Doksorubicin

Doksorubicin
(IUPAC) ime
	(7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hidroksi-6-metiloksan-2-il]oksi-6,9,11-trihidroksi-9-(2-hidroksiacetil)-4-metoksi-8,10-dihidro-7H-tetracen-5,12-dion
Klinički podaci
Robne marke	Doksil
AHFS/Drugs.com	Monografija
MedlinePlus	a682221
Identifikatori
CAS broj	23214-92-8
ATC kod	L01DB01
PubChem	31703
DrugBank	DB00997
ChemSpider	29400
UNII	80168379AG
KEGG	D03899
ChEBI	CHEBI:28748
ChEMBL	CHEMBL179
Hemijski podaci
Formula	C27H29NO11
Mol. masa	543,52 g/mol
SMILES	eMolekuli & PubHem
InChI
	InChI=1S/C27H29NO11/c1-10-22(31)13(28)6-17(38-10)39-15-8-27 (36,16(30)9-29)7-12-19(15)26(35)21-20(24(12)33)23 (32)11-4-3-5-14(37-2)18(11)25(21)34/h3-5,10,13,15, 17,22,29,31,33,35-36H,6-9,28H2,1-2H3/t10-,13-,15-,17-,22+,27-/m0/s1 ; Key: AOJJSUZBOXZQNB-TZSSRYMLSA-N
Farmakokinetički podaci
Bioraspoloživost	5% (Oralno)
Metabolizam	CYP3A4
Poluvreme eliminacije	12–18,5 časova nakon oslobađanja iz lipozoma
Izlučivanje	Bilijarno i fekaln o
Farmakoinformacioni podaci
Trudnoća	D(AU) D(US)
Pravni status	POM (UK) ℞-only (SAD)
Način primene	Intravenozno

Doksorubicin (adriamicin, hidroksidaunorubicin) je lek koji se koristi hemoterapiji. On je antraciklinski antibiotik, blisko srodan asa prirodnim proizvodom daunomicinom, i poput svih antraciklina, on deluje putem interkalacije DNK.

Doksorubicin se često koristi za tretiranje širokog opsega kancera, koji obuhvata hematološke malignosti, nih tipova karcinoma, i sarkome mekog tkiva.

Doksorubicinovo najozbiljnije nepoželjno dejstvo je potencijalno smrtonosno oštećenje srca.

Ovaj lek se dozira intravenozno, u obliku hidrohloridne soli. Neka od njegovih prodajnih imena su Adriamycin PFS, Adriamycin RDF, i Rubex.^[7] Doksorubicin je fotosenzitivan, te su kontajneri često oblošeni aluminijumskom folijom i/ili voštanim papirom.

Doksorubicin je dostupan u lipozomskoj formulaciji kao Doxil, Caelyx i Myocet.

Ovaj molekul je originalno izolovan tokom 1950-tih iz bakterija u uzorku zemljišta iz Italije.

Mehanizam dejstva

Dijagram interkalacije DNK sa dva molekula doksorubicina. (1D12)^[8]

Doksorubicin formira interakcije sa DNK putem interkalacije čime se inhibira makromolekulska biosinteza.^[9]^[10] On inhibira rad enzima topoizomeraza II, koji opušta supernamotaje tokom transkripcije DNK. Doksorubicin stabilizuje kompleks topoizomerase II nakon prekidanja DNK lanca radi replikacije, čime se sprečava otpuštanje dvostrukog heliksa i time se zaustavlja proces replikacije.

Planarna aromatična hromoforna porcija molekula se interkalira između dva bazna para DNK molekula, dok se šestočlani šećer smešta u mali žleb i formira interakcije sa bočnim baznim parovima u neposrednom susedstvu mesta interlalacije. Ovaj mod vezivanja je uočen u nekoliko kristalnih struktura.^[8]^[11]

