M-Phase (Mitosis) Inhibitors Parang

microtubules

polymeric heterodimers consisting of alpha and beta tubulin proteins

On which end of the tubule does polymerization occur

(+) end

polymerization

elongation ; involves addition of tubulin dimers (usually involves (+) end but could be both)

depolymerization

collapse/shortening of structure

What happens as a result of inhibiting depolymerization or polymerzation of tubulins?q

mitotic arrest and apoptosis

Name the two classes of mitosis inhibitors

taxanes and vinca alkaloids

Taxanes MOA

binds to polymerized (elongated) B-tubulin at specific hydrophobic receptor site → promotes polymerization/elongation phase → inhibits disassembly of tubule

Usage of taxanes results in the formation of what?

asters (large and dense structures that contain stabilized microtubule bundles)

Between the northern and southern region of taxanes, which is more important?

southern region (most changes will be made in northern region)

Essential FG for taxanes

1. C13 isoserine side chain

2. C2 Benzoyl esters

3. C4 acetyl esters

4. intact oxetane ring

paclitaxel needs to be admin with _____

formulation containing alcohol and kollipher

Why does paclitaxel need to be admin w/ alcohol + kollipher

it is very hydrophobic

Result of admin paclitaxel w/ alcohol + kollipher

enhanced risk of hypersensitivity reactions

What is used to keep hypersensitivity rxn at bay when admin paclitaxel w/ alcohol + kollipher

antihistamine/corticosteroid pretreatment

Name the albumin-bound formation of paclitaxel

abraxane

name the solution formulation of paclitaxel

taxol, onxol

benefits of abraxane over taxol/onxol

abraxane uses albumin to increase the water solubility of paclitaxel, meaning it does not require alcohol + kollipher, reducing concern of hypersensitivity reactions

Explain how abraxane is more selective to tumor cells

EPR (enhanced permeabiity and retention)

• enhanced permeability → endothelial cells of tumors are less organized and have more gaps → more opportunity for the nanoparticle to penetrate

• enhanced retention → tumor cell lacks lymphatic drainage system that normal cells would have

Why would paclitaxel and capecitabine be admin together?

paclitaxel is able to upregulate thymidine phosphorylase, which is one of the enzymes responsible for activating capecitabine → faster activation

When would we want to admin capecitabine w/ paclitaxel?

if pt is showing resistance to capecitabine

Which has better water solubility: docetaxel or paclitaxel?

docetaxel

Explain why docetaxel has a better water solubility than paclitaxel

it has a free C10-OH group

Why may docetaxel be more preferred than paclitaxel

it has improved water solubility, so it can be formulated w/ polysorbate 80 rather than kollipher EL → reduced risk of hypersensitivity reaction (but still possible - so pt should still receive corticosteroid premedication)

What is cabazitaxel?

a dimethoxy analog of docetaxel

Advantage of cabazitaxel over docetaxel & paclitaxel

lower affinity to P-gp → increased retention in tumor cells

What agent should be used in docetaxel or paclitaxel resistant cells ?

cabazitaxel (as it will not be effluxed by P-gp)

Is cabazitaxel formulated w/ polysorbate 80 or Kolliphor El?

polysorbate 80

resistance mechanism to taxanes (except cabazitaxel)

overexpression of efflux pumps

What is the advantage of epothilones from taxanes?

enhanced water solubility & less resistance (d/t lack of P-gp affinity)

Concern w epothilone admin

admin w/ Kollipher EL → risk of hypersensitivity reactions (needs prophylactic premedication)

• but since it does have enhanced water solubiity it doesnt need as much Kollipher EL compared to the taxanes

How do vinca alkaloids halt cell division

inhibits polymerization

Name the two segments that are important for vinca alkaloids

catharanthine and vindoline

How do vinca alkaloids differ in structure from each other

1. length of alkyl chain bridging 6’ and 9’ of catharnthine moiety

2. substituents at C4

3. substituents at N1 vindoline indole nitrogen

which vinca alkaloid is mediated by P-gp as a resistance mechanism

vincristine

Name a natural drug that is similar to vinca alkaloids

eribulin mesylate

which vinca alkaloid has the longest half life ?

vincristine

Marqibo

Vincristine formulated inside a liposome