Bleomycin

Catalina Cuervo

Outline of Topics

• Introduction to Bleomycin• Structure• Mechanism• Resistance• Analogs• Conclusion

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

• 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

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

• 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

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%)

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

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

Metal Complex

• BLMs can form metal complexes with Fe, Cu, Co, Zn, Mn

• For therapeutic effects the Fe-BLM complex is used

Cycle of Events: Activation of Bleomycin

Activation of Bleomycin Complex

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

Mechanism

• Two mechanisms account for DNA strand scission

• Differences between mechanisms: products formed and amount of oxygen needed

Mechanism 1

Mechanism 2

• Strand scission mediated by Bleomycin is sequence selective

• 5‘-GT-3‘ and 5‘-GC-3‘• Always at the 3‘ side of G

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

Analogs

• The major problems with Bleomycin stem from the drug’s cytotoxicity

• Liblomycin and Victomycin are succeeding Bleomycin because they exhibit milder cytotoxicity

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)