Pharmacology of M-Phase Specific Agents

How do M-phase specific agents work?

They inhibit microtubule dynamics, either preventing polymerization or collapse, leading to mitotic arrest.

What does mitotic arrest mean?

The cell is unable to complete mitosis and gets stuck in the M-phase.

What are the structural subunits of microtubules?

Alpha and beta tubulin heterodimers.

What are the roles of the + and - ends of microtubules?

+ end supports growth with GTP; - end is prone to collapse

How do antimicrotubule agents affect microtubule dynamics?

They either inhibit polymerization (growth) or inhibit collapse (stabilization).

Which drugs inhibit microtubule polymerization?

Vinca alkaloids and Eribulin.

Which drugs inhibit microtubule depolymerization (collapse)?

Taxanes and Ixabepilone.

Where do antimicrotubule agents bind on microtubules?

Most bind the β-tubulin subunit, interfering with GTP binding and polymerization.

How do Vinca alkaloids and Eribulin affect microtubules?

They bind β-tubulin and block GTP binding, preventing polymerization at the + end.

How do Taxanes like Paclitaxel work?

They stabilize microtubules by preventing depolymerization.

What makes Ixabepilone useful in taxane-resistant cancers?

It binds a different site on β-tubulin, overcoming resistance due to taxane binding site mutations.

Name four Vinca alkaloids.

Vinblastine, Vincristine, Vindesine, Vinorelbine.

Name three taxane-related drugs.

Paclitaxel, Docetaxel, Cabazitaxel.

What is the MOA of Cabazitaxel?

Similar to other taxanes, it stabilizes microtubules to prevent depolymerization.

Why is paclitaxel formulated with Cremophor EL in Taxol?

Paclitaxel is poorly water-soluble, so Cremophor EL (a castor oil derivative) is used to make it IV-compatible.

What is a major drawback of Cremophor EL in Taxol?

It can cause hypersensitivity reactions.

How is nab-paclitaxel (Abraxane) different from Taxol?

It uses albumin-bound nanoparticles instead of Cremophor EL, reducing hypersensitivity.

Why is the maximum tolerated dose higher for Abraxane than Taxol?

Abraxane has better tumor targeting and less distribution to bone marrow, leading to fewer off-target effects.

What is the role of albumin in nab-paclitaxel (Abraxane)?

It facilitates receptor-mediated transcytosis and enhances tumor targeting via the EPR effect.

How does Abraxane improve tumor delivery?

Through albumin-mediated uptake and the EPR effect, leading to increased drug concentration in tumors.

What is the mechanism of action of eribulin mesylate?

It inhibits tubulin polymerization and microtubule elongation.

Which end of the microtubule does eribulin act on?

It binds the positive (+) end and prevents further polymerization.

What are some mechanisms of resistance to antimicrotubule agents?

Upregulation of β-tubulin, mutation in β-tubulin binding sites, and efflux pump overexpression.

Why is cabazitaxel effective against resistant tumors?

It is not a substrate of efflux pumps, unlike paclitaxel or docetaxel.

What is the clinical advantage of using cabazitaxel over paclitaxel?

It avoids efflux-mediated resistance and remains effective in resistant cancer cells.