Bleomycin - Clemson University

Download Report

Transcript Bleomycin - Clemson University

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 (2532%)
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)