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 A 2 (55-70%) and B 2 (25- 32%)

9. 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

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

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

13. Cycle of Events: Activation of Bleomycin

14. Activation of Bleomycin Complex

15. 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

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

17. Mechanism 1

18. Mechanism 2

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

20. 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

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

22. 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)