Microtubule inhibitors, as their name implies, disrupt the microtubules and inhibit mitosis,
which is a specific phase of the cell cycle.
Anticancer agents in this class include the vinca alkaloids and the taxanes.
But first things first.
The cytoskeleton is a network of proteins within the cell that gives each cell its shape,
and it anchors organelles in place.
But it’s also a dynamic network, which can change shape when the cell wants to move,
contract, divide, or pull in or push out molecules.
It’s made up of three proteins: actin filaments, intermediate filaments, and microtubules.
Microtubules are made of alternating round proteins called α- and β-tubulins, which
form long strands called protofilaments.
Thirteen of these protofilaments come together to form a single microtubule.
Microtubules play a super important role in cell division.
During cell division there are two centrosomes inside the cell, and each centrosome is made
out of two centrioles.
Each centriole is in turn made up of nine sets of microtubule triplets.
Now cell division, or mitosis, can be divided into four subphases: prophase, metaphase,
anaphase, and telophase.
During prophase, the membrane around the nucleus disintegrates, and the chromosomes condense.
During metaphase, chromosomes move towards the middle of the cell, on a line called the
metaphase plate.
Each chromosome is made up of a pair of sister chromatids which are joined together in the
centromere where there’s a specific protein complex called the kinetochore.
When the chromosomes are in place, each centrosome sends out thread-like projections called spindle
fibers, that attach to the centromere of each chromosome.
Spindle fibers consist of microtubules that originate from the centrioles and polymerize
in the direction of the kinetochores.
Next, during anaphase, the centrosomes start pulling on the spindle fibers to pull the
sister chromatids apart, forming the mitotic spindle.
It looks a bit like a fishing line being cast out to its target, and then the line gets
reeled in, pulling the kinetochore and it’s attached sister chromatid away from its partner
chromosome.
Finally, there’s the telophase during which a nuclear membrane forms around each new set
of 46 single-chromatid chromosomes.
After that, during cytokinesis, the cell membrane pinches in until the two daughter cells separate.
Alright, now cancer cells replicate rapidly so they are constantly undergoing mitosis
and the microtubules are always at work.
This means that microtubule inhibitors will affect these cells more than our healthy cells,
most of which only divide occasionally.
Interfering with the formation of microtubules will cause mitosis to fail and the cell will
eventually die without replicating.
The two commonly used anticancer microtubule inhibitors include the vinca alkaloids and
the taxanes.
All anticancer microtubule inhibitors are given intravenously.
Okay, let’s start with vinca alkaloids, which include vinblastine, and vincristine.
Vinca alkaloids bind to β-tubulin and block its polymerization into protofilaments, which
form microtubules, centrioles, centrosomes, and spindle fibers.
This means the cell can’t form stable mitotic spindles and will stop at metaphase.
So, vinca alkaloids act in the M phase of the cell-cycle and are cell-cycle specific.
Moving on to indications.
Vinca alkaloids are used for solid tumors like: breast cancer; pediatric tumors like
rhabdomyosarcoma and nephroblastoma or Wilms tumor; and leukemias.
Now, vincristine and vinblastine are both used for Hodgkin’s and non-Hodgkin’s lymphoma.
Let’s move on to side effects.
Vinca alkaloids disrupt the progression of mitosis in all rapidly dividing cells in the
body including hair follicles and gastrointestinal epithelium, so vinblastine and vincristine
cause alopecia, or loss of hair, and gastrointestinal symptoms.
In addition, they are associated with bone marrow suppression since the cells here are
constantly making the platelets, red, and white blood cells.
Now, vinblastine causes more bone marrow suppression, but vincristine is more neurotoxic as it interferes
with microtubule polymerization in neuronal axons disrupting the neuronal activity.
Neurotoxicity usually manifests as peripheral neuropathy causing symptoms like a decrease
in sensation in the toes and fingers, sometimes called a glove and stocking distribution,
as well as autonomic nervous system malfunction with orthostatic hypotension, urinary retention,
and constipation.
