In this first part of the lecture covering the pharmacology of drugs used for treatment
of cancer, we’re gonna discuss anticancer enzymes and hormonal therapy. But first things
first, let’s briefly discuss what cancer is and how it develops. So cancer is generally
defined as the uncontrolled growth of abnormal cells in the body. While the normal cell growth
is carefully regulated to meet the needs of the whole organism, cancer cells evade normal
controls regulating cell proliferation and survival. Now in order to get a better understanding
of how this happens first we need to review the cell cycle. So, when a cell receives message
to divide, it goes through a process known as the cell cycle, which includes several
phases for the division to be completed. The cycle starts with the first gap phase, know
as G1 phase, during which the cell grows in size and prepares enzymes for DNA replication.
At this point, under certain conditions, cell can exit the cell cycle and remain in the
so-called G0 phase as non-dividing, non-growing quiescent cell. But, if the cycle progresses,
the cell will enter the second phase, know as the S, or synthesis phase, in which DNA
replication occurs. During this phase, the cell makes an identical copy of each of its
chromosomes. After this, the cell moves to a G2, or second gap phase, in which it continues
to grow and prepares itself to divide. The final phase of the cycle, known as the M,
or mitosis phase, is the point at which the cell division occurs. Now, the process of
mitosis itself is divided into few different stages. The main stages are; Prophase, during
which chromosomes appear condensed and nuclear envelope breaks down; Metaphase, during which
the network of microtubules growing from the centrioles at the cell poles, align the chromosomes
in the middle of the cell; Anaphase, during which the chromosomes are separated and moved
to opposite sides of the cell; and lastly Telophase and Cytokinesis, during which nuclear
membranes form around the separated chromosomes, and cell walls pinch off bringing about the
separation into two daughter cells. Immediately following the M phase, newly formed cells
either leave the cycle and become dormant, or return to the G1 phase, should they need
to divide again. Now because cell cycle is a continuous process,
surveillance mechanisms, known as checkpoints, exist to ensure each phase is completed properly
before progression to the next stage. The three main checkpoints are: the G1 checkpoint,
the G2 checkpoint and the M checkpoint. Now its important to remember that not all cells
have to pass through each of these checkpoints in order to replicate. Many types of cancer
are caused by mutations in tumor suppressor genes that allow the cells to speed through
the various checkpoints or even skip them altogether. So, one of the common approaches
in treatment of cancer is to use chemotherapy agents that target fast-dividing cells at
different phases of the cell cycle. Generally, those drugs that are cytotoxic during specific
phase of the cell cycle are referred to as cell cycle-specific drugs. On the other hand,
drugs that are cytotoxic in any phase of the cell cycle are referred to as cell cycle-nonspecific
drugs. So now let’s explore these drugs in more
details starting with the ones acting in G1 phase. During this phase, the cell synthesizes
majority of proteins that are needed later on for DNA replication and cell division.
One of the building blocks of many of those proteins is an amino acid called asparagine.
Now, healthy non-malignant cells can synthesize asparagine with the help of the enzyme asparagine
synthetase. However, some tumor cells, such as leukemic cells, lack this enzyme and depend
on exogenous supply of asparagine for their survival. This is where drug called Asparaginase
come into play. Asparaginase is an enzyme that speeds up the breakdown of asparagine
into aspartic acid and ammonia. This results in the depletion of asparagine, inhibition
of protein synthesis, cell cycle arrest in the G1 phase, and ultimately apoptosis in
susceptible leukemic cell populations. For patients with acute lymphocytic leukemia who
develop an allergy to Asparaginase, there is a slightly changed version of the drug
available, called Pegaspargase, which is essentially asparaginase linked to polyethylene glycol
(PEG) molecule. In contrast to Asparaginase, Pegaspargase is less likely to cause allergic
reaction, has longer duration in the body and can be given less frequently.
Now, the progress from G1 to S phase depends on the actions of molecular pathways that
are influenced by hormone-regulated genes. The primary hormone that has been implicated
in the promotion of carcinogenesis, especially in tissues of the female reproductive tract
and the breast, is estrogen. The majority of the cellular effects of estrogen are mediated
through intracellular estrogen receptors (abbreviated here as ER). Upon binding of estrogen to the
estrogen receptor in the cytoplasm, a conformational change occurs inducing receptor dimerization.
This complex is then translocated to the nucleus, where it binds to specific regions on chromatin
thereby activating the transcription of specific genes, leading to increased cell growth and
proliferation rate. Now, there are four ways in which estrogen-dependent processes important
in development of certain cancers such as breast cancer, may be interrupted.
