So in our previous lecture on pharmacology of drugs used for treatment of cancer, we
covered antimetabolites, which tend to exert greatest cytotoxicity in the S-phase of the cell cycle.
In this presentation we will shift our focus to agents that mostly affect the last two
phases of the cycle, the G2 phase and the M phase, namely topoisomerase inhibitors and
microtubule inhibitors.
And lastly we will discuss the cell-cycle nonspecific drugs, namely antitumor antibiotics,
alkylating agents, platinum coordination complexes, tyrosine kinase inhibitors, and monoclonal antibodies.
But first things first, let’s take a closer look at what happens during the cell transition
from the S phase to G2 phase and mitosis.
So, during DNA replication and transcription, DNA becomes overwound ahead of a replication fork.
If left unchecked, this torsion would eventually prohibit polymerase enzymes from binding to
the DNA strand and performing their functions.
In order to prevent and correct this problem, enzymes known as topoisomerases catalyze the
breaking and rejoining of DNA strands to relax the coil and extend the DNA molecule.
Different topoisomerases carry out different functions.
For example, topoisomerase type I cuts one strand, then passes the intact strand through
the cut, and reseals the gap, whereas topoisomerase type II cuts both strands of the DNA creating
a gate through which a second segment of the double helix is passed.
Now, these DNA topoisomerases are the target of anti-cancer drugs collectively known as
topoisomerase inhibitors.
They are often divided according to the enzyme they inhibit.
So, drugs such as Irinotecan and Topotecan selectively inhibit topoisomerase type I,
and drug such as Etoposide selectively inhibit topoisomerase type II.
The resulting inhibition of DNA resealing step, leads to large amounts of fragmented
DNA, which arrests cell cycle progression to mitosis, and ultimately triggers apoptosis.
Now, what about the cancer cells that make it to the M phase of the cell cycle?
So during the mitosis phase of the cell cycle, two sets of fully formed chromosomes need
to be separated to produce two daughter cells.
In order for that to happen, first, microtubules must be assembled and stabilized in the correct position.
Each microtubule is constructed from alternating α-tubulin and β-tubulin molecules to form
a stiff, hollow cylindrical structure.
As the microtubules lengthen and shorten by addition and loss of tubulin subunits at their
ends, they push and pull chromosomes apart to opposite ends of the cell.
Now, this dynamic process is extremely sensitive to our next class of anti-cancer drugs known
as microtubule inhibitors.
Microtubule inhibitors act simply by interfering with the dynamics of the microtubule growing
referred to as polymerization and microtubule shortening referred to as depolymerization.
One group of inhibitors, which include vinca alkaloid drugs such as Vincristine, Vinblastine,
and Vinorelbine destabilize microtubule structure by binding to beta-tubulin subunit of the
alpha/beta-tubulin heterodimer and inhibiting polymerization of tubulin into microtubules.
In contrast, the second group of inhibitors, which include taxane drugs such as Paclitaxel,
Docetaxel, and Cabazitaxel promote stabilization of the microtubule by binding to their own
distinct sites on β-subunit located in inner side of microtubule lumen thereby inhibiting
tubulin depolymerization, resulting in large, stable, and dysfunctional microtubules.
Without properly functioning microtubules, chromosomes cannot align and divide which
leads to cell cycle arrest at M phase, and apoptosis.
Allright, so this completes our discussion of the cell-cycle specific drugs.
Now for the reminder of this presentation we will be focusing on the discussion of cell-cycle
nonspecific drugs.
As a quick reminder, cell-cycle nonspecific drugs refer to a class of antitumor agents
that target all cancer cells regardless of their place in the cell cycle.
Now let’s start by discussing our first group of cell-cycle nonspecific drugs that
is antitumor antibiotics.
So, most of antitumor antibiotics belong to a class of drugs called anthracyclines, which
represent a family of natural products originally derived from Streptomyces bacterium with activity
against breast cancer, leukemias, lymphomas, and sarcomas.
The anthracyclines are believed to exert their cytotoxic effects through a variety of mechanisms.
One of the proposed primary mechanisms involves the interaction of anthracyclines with DNA
molecule through intercalation, which is a process by which a drug inserts itself between
adjacent DNA base pairs.
The intercalation leads to significant disturbance of the DNA conformation and results in inhibition
of transcription and replication.
In addition to that, anthracyclines intercalated into DNA, form a stable complexes with topoisomerase
type 2, which results in DNA fragmentation, ultimately prompting the cancer cell to undergo
apoptosis.
As a secondary mechanism, in the presence of oxidoreductive enzymes and iron, the quinone
portion of anthracycline molecule can undergo redox reactions to generate highly reactive
free oxygen radicals.
Excessive amounts of these free radicals damage cell membranes, proteins, and lipids, and
also trigger cell apoptosis.
Examples of anthracycline antibiotics include: Doxorubicin, Daunorubicin, Epirubicin and Idarubicin.
Now, one antitumor antibiotic that is an exception here is Bleomycin.
Bleomycin is different from anthracycline antibiotics in that it is generally considered
to be cell cycle specific, having its major effects on cells in the G2 phase of the cycle.
Bleomycin’s mechanism of action involves entry into the cell, where it forms an active
complex with iron and oxygen, which then binds to DNA and generates highly reactive free
radicals that are responsible for scission of the DNA strand.
The end result is accumulation of G2 phase cells, which are unable to progress to mitosis.
Now moving on to our next group of cancer drugs that is alkylating agents.
So alkylating agents work simply by transferring their reactive alkyl group to DNA, particularly
to the guanine base.