Alright, next are the taxanes, which are also alkaloid derivatives, and include paclitaxel
and docetaxel.
Taxanes also act on microtubules, but they act differently from vinca alkaloids.
They enhance tubulin polymerization into protofilaments and microtubules, but they also bind directly
to the spindle fibers and stabilize them.
So they act like cement that overstablizes the microtubules and prevents them from depolymerizing
and breaking down.
This is a problem because the microtubules need to break down during anaphase so the
cell can divide.
So, taxanes are also cell-cycle specific and act on M phase.
Moving on to indications.
They are used for a variety of solid tumors including breast, ovarian, lung, gastroesophageal,
prostate, bladder, and head & neck cancers.
Side effects include alopecia, myelosuppression and neurotoxicity, which again presents as
a glove and stocking peripheral neuropathy.
Also, they are associated with a possible hypersensitivity reaction during infusion.
Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these
pharmacology facts about microtubule inhibitors.
Okay, so let’s imagine we are in ancient Rome and there’s a temple being constructed
with 4 microtubule pillars.
Now the first two pillars can’t be finished because there are vines growing all over them,
which represent the Vinca alkaloids.
One vine plant has fruits that look like little bombs for vinblastine, while the other has
fruits that look like crystals for vincristine.
For indications, let’s use crabs to represent cancer, since in the zodiac, cancer is a giant
crab.
Between the two pillars, there’s a solid, stone crab statue to help you remember both
drugs are used to treat solid tumors.
On top of the statue is a baby crab because they are also used for pediatric tumors like
Wilms tumor.
Finally, the stone crab is carrying a giant bone club with little white crabs in the bone
marrow.
This represents leukemia, which originates in the bone marrow.
Finally, we can use a hedgehog for hodgkin's lymphoma and a spike-less hedgehog for non-hodgkin’s
lymphoma.
They are both pigging out on a pile of crystal and bomb fruits on the ground since both drugs
can be used to treat these diseases.
To make things worse, some of his bones also blew off and remain shattered on the ground,
which helps you remember vinblastine suppresses the bone marrow.
For vincristine, let’s cover the little hedgehog’s legs in bandages to help you
remember the glove and stocking peripheral neuropathy.
For the shared side effects, we’ll have a bald man sitting by the statue for alopecia,
he’s vomiting at the foot of the statue which represents the GI side effects.
Okay moving on to the taxanes which will be represented by two tax collectors by the 3rd
and 4th pillar.
One of them is a doe for docetaxel and the other is a pack mule for pactaxel.
They spent the money they collected on cement to make the pillars ultra durable.
Okay, for indications of these two drugs, let’s put another statue of a stone crab
between them since they are also used for solid tumors.
This crab is holding a pair of bras in one claw for breast cancer, and an egg in the
other claw for ovarian cancer, which are two of the most common uses.
For side effects, let’s have a janitor cleaning the statue.
He’s also bald, for alopecia, and he’s sweeping away some broken bones, which represents
bone marrow suppression.
His hands and feet are wrapped in bandages for peripheral neuropathy, and there’s a
syringe sticking out of his arm which is covered in a red rash.
This will help you remember that these drugs can cause a hypersensitivity reaction at the
injection site.
All right, as a quick recap…
Microtubule inhibitors such as vinca alkaloids and taxanes are used as anticancer agents.
Vinca alkaloids include vincristine and vinblastine.
They work by binding to β-tubulin and blocking microtubule formation and thus the affected
cells are arrested in metaphase.
They are used for the treatment of solid tumors, pediatric tumors, leukemias, and lymphomas.
Taxanes include paclitaxel and docetaxel and they work by over-stabilizing microtubules
and preventing their breakdown during anaphase.
Again, cells are arrested in metaphase, so both vinca alkaloids and taxanes are cell-cycle
specific agents.
Taxanes are used for the treatment of solid tumors like breast and ovarian cancers.
But wait, there’s more: Here’s a mind map with all of the mnemonics.
Go ahead and pause the video so you can test yourself to see what you remember.
Stay tuned for the answers after the credits.