WRITTEN REPORT

IN
PHARMACOLOGY

ENCARNACION, PAUL
REGALA, CHRISTINE JOY
CELAJES, SHARI MAE
DINGLASA, ALDRIN
HIZON, KARL PATRICK
ISIDRO, DESIREE MARIEL
MALAPASCUA, PAOLA JOY
JARCIA, EMIL CRIS
VERGARA, JENSEN
Cancer Chemotherapy

Cancer is a group of diseases that are marked by rapid, uncontrolled cell proliferation and conversion of
normal cells to a more primitive and undifferentiated state. Neoplasms are large tumors formed from excessive
cell proliferation. They may be benign or malignant. Malignant tumors continue to proliferate and can
metastasize to other tissues.
Cancer specifically refers to the malignant forms of neoplastic disease which can be fatal. Although,
benign tumors can also be life threatening when large benign tumors obstruct the GIT or press on the parts of the
CNS.
Some examples of different types of cancer:
 Carcinomas – arising from epithelial tissues
 Sarcomas – arising from mesenchymal tissues
 Leukemia – cancerous proliferation of leukocytes
 Hodgkin disease
 Wilms tumor

The exact cause of many cases of CA is unknown. But several factors (environmental, viral, genetic,
exposure to carcinogens) may increase a person’s susceptibility to various types of cancer. On the other hand,
positive lifestyle changes may be crucial in preventing certain forms of cancer. Routine checkups and early
detection is vital in reducing cancer mortality.
3 primary treatment modalities:
 Surgery
 Radiation treatment
 Cancer chemotherapy

General Principles of Cytotoxic Strategy

The basic strategy of anticancer drugs is to limit cell proliferation of the cancerous cells by killing or
weakening its growth. Unique problem of pharmacological treatment of cancer is the concept of selective toxicity
becomes more difficult because cancer cells are still human cells not like foreign invaders and parasites which are
selectively target by drugs.
Most anticancer drugs’ basic strategy is to inhibit DNA/RNA synthesis and function, or to directly inhibit
cell division preventing replication. Since anticancer drugs are not very selective, healthy cells also suffer but to a
lesser extent compared to CA cells who need undergo mitosis at a much higher rate.

Cell-Cycle-Specific vs Cell-Cycle-Nonspecific Drugs

Phases of life cycle of cells:
 Resting phase – G0
 Pre-DNA synthesis phase – G1
 Period of DNA synthesis – S
 Post DNA synthesis phase – G 2
 Period of actual cell division (mitosis) – M

Certain anticancer drugs are referred to as cell cycle specific because they exert their effect only when the
CA cell in a certain phase but not in the resting phase. Other drugs are classified as cell cycle nonspecific because
they exert their effects on the cell regardless of the cell cycle’s phase. This includes most alkylating agents and
antineoplastic antibiotics.
Concepts of Growth fraction and Total Cell Kill
Growth Fraction – refers to the percentage of proliferating cells relative to total neoplastic population. Cells
included in the growth fraction are more susceptible to anticancer drugs and must be killed to prevent from
metastasizing.
Total Cell Kill – refers to the fact that every cell capable of replicating must killed in order to eliminate the CA
completely. A 0.01% of the CA cell that may remain may replicate to sufficient numbers and still cause death.
Remission – the disease is considered in remission when the number of CA cells is reduced by chemotherapy
regimens to a number that can be dealt with by the body’s cytotoxic immune responses.
Prevalence and Management of Adverse Effects

 Because antineoplastic agents often impair replication of normal tissues, these drugs are generally associated
with a number of common and relatively severe adverse effects. Normal human cells must often undergo
controlled mitosis to sustain normal function.
 This fact is especially true for certain tissues such as hair follicles, bone marrow, immune system cells, and
epithelial cells in the skin and gastrointestinal tract.
 In fact, the primary reason for most of the common adverse effects (e.g., hair loss, anemia, nausea) is that
normal cells are also experiencing the same toxic changes as the tumor cells.
 The cancer cells, however, tend to suffer these toxic effects to a greater extent because of their increased rate
of replication and cell division. Still, healthy cells often exhibit some toxic effects, even at the minimum
effective doses of the chemotherapeutic agents.
 Consequently, antineoplastic drugs typically have a very low therapeutic index compared with drugs that are
used to treat less serious disorders.
 Some side effects, however, can be treated with other drugs. In particular, gastrointestinal disturbances may
be relieved to some extent by administering traditional antiemetic agents such as glucocorticoids
(dexamethasone) or drugs that block dopamine receptors (metoclopramide).
 In addition, newer antiemetic and antinausea agents such as dolasetron (Anzemet), granisetron (Kytril),
ondansetron (Zofran), and palonosetron (Aloxi) have been developed to treat chemotherapy-induced nausea
and vomiting.
 These newer agents, which block a specific type of CNS serotonin receptor known as the 5-
hydroxytryptamine type 3 (5-HT3) receptor, reduce the nausea and vomiting caused when serotonin binds to
that receptor.
 A new agent known as aprepitant (Emend) is available that blocks the neurokinin-1 receptor in the CNS,
thereby inhibiting the nausea and vomiting mediated by other neuropeptides such as substance P.
 Hence, several drugs are now available that can be used alone or in combinations to reduce the severity of
gastrointestinal distress commonly associated with cancer chemotherapy agents.

