Cytotoxic Antibiotics

• Examples of cytotoxic antibiotics include:

  1. Anthracyclines

  • doxorubicin
  • daunorubicin
  • epirubicin
  • idarubicin

  2. Bleomycin
• MOA of bleomycin:

  1. has greatest effect on cells in G2 and M phase
  2. its cytotoxicity is secondary to DNA strand breakage, produces via formation of free radical

  • depends on the binding of an bleomycin-iron complexes to DNA

  - this complexes can reduce the molecular oxygen to free oxygen radicals

  - causes primary single-strand breaks in DNA
• Toxicity of Bleomycin:

  1. bleomycin is inactivated within the cells by enzyme aminohydrolase

  • it is widely distributed
  • but present in low concentration in skin and lungs
  • most serious toxicity: pulmonary toxicity

  - progressing from rales, cough to fatal pulmonary fibrosis

  • other common toxicities: mucocutaneous reactions, alopecia
• MOA of anthracyclines:

  1. intercalates in DNA

  • insert nonspecifically between base pairs
  • bind to sugar-phosphate backbone of DNA

  2. inhibits replication via action of topoisomerase II (catalyzes nick in DNA strands)

  • intercalated strand
  • permanently cleaved helix

  3. Generation of semiquinone of free radicals and oxygen free radicals

  
  

  4. Binding to cell membranes

  • alters fluidity and ion transport
• Toxicity of anthracyclines:

  1. Dose limiting toxicity

  • neutropenia followed by musositis

  
  

  2. prominent AE - caridiotoxicity

  • attributed by free radical MOA
  • myocardium

  - lack of enzymes that convert free radicals to less reactive compounds

  - high levels of enzymes that activates anthracyclines

  • presents in 2 forms

  - acute and chronic