Understanding the Mechanism of Action of Certain Chemotherapy Agents

• The cytoskeleton provides the structural framework for the cell:
  • It is composed of three main types of protein polymers:
    • Actin filaments
    • Intermediate filaments
    • Microtubules
  • Actin filaments:
    • Are found in nearly all types of cells
    • They form a cortical layer beneath the plasma membrane of most cells
    • They form the stress fiber of fibroblasts
    • They form the cytoskeleton of microvilli of intestinal epithelial cells.
    • In muscle cells:
      • The interaction between the heads of myosin (thick filaments) and actin (thin filaments):
        • Requires hydrolysis of ATP to separate the filaments at the end of the power stroke
      • Calcium and troponin C (an actin-associated protein):
        • Are also required to expose the binding site for myosin on the actin filament
  • Intermediate filaments:
    • Are a heterogeneous group of proteins
    • That extend from the nucleus to the cell surface.
    • They interact with other cytoskeletal filaments and binding proteins to produce their effects.
  • Microtubules:
    • Arise from the centrosome:
      • With the cell’s microtubule-organizing center being located near the nucleus
    • Microtubules are in a constant dynamic equilibrium:
      • Between assembly and disassembly
    • Movement of cellular components, such as vacuoles, along the microtubules requires:
      • ATP and either of two associated proteins:
        • Kinesin:
          • For movement away from the centrosome
        • Dynein:
          • For movement toward it.
    • Cilia and flagella contain:
      • Columns of doublet microtubules in a 9-2 arrangement:
        • Nine doublets in a circle surrounding two central doublets
      • Movement is accomplished when the doublets slide along each other:
        • In a process mediated by dynein and fueled by hydrolysis of ATP.
    • Microtubules also play an important role in cell division:
      • Assembly of the mitotic spindle involves:
        • Replication and splitting of the microtubule-organizing center:
          • Into the two spindle poles and reorganization of the cytoskeletal microtubules to form the:
            • Spindle apparatus.

 

• Taxanes:
  • Function as mitotic inhibitors:
    • By inhibiting depolymerization of the mitotic spindle:
      • Which results in a “frozen” mitosis.
  • Paclitaxel:
    • Is a natural taxane that prevents depolymerization of cellular microtubules.

• The vinca alkaloids (e.g., vinblastine, vincristine):
  • Also inhibit cell division:
    • But by disrupting the mitotic spindle.
• Doxorubicin (Adriamycin):
  • Intercalates between DNA base pairs:
    • Impairs the progression of topoisomerase II:
      • Which unwinds DNA for transcription

 

 

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