Alkylating Agents

 This agents exert cytotoxic effects by inducing binding within DNA strands and by preventing DNA function and
replication.
 This drug causes cross-links to be formed between the strands of the DNA double helix or within a single DNA
strand
 In either case, these cross-links effectively tie up the DNA molecule, eliminating the ability of the DNA double
helix to untwist.
o The genetic code of the cell cannot be reproduced, and cell reproduction is arrested
o Impairs cellular protein synthesis because the DNA double helix cannot unwind to allow formation of
messenger RNA strands
o Therefore cell cannot synthesize vital cellular proteins
 Alkylating agents likewise initiate a process of cell death (apoptosis) by disrupting DNA function, in which
several degradative enzymes are released and begin to destroy the cell.
 Alkylating agents are so named because they typically generate a chemical alkyl group on one of the bases,
such as guanine in the DNA chain.
 This alkyl group acts as the bridge that ultimately links two base in the DNA molecule.
 The bonds formed by this cross-linking are strong and resistant to breakage. Thus, the DNA double helix
remains tied up for the cell’s life.
 Anticancer drugs that work primarily as alkylating agents are:
 o Altretamine (Hexalen)
o Busulfan (Myleran)
o Carmustine (BCNU, BiCNU)
o Chlorambucil (Leukeran)
o Cyclophosphamide (Cytoxan, Neosar)
o Dacarbazine (DTIC-Dome)
o Ifosfamide (IFEX)
o Lomustine (CeeNU)
o Mechlorethamine (Mustargen, nitrogen mustard)
o Melphalan (Alkeran)
o Procarbazine (Matulane)
o Streptozocin (Zanosar)
o Thiotepa (Thioplex)
o Uracil mustard (Generic)

 These agents represent the largest category of anticancer drugs and are used to treat a variety of leukemias,
carcinomas, and other neoplasms.

Antimetabolites
 Cells are able to synthesize genetic material (DNA,RNA) from endogenous metabolites known as purine and
pyrimidine nucleotides
 Certain anticancer drugs are structurally similar to these endogenous metabolites and compete with these
compounds during DNA/RNA biosynthesis.
 They interfere with the normal metabolites during cellular biosynthesis.
 This drugs can impair the biosynthesis of genetic material in two primary ways:
o First, the drug may be incorporated directly into the genetic material, thus forming a fake and
nonfunctional genetic product.
o The second manner in which antimetabolites may impair DNA/RNA biosynthesis is by occupying the
enzymes that synthesize various components of the genetic material.
 In either case, the cell’s ability to synthesize normal DNA and RNA is impaired, and the cell cannot replicate its
genetic material or carry out normal protein synthesis because of a lack of functional DNA and RNA.
 Antimetabolite agents:
o Capecitabile (Xeloda)
o Cladribine (Leustatin)
o Cytarabine (Cytosar-U, depocyt)
o Floxuridine (FUDR)
o Mathotrexate (Generic)
o Pemetrexed (Alimta)
o Pentostatin (Nipent)
o Thioguanine (Generic)
Antibiotics
 The exact mechanism of action for these antibiotics is to exert antineoplastic effects is still being investigated.
 These drugs may act directly on DNA by becoming intercalated (inserted) between base pairs in the DNA
strand.
 This insertion would cause a general disruption or even lysis of the DNA strand, thus preventing DNA
replication and RNA synthesis
 Alternatively, these antibiotics may act in other ways, including:
o Direct effects on the cancerous cell membrane
o Inhibiting DNA-related enzymes
o Forming highly reactive free radicals that directly damage the DNA molecule.
Plant Akaloids
 Alkaloids are nitrogen-based compounds frequently found in plants.

Used in treating cancer in humans include:

 Traditional agents
 Vincristine : inhibit the formation of the mitotic apparatus
 Vinblastine : inhibit the formation of the mitotic apparatus
 Newer agent
 Vinorelbine : inhibit the formation of the mitotic apparatus
 Paclitaxel : inhibit breakdown of these microtubules
 Docetaxel : inhibit breakdown of these microtubules

Inhibit specific enzymes known as topoisomerase enzymes:

 Etoposide: I
 Irinotecan: II
 Teniposide: I
 Topotecan: II
- these drugs disrupt the function of the microtubules that are involved in the mitotic apparatus of the cell (the
mitotic spindle).

