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Bleomycin

Bleomycin. Catalina Cuervo. Outline of Topics. Introduction to Bleomycin Structure Mechanism Resistance Analogs Conclusion. Bleomycin. Phleomycin was discovered in 1956 by Hamao Umezawa

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Bleomycin

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  1. Bleomycin Catalina Cuervo

  2. Outline of Topics • Introduction to Bleomycin • Structure • Mechanism • Resistance • Analogs • Conclusion

  3. Bleomycin • Phleomycin was discovered in 1956 by Hamao Umezawa • Exhibited inhibition of Ehrlich carcinoma with high therapeutic index but showed renal toxicity in dogs • During a search for antibiotics of similar type, Bleomycin (BLM) was discovered • Bleomycin showed reversible heptatotoxicity, but no renal toxicity

  4. BLMs are glycopeptide antibiotics isolated from streptomyces verticillus • They are used as a chemotherapeutic agent to treat primarily head and neck cancer,testicular cancer, and lymphomas • BLMs interacts with DNA and induce damage • BLMs chelate iron and combine with oxygen molecules to form the active form

  5. Side effects: • 1% patients-BLM induced pulmonary fibrosis and die • 1% lymphoma patients-idiosyncratic reaction (confusion, fever, chills, and wheezing) • 10% patients-pneumonitis • 50% patients develop other side effects including rash and tenderness of skin

  6. Treatment is discontinued in 2% of patients because of side effects • Because of allergic reactions in some lymphoma patients, a very small dose is administered (1-2 units) • Normal dose ranges from 0.25 unit per kilogram of body mass twice a week to 1 unit daily

  7. Structure • BLMs have the same backbone • They differ by their terminal amine • The mixture of BLMs that is used clinically is A2 (55-70%) and B2 (25-32%)

  8. Structure is separated into three domains: 1.Metal-binding domain: ß-aminoalaninamide, pyrimidine, ß-hydroxyhistidine -Responsible for formation of the complex with Fe(II) 2.DNA binding domain: bithiazole ring system and terminal amine substituent

  9. 3.Carbohydrate moiety: aids in membrane permeability and recognizes tumor cells

  10. Metal Complex • BLMs can form metal complexes with Fe, Cu, Co, Zn, Mn • For therapeutic effects the Fe-BLM complex is used

  11. Cycle of Events: Activation of Bleomycin

  12. Activation of Bleomycin Complex

  13. Binding of BLM to DNA • The minor groove of the DNA helix is the binding site for BLM • Active BLMs bind to guanine bases in DNA through the bithiazole unit

  14. Mechanism • Two mechanisms account for DNA strand scission • Differences between mechanisms: products formed and amount of oxygen needed

  15. Mechanism 1

  16. Mechanism 2

  17. Strand scission mediated by Bleomycin is sequence selective • 5‘-GT-3‘ and 5‘-GC-3‘ • Always at the 3‘ side of G

  18. Resistance • Resistance of cells to BLM is caused by an aminopeptidase (BLM hydrolase) that hydrolyses the carboxamide group of the L-aminoalaninecarboxamide substituent in the antibiotic that does not contain the metal

  19. Analogs • The major problems with Bleomycin stem from the drug’s cytotoxicity • Liblomycin and Victomycin are succeeding Bleomycin because they exhibit milder cytotoxicity

  20. Conclusion • Bleomycins are antitumor agents • Glycopeptides with the same backbone but differ in the structure of their terminal amine • Cause DNA breakage, a process that requires oxygen and Fe(II)

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