Mitotic Spindle Inhibitors

MITOTIC SPINDLE INHIBITORS


MITOTIC SPINDLE INHIBITORS

  • Drug groups included:
    • Vinca alkaloids, taxanes, ixabepilone, eribulin mesylate & estramustine.

1. Vinca alkaloids:

  • Drugs: Vincristine, vinblastine & vinorelbine.
  • Vinca alkaloids result in SIADH.

MOA:

  • Acts by inhibiting polymerization of microtubules→ thus, inhibiting mitotic spindle formation.
  • Effective in M-phase of cell cycle.

Drug effects:

  • Vinblastine – Causes bone marrow suppression.
  • Vincristine – 
    • Marrow sparing
    • Neurotoxic (peripheral neuropathy).

Uses:

  • Curative therapy of metastatic testicular tumors – Mainly Vinblastine.
  • DOC for inducing remission in childhood leukemias – Vincristine with glucocorticoids.
    • Combination also used for pediatric solid tumors (Wilm’s tumor, neuroblastoma, rhabdomyosarcoma) & lymphomas.

2. Taxanes:

  • Drugs: Paclitaxel, docetaxel & cabazitaxel.
  • MOA: Acts by preventing disassembly of microtubules  –> Thus, interfering with mitotic spindle formation.
  • Both drugs cause bone marrow suppression & neurotoxicity.
  • Paclitaxel:
    • Causes hypersensitivity reactions.
    • Due to cremophor-containing vehicle.
    • Protein-bound paclitaxel (nab-paclitaxel) – Decreased risk of hypersensitivity reactions.
  • Drug interactions:
    • Cisplatin decreases paclitaxel clearance.
    • Paclitaxel decreases doxorubicin clearance.
  • Cabazitaxel:
    • A microtubule inhibitor.
    • Indicated in hormone-refractory metastatic prostate cancer – In combination with prednisone.

3. Ixabepilone:

MOA:

  • Acts by binding to tubulin & promoting microtubule stabilization —> Hence, arresting cells in the G2-M phase of cell cycle.
  • New drug approved for treatment of advanced breast carcinoma resistant to anthracyclines and taxanes.
  • Given in combination with capecitabine.

4. Eribulin Mesylate:

  • Microtubule inhibitor.
  • Approved recently for metastatic breast cancer treatment.

5. Estramustine:

  • Combination of estrogen & mechlorethamine (nitrogen mustard).
  • MOA: Acts as anti-mitotic drug by binding to tubulin.
  • Used for prostatic carcinoma treatment.
  • Produce estrogenic side effects (gynaecomastia & impotence).

Exam Important

  • Mitotic spindle inhibitors include Vinca alkaloids, taxanes, ixabepilone, eribulin mesylate & estramustine.
  • Vinca alkaloids result in SIADH.
  • Vinca alkaloids act by inhibiting polymerization of microtubules, thus inhibiting mitotic spindle formation.
  • Vinca alkaloids are effective in M-phase of cell cycle.
  • Vinblastine is mainly used for Curative therapy of metastatic testicular tumors.
  • Vincristine with glucocorticoids is DOC for inducing remission in childhood leukemias.
  • Vincristine is marrow sparing but is neurotoxic (peripheral neuropathy).
  • Paclitaxel causes hypersensitivity reactions, due to cremophor-containing vehicle.
  • Protein-bound paclitaxel (nab-paclitaxel) has decreased risk of hypersensitivity reactions.
  • Cabazitaxel is indicated in hormone-refractory metastatic prostate cancer, in combination with prednisone.
  • Ixabepilone acts by binding to tubulin & promoting microtubule stabilization —> Hence, arresting cells in the G2-M phase of cell cycle.
  • Ixabepilone is a new drug approved for treatment of advanced breast carcinoma resistant to anthracyclines and taxanes.
  • Eribulin Mesylate is a microtubule inhibitor.
  • Estramustine is a combination of estrogen & mechlorethamine (nitrogen mustard).
  • Estramustine acts as an anti-mitotic drug by binding to tubulin.
  • Estramustine is used for prostatic carcinoma treatment.
  • Estramustine produces estrogenic side effects (gynaecomastia & impotence).
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