Adriamycin / Duanomycin ----A DNA Intercalator Libin Du 04/16/2002

Outline 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, soft- tissure 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 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 low- dose schedule are effective; Synthesis of anologues: no analogues are clinically used currently; Combination therapy:reduced cardiotoxicity when administrated with antioxidants;

Resistance