Download Adriamycin/Duanomycin

Adriamycin/Duanomycin
----A DNA Intercalator
Libin Du
04/16/2002
Outline
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Structure and application
Anthracycline Family
Discovery of Adriamycin
How it is used
Mechanism
Synthesis
Use and Side effect
Future
Structure
Application
• Adriamycin: solid tumors arising in the
breast, bile ducts, endometrial tissure, the
esophagus and liver, osteosarcomas, softtissure sarcomas and non-Hodgkin’s
lymphoma;
• Duanmycin: acute myeloid leukemia;
How it is used
• A red fluid;
• By injection into a vein (intravenously);
• Used as doxorubicin hydrochloride;
Anthracycline Family
Discovery of Adriamycin
• 1969 by F. Arcamone et al;
• Lead compound: daunomycin;
• By mutagenic treatment of Streptomyces
peucetius, the daunomycin producing
microorganism;
• A new mutant, Streptomyces peucetius var.
caesius;
• Adriamycin: a metabolite of the new mutant;
Pharmacokinetics
• Ubiquitous body distribution;
• Little or no preferential accumulation in
some tumor tissues;
• Improved by modifying its mode of
delivery;
• Drug delivery systems used: liposomes,
microspheres, antibodies, poly aminoacids,
soluble synthetic polymers;
Mechanism(Pharmacodynamics)
• Radical based mechanism involving
formation of super oxide or other radical;
• Intercalation based pathway involving DNA
topoisomerase II;
• Alkylation of some critical biomolecule by
quinone methide, or other reactive
intermediate;
Radical Based Pathway
• The quinone structure permits adriamycin and
daunomycin to act as electron acceptors;
• The addition of the free electron converts the
quinones to semiquinone free radicals, which may
introduce free-radical injury to DNA of
themselves as well as after interaction with
molecular oxygen to form superoxide, hydroxyl
radicals, and peroxides.
Intercalating DNA and topoisomerase II
• In DNA topoisomerization, a covalent complex
between topoisomerase II and DNA is an
obligatory intermediate;
• This complex can be stabilized by adriamycin;
• The stabilization interfere with vital functions
involving DNA replication;
• This may lead to cell death;
Alkylation of DNA by a quinoone methide
Alkylation of DNA via Formaldehyde
Formaldehyde formation in the presence of molecular oxygen
Formaldehyde formation by drug-iron
complex-catalysis
Drug-DNA Complex
Crystal structure of drug-DNA complex via formaldehyde
Side Effect
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Hair loss
Nausea and vomiting
Temporary reduction in bone marrow function
Mouth sores and ulcers
Discoloured urine
Skin changes
Sensitivity to the sun
Changes in the way your heart works
Diarrhoea
Changes in nails
Adriamycin-induced heart failure
• The major dose-dependent toxicity;
• Congestive heart failure which is fatal;
• Low levels of free-radical scavenging
enzymes such as catalase and glutathione
peroxidase in heart;
• Meachnism: free radical damage in the
cardiac tissure;
Prevention of cardiomyopathy
• Dosage optimization: a low dose schedule
with continuous infusion and weekly lowdose schedule are effective;
• Synthesis of anologues: no analogues are
clinically used currently;
• Combination therapy:reduced cardiotoxicity
when administrated with antioxidants;
Resistance
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