elsaid - M phase agents

M-phase specific antineoplastic agents

• vinca alkaloids

• taxanes

• ixabepilone

• eribulin

MOA and effect of M-Phase specific agents

• these drugs inhibit key processes in mitotic phase (by targeting microtubules) and this results in mitotic arrest

• work synergistically with DNA-damaging and S-phase antineoplastic drugs

microtubule dynamics

• hollow tubes that are composed of a heterodimer of 𝜶 and β tubulin

• microtubules are unstable structures (that undergoes elongation and collapse that are important in the process of mitosis (separate the chromosomes)

• microtubules have a (+) end (GTP-bound tubulin) and a negative end (-)

• anti-microtubule drugs can be classified into drugs that inhibit tubulin polymerization or inhibit microtubule collapse

eribulin

• binds to the (+) ends of the microtubules

• prevent polymerization —> prevent growth

vinblastine (a vinca alkaloid)

• binds to the β-tubulin near the (+) end

• prevent polymerization —> prevent growth

paclitaxel (taxol)

• binds to the β-tubulin inside the microtubule

• prevents depolymerization —> prevents the collapse

ixabepilone

• binds to the β-tubulin inside the microtubule

• prevents depolymerization —> prevents the collapse

exchangeable GTP binding site

located on the β-tubulin

non-exchangeable GTP binding site

located on the 𝜶-tubulin

vinca alkaloids

taxanes

paclitaxel formulations

1st generation — paclitaxel (Taxol)

• formulation:

  • Cremophor EL excipient: polyoxyethylated castor oil —> infusion related reaction due to hypersensitivity

• maximum tolerated dose = 175 mg/m²

2nd generation — nab-paclitaxel (Abraxane)

• formulation:

  • biological polymer: donor-derived human serum albumin (HSA) —> no hypersensitivty

• maximum tolerated dose = 260 mg/m²

  • higher dose bc it has more concentration in the cancer cell —> less off-target side effects (bone marrow suppression)

nab-paclitaxel (Abraxane)

conjugation of albumin to paclitaxel leads to several favorable outcomes:

1. reduce Cremophor excipient concentration (responsible for hypersensitivity reactions with Paclitaxel)

2. enhanced receptor-mediated transcytosis via endothelial cells due to the presence of albumin receptors on endothelial cells

3. EPR effect improves drug accumulation in the tumor

4. reduction in off-target toxicity leads to an increase in maximum tolerated dose for nab-Paclitaxel compared to Paclitaxel

eribulin mesylate

eribulin inhibits tubulin polymerization and microtubule enlongation by inhibiting GTP binding

mechanisms of resistance towards antimicrotubules

• up-regulation of β-tubulin expression

• mutation in β-tubulin binding sites

• efflux pump over-expression (cabazitaxel is NOT a substrate of the efflux pump in contrast to Paclitaxel or Docetaxel