So, the first and the most direct method to reduce the amount of estrogen in the body
is to simply interfere with its production by targeting an enzyme called Aromatase. The
aromatase enzyme is substantially concentrated in adipose and hepatic tissues and is also
found in elevated concentrations in breast cancer. It is primarily needed for the conversion
of androstenedione and testosterone to estrone and estradiol, respectively. Estrone and estradiol
are biologically active estrogens, which bind to and activate estrogen receptors, thereby
promoting cell proliferation. Aromatase inhibitors such as Anastrozole, Letrozole, and Exemestane,
work by blocking aromatase enzyme, which in turn reduces the production of estrogens particularly
in postmenopausal women. Now, the second estrogen-sequestering method
is to interfere with the binding of estrogen to the estrogen receptors. This can be accomplished
with the use of selective estrogen receptor modulators (SERMs) such as Tamoxifen and Raloxifene.
In hormone receptor-positive cancer cells, these agents competitively bind to the estrogen
receptor protein and adopt a different conformation to the one seen with estrogen bound. The complex
then dimerises and it’s transported from the cytosol into the cell's nucleus where
it binds to DNA to form a new complex that is unable to function in the same way as the
one formed with estrogen. The overall result is the inhibition of growth-promoting effects
of estrogen. Now, the third method is to reduce or eliminate
estrogen receptor expression. This can be accomplished with the use of selective estrogen
receptor down-regulator such as Fulvestrant, which works by binding to estrogen receptor
monomers and inhibiting receptor dimerization. This in turn leads to accelerated receptor
degradation, thus making the receptor unavailable to estrogen.
Now, the last approach to reduce estrogen levels is to suppress ovaries, which are the
main source of estrogen particularly in premenopausal women. The ovaries produce and secrete estrogens
in response to follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which
are released from the pituitary gland when signaled by the hypothalamus. To carry its
message, the hypothalamus produces a chemical signal in the form of gonadotropin-releasing
hormone (GnRH for short), which exerts its stimulatory effects by activating GnRH receptors
expressed on the pituitary gland. Now, these receptors are the target of GnRH agonists
such as Leuprolide, Goserelin, and Triptorelin, which work by overstimulating GnRH receptors,
resulting in receptor desensitization over time. This in turn leads to reduced secretion
of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and ultimately reduced production
of estrogen. Although GnRH agonists can be helpful in treatment
of women with breast cancer, they are more often used in treatment of men with prostate
cancer. This is because in males luteinizing hormone (LH) directs the testes to produce
testosterone. Free circulating testosterone can enter prostate cells, where, with the
help of 5-alpha reductase enzyme, it can be converted to its more potent metabolite, dihydrotestosterone
(DHT), and then bind to the androgen receptor (abbreviated here as AR). This hormone-receptor
complex then dimerizes with another hormone-bound receptor and translocates into the nucleus
where it binds to specific DNA sequences thus triggering expression of genes involved in
cell growth and proliferation. Now, because GnRH agonists, initially stimulate pituitary
gland leading to surge in testosterone levels and under certain circumstances, a flare-up
of the tumor, scientists have been developing GnRH antagonists that do not cause surge in
testosterone or clinical flare. Example of this is an agent called Degarelix, which works
simply by blocking the receptor for gonadotropin-releasing hormone in the pituitary gland thereby reducing
the release of the luteinizing hormone, causing a rapid sustained suppression of testosterone
release from testes and subsequently reducing the size and growth of the prostate cancer.
Now, another approach to reduce the effects of testosterone and dihydrotestosterone, is
to interfere with their binding to the androgen receptor (AR). This can be accomplished with
the use of so-called nonsteroidal antiandrogens such as Flutamide, Bicalutamide, and Nilutamide,
which work by binding to androgen receptors and competitively inhibiting their interaction
with testosterone and dihydrotestosterone, thus preventing the effects of these hormones
in the prostate gland. Now, the last treatment option, usually reserved
for prostate cancer that is not responding to androgen deprivation therapies that we
have discussed so far, is a drug called Abiraterone. The target of this drug is an enzyme called
cytochrome P450 17 alpha-hydroxylase (CYP17A1 for short), which is expressed in testicular,
adrenal, and prostate cancer cells and is responsible for the conversion of androgen
precursors to testosterone. Abiraterone works simply by inhibiting CYP17A1 enzyme, thus
disrupting androgen synthesis thereby reducing serum levels of testosterone and other androgens
within these tissues, and ultimately leading to shrinkage of hormone-sensitive prostate
cancer cells. Now when it comes to side effects, Asparaginase,
and Pegaspargase may cause fatigue and poor appetite, mouth sores, pancreatitis, and blood
clots. Aromatase inhibitors as well as GnRH agonists and antagonists may cause fatigue,
muscle and joint pain, hot flashes and osteoporosis. Selective estrogen receptor modulators for
the most part share similar side effects, in addition to being more likely to cause
blood clots, stroke and endometrial cancer. Lastly, antiandrogens, when used in men, may
cause breast enlargement, hot flashes, sexual dysfunction, and osteoporosis. And with that
I wanted to thank you for watching, I hope you enjoyed this video and as always stay
tuned for more.