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.