULAR FORMULA :: C22-H28-N4-O6

MOLECULAR WEIGHT :: 444.54

WISWESSER LINE NOTATION :: L C666 BV IVJ DQ GQ KM2M2Q NM2M2Q

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 7100 ug/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 20910 ug/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 6600 ug/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Unreported

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 86500 ug/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 16 mg/kg/6W-I

TOXIC EFFECTS :: Cardiac - EKG changes not diagnostic of specified effects Liver - other changes Blood - changes in leukocyte (WBC) count

TYPE OF TEST :: Specific locus test

TYPE OF TEST :: Sex chromosome loss and nondisjunction

TYPE OF TEST :: DNA damage

MUTATION DATA

TYPE OF TEST :: Mutation in mammalian somatic cells

TEST SYSTEM :: Rodent - hamster Lung

DOSE/DURATION :: 100 ng/L

REFERENCE :: PAACA3 Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- Volume(issue)/page/year: 26,217,1985

Safety Information

[ Hazard Codes ]:
T,T+

[ Risk Phrases ]:
R46

[ Safety Phrases ]:
53-36/37/39-45-22

[ RIDADR ]:
3077.0

[ WGK Germany ]:
3

[ RTECS ]:
CB5748500

[ Hazard Class ]:
9.0