Reference

↑ Li Q, Cheng T, Wang Y, Bryant SH (2010). „PubChem as a public resource for drug discovery.”. Drug Discov Today 15 (23-24): 1052-7. DOI:10.1016/j.drudis.2010.10.003. PMID 20970519. edit
↑ Evan E. Bolton, Yanli Wang, Paul A. Thiessen, Stephen H. Bryant (2008). „Chapter 12 PubChem: Integrated Platform of Small Molecules and Biological Activities”. Annual Reports in Computational Chemistry 4: 217-241. DOI:10.1016/S1574-1400(08)00012-1.
↑ Hettne KM, Williams AJ, van Mulligen EM, Kleinjans J, Tkachenko V, Kors JA. (2010). „Automatic vs. manual curation of a multi-source chemical dictionary: the impact on text mining”. J Cheminform 2 (1): 3. DOI:10.1186/1758-2946-2-3. PMID 20331846. edit
↑ Joanne Wixon, Douglas Kell (2000). „Website Review: The Kyoto Encyclopedia of Genes and Genomes — KEGG”. Yeast 17 (1): 48–55. DOI:10.1002/(SICI)1097-0061(200004)17:1<48::AID-YEA2>3.0.CO;2-H.
↑ Gaulton A, Bellis LJ, Bento AP, Chambers J, Davies M, Hersey A, Light Y, McGlinchey S, Michalovich D, Al-Lazikani B, Overington JP. (2012). „ChEMBL: a large-scale bioactivity database for drug discovery”. Nucleic Acids Res 40 (Database issue): D1100-7. DOI:10.1093/nar/gkr777. PMID 21948594. edit
↑ Laginha, K.M. "Determination of Doxorubicin Levels in Whole Tumor and Tumor Nuclei in Murine Breast Cancer Tumors." Clinical Cancer Research. October 1, 2005. Vol. 11 (19). Retrieved on April 19, 2007.
↑ Doxorubicin (Systemic). Mayo Clinic. Last updated on: June 15, 1999. Retrieved on April 19, 2007.
↑ ^8,0 ^8,1 Frederick CA, Williams LD, Ughetto G, et al. (March 1990). „Structural comparison of anticancer drug-DNA complexes: adriamycin and daunomycin”. Biochemistry 29 (10): 2538–49. DOI:10.1021/bi00462a016. PMID 2334681. Crystal structure is available for download as a PDB file.
↑ Fornari FA, Randolph JK, Yalowich JC, Ritke MK, Gewirtz DA (April 1994). „Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells”. Molecular Pharmacology 45 (4): 649–56. PMID 8183243.
↑ Momparler RL, Karon M, Siegel SE, Avila F (August 1976). „Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells”. Cancer Res 36 (8): 2891–5. PMID 1277199.
↑ Pigram WJ, Fuller W, Hamilton LD (January 1972). „Stereochemistry of intercalation: interaction of daunomycin with DNA”. Nature New Biol 235 (53): 17–9. PMID 4502404.

Povezano

Vanjske veze

Pregled Arhivirano 2015-03-14 na Wayback Machine-u
Adriamicin Arhivirano 2009-02-03 na Wayback Machine-u

[1] Li Q, Cheng T, Wang Y, Bryant SH (2010). „PubChem as a public resource for drug discovery.”. Drug Discov Today 15 (23-24): 1052-7. DOI:10.1016/j.drudis.2010.10.003. PMID 20970519. edit

[2] Evan E. Bolton, Yanli Wang, Paul A. Thiessen, Stephen H. Bryant (2008). „Chapter 12 PubChem: Integrated Platform of Small Molecules and Biological Activities”. Annual Reports in Computational Chemistry 4: 217-241. DOI:10.1016/S1574-1400(08)00012-1.

[3] Hettne KM, Williams AJ, van Mulligen EM, Kleinjans J, Tkachenko V, Kors JA. (2010). „Automatic vs. manual curation of a multi-source chemical dictionary: the impact on text mining”. J Cheminform 2 (1): 3. DOI:10.1186/1758-2946-2-3. PMID 20331846. edit

[4] Joanne Wixon, Douglas Kell (2000). „Website Review: The Kyoto Encyclopedia of Genes and Genomes — KEGG”. Yeast 17 (1): 48–55. DOI:10.1002/(SICI)1097-0061(200004)17:1<48::AID-YEA2>3.0.CO;2-H.

[5] Gaulton A, Bellis LJ, Bento AP, Chambers J, Davies M, Hersey A, Light Y, McGlinchey S, Michalovich D, Al-Lazikani B, Overington JP. (2012). „ChEMBL: a large-scale bioactivity database for drug discovery”. Nucleic Acids Res 40 (Database issue): D1100-7. DOI:10.1093/nar/gkr777. PMID 21948594. edit

[Laginha-6] Laginha, K.M. "Determination of Doxorubicin Levels in Whole Tumor and Tumor Nuclei in Murine Breast Cancer Tumors." Clinical Cancer Research. October 1, 2005. Vol. 11 (19). Retrieved on April 19, 2007.

[mayo_info-7] Doxorubicin (Systemic). Mayo Clinic. Last updated on: June 15, 1999. Retrieved on April 19, 2007.

[frederick-8] 8,0 ^8,1 Frederick CA, Williams LD, Ughetto G, et al. (March 1990). „Structural comparison of anticancer drug-DNA complexes: adriamycin and daunomycin”. Biochemistry 29 (10): 2538–49. DOI:10.1021/bi00462a016. PMID 2334681. Crystal structure is available for download as a PDB file.

[fornari-9] Fornari FA, Randolph JK, Yalowich JC, Ritke MK, Gewirtz DA (April 1994). „Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells”. Molecular Pharmacology 45 (4): 649–56. PMID 8183243.

[momparler-10] Momparler RL, Karon M, Siegel SE, Avila F (August 1976). „Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells”. Cancer Res 36 (8): 2891–5. PMID 1277199.

[pigram-11] Pigram WJ, Fuller W, Hamilton LD (January 1972). „Stereochemistry of intercalation: interaction of daunomycin with DNA”. Nature New Biol 235 (53): 17–9. PMID 4502404.

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