This leads to the formation of cross-linked bonds between functional groups in the DNA,
which in turn prevents DNA from being separated for synthesis or transcription.
Furthermore, alkylated guanine bases may erroneously start pairing with wrong partners; adenine,
thymine or another guanine.
If these mispairings are not corrected, they quickly lead to permanent mutations.
Lastly, DNA fragmentation might result from attempt by DNA repair enzymes to replace alkylated bases.
Examples of alkylating agents include nitrogen mustards such as Chlorambucil, Cyclophosphamide,
Ifosfamide, and Melphalan; Nitrosoureas such as Carmustine, and Lomustine; Triazines such
as Dacarbazine, and Temozolomide; and Alkyl sulfonates such as Busulfan.
Now our next group of cancer drugs that is platinum coordination complexes, act through
a similar cross-linking mechanism, although they do not have reactive alkyl groups.
Instead, typical platinum-based agents generate various reactive platinum species by losing
one or more of their so-called leaving groups, in this example a chloride ligand, which is
then replaced by water molecules to form mono and di- aqua platinum complexes.
These activated, highly reactive complexes are then able to react with DNA bases, leading
to formation of intrastrand and interstrand cross-links.
When polymerases transcribe DNA, they stall at the platinum cross-link and recruit the
repair enzymes.
If these enzymes are unable to repair the lesion, the cell triggers apoptosis.
Examples of platinum coordination complexes include Cisplatin, Carboplatin, and Oxaliplatin.
Now moving on to our next group of cancer drugs that is tyrosine kinase inhibitors.
Before we discuss their mechanism of action, first we need to briefly discuss
receptor tyrosine kinases.
So, in response to extracellular signals from growth factors and cytokines, receptor-associated
enzymes called tyrosine kinases bind ATP and catalyze transfer of their phosphate groups
to tyrosine residues within the intracellular domain.
These phosphorylated tyrosines then serve as a docking site for different proteins,
which activate downstream signaling pathways that regulate cellular processes such as cell
proliferation, survival, migration, and differentiation.
Now, in the presence of cancerous mutation, the growth factor is no longer needed for
receptor activation.
Instead the receptor is constantly autophosphorylated, resulting in unregulated downstream signaling,
promoting uncontrolled cell proliferation and survival.
Small-molecule tyrosine kinase inhibitors are drugs, designed to block the ATP-binding
site of these kinases, preventing autophosphorylation and thus competitively inhibiting tyrosine
kinase activity and downstream signaling.
In regard to cancer, different types of tyrosine kinase receptors have been identified as potential
targets for tyrosine kinase inhibitors.
This led to development of agents such as Imatinib, Dasatinib, and Nilotinib that selectively
inhibit BCR-ABL receptor, which drives development of chronic myeloid leukemia; Lapatinib that
selectively inhibits HER2, which drives development of breast cancer; Sunitinib that selectively
inhibits platelet-derived and vascular endothelial growth factor receptors (PDGF and VEGF), which
drive development of gastrointestinal tumors; and Erlotinib that selectively inhibits epidermal
growth factor (EGF) receptor, which drives development of lung cancer.
Now some of these receptors are also a target of specifically designed monoclonal antibodies.
For example, Trastuzumab is an antibody that binds to the extracellular domain of HER2
receptor thereby inhibiting HER2 signaling pathways and triggering immune-mediated responses
against HER2-overexpressing cells.
Similarly, Cetuximab binds to epidermal growth factor receptors (EGFR) thereby inhibiting
epidermal growth factor-dependent signaling and inducing clearance of antibody-coated
cells by the immune system.
The next monoclonal antibody, Bevacizumab, instead of binding to the growth factor receptor
itself, it acts by selectively binding circulating vascular endothelial growth factor, thereby
inhibiting its binding to the cell surface receptor.
This in turn blocks new blood vessel formation in growing tumors, leading to stasis or regression
of tumor growth.
Now the last monoclonal antibody that has provided a new approach to treating cancer,
particularly Non-Hodgkin's lymphoma and chronic lymphocytic leukemia, is Rituximab.
So unlike the other antibodies, Rituximab binds to the cell surface protein, widely
expressed on normal and malignant B-lymphocytes, called CD20.
This binding in turn triggers complement-dependent cytotoxicity, antibody-dependent cytotoxicity
and apoptosis, resulting in elimination of cancerous B-lymphocytes from the body, allowing
a new population of healthy B-lymphocytes to develop.
Now when it comes to side effects associated with the drugs that we discussed in this video,
a quick and useful tool to help remember many of the common toxicities, is a drawing of
so-called “chemo man”.
So here we have head, and torso, with arms and legs in the shape of letter V. These V-shape
extremities help us remember that vinca alkaloids especially Vincristine, may cause peripheral
neuropathy.
Hands and feet are drawn in the shape of letter T, which helps us remember that Taxanes, especially
Paclitaxel, may also cause peripheral neuropathy.
The Ears and kidneys are drawn in the shape of letter C.
This helps us to remember that Cisplatin and Carboplatin may cause ototoxicity and nephrotoxicity.
The lungs are drawn in the shape of letter B, which helps us to remember that Bleomycin
and Busulfan may cause pulmonary fibrosis.
The heart is drawn in the shape of letter D.
This helps us to remember that Doxorubicin and Daunorubicin may cause cardiotoxicity.
Lastly the bladder can be represented by letter C and Y to help us remember that Cyclophosphamide
may cause hemorrhagic cystitis.
And with that I wanted to thank you for watching, I hope you enjoyed this video and as always
stay tuned for more.