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Adriamycin / Duanomycin

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

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Adriamycin / Duanomycin

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

  2. Outline • Structure and application • Anthracycline Family • Discovery of Adriamycin • How it is used • Mechanism • Synthesis • Use and Side effect • Future

  3. Structure

  4. 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;

  5. How it is used • A red fluid; • By injection into a vein (intravenously); • Used as doxorubicin hydrochloride;

  6. Anthracycline Family

  7. 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;

  8. 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;

  9. 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;

  10. 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.

  11. 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;

  12. Alkylation of DNA by a quinoone methide

  13. Alkylation of DNA via FormaldehydeFormaldehyde formation in the presence of molecular oxygen

  14. Formaldehyde formation by drug-iron complex-catalysis

  15. Drug-DNA Complex

  16. Crystal structure of drug-DNA complex via formaldehyde

  17. 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

  18. 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;

  19. 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;

  20. Resistance

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