Specific agents:
 Docetaxel (Taxotere)
 Etoposide (Etopophos VePesid)
 Irinotecan(Camptosar)
 Paclitaxel (Taxol)
 Teniposide(Vumon)
 Topotecan (Hycamtin)
 Vinblastine (Velban, Velsar)
 Vincristine (Oncovin, Vincasar)
 Vinorelbine (Navelbine)

Hormones
 Several forms of cancer are referred to as hormone sensitive because they tend to be exacerbated by
certain hormones and attenuated by others.
 In particular, adrenocorticosteroids and the sex hormones (androgens, estrogens, progesterone) may
influence the proliferation of certain tumors. Hence, drugs that either mimic or block
 (antagonize) the effects of these hormones may be useful in treating certain hormone-sensitive forms of
cancer.
 Hormonal anticancer drugs are typically used as adjuvant therapy; that is, they are used in conjunction
with surgery, radiation treatment, and other anticancer drugs.
 these drugs work by direct inhibitory effects on cancerous cells or by negative feedback mechanisms
 In other cases, drugs can directly block the effects of the endogenous hormone and prevent that hormone
from stimulating specific tumors.
 In particular, androgen receptor blockers can treat prostate cancer
 Antiestrogen can likewise help prevent and treat breast and uterine cancers that are stimulated by
estrogen.
 that decrease the endogenous hormonal stimulation of the tumor
 by blocking the effects of testosterone on the prostate gland
Specific agent:
 Fulvestrant (Faslodex) : “pure” antiestrogen because this drug binds to all estrogen receptors without
activating them; that is, true estrogen receptor antagonist or blocker.
 Tamoxifen: selective estrogen receptor modulator (SERM)
- meaning that this drug blocks estrogen receptors on certain tissues (breast, uterus), while
stimulating other estrogen receptors in bone, cardiovascular tissues, skin, and so forth
 Aromatase inhibitors
- do not block estrogen receptors, but instead reduce estrogen production, thereby decreasing the
influence of estrogen on breast tumors.
- decrease estrogen production in breast and other tissues by inhibiting the aromatase enzyme that is
responsible for estrogen biosynthesis.

Such as:
 anastrozole (Arimidex)
 Letrozole (Femara)
 Exemestane (Aromasin)

Anti-neoplastic Hoemones:
 Adrenocorticosteroids
Prednisone
Prednisolone
Others
 Androgens
Fluoxymesterone
Methyltestosterone
 Testosterone
Antiandrogens
Bicalutamide
Flutamide
Nilutamide
 Aromatase inhibitors
Anastrozole
Exemestane
Letrozole
 Estrogens
Diethylstilbestrol
Estradiol
Others
 Antiestrogens
Fulvestrant
Tamoxifen
 Progestins
Hydroxyprogesterone
Medroxyprogesterone
Megestrol
 Gonadotropin-releasing hormone drugs
Abarelix
Leuprolide
Goserelin
Triptorelin
Biologic Response Modifiers
 they enhance the body’s ability to respond to neoplasms
 currently used to treat certain types of leukemias, lymphomas, Kaposi sarcoma, and cancer in other
organs and tissues
 classified as biologic response modifiers because exert a number of beneficial effects, including antiviral
and antineoplastic activity.
 that is, these drugs are not necessarily cytotoxic, but they affect the mechanisms that regulate cell
division or influence specific aspects of immune function that help inhibit or destroy the cancerous tissues

Specific Agents:
Interferons
 to impair cancerous cell growth is not clear.
 affect several aspects of tumor growth, including the inhibition of cancerous genes (oncogenes),
the activation of cytotoxic immune cells (natural killer cells), and the inhibition of other aspects
of cell metabolism and proliferation in cancerous tissues.
Interleukin-2 (IL-2)
 endogenous cytokine that normally exerts a number of beneficial immunologic responses.
 stimulates the growth and differentiation of T-cell lymphocytes that are selectively toxic for
tumor cells. Hence, recombinant
 DNA techniques are now used to synthesize IL-2
 so that this agent can be used to treat cancers such as renal cancer and malignant melanoma
Research continues to identify the antineoplastic role of interleukins, interferons, and other cytokines
Agents:
 Interferons
 Interferon alfa-2a
 (Roferon-A)
 Interferon alfa-2b
 (Intron-A)
 Interleukin-2
 Aldesleukin (Proleukin)

Monoclonal antibodies
 method for targeting an anticancer drug against cancerous tissues.
 These drugs are manufactured using cell cloning techniques that produce an antibody that is
specific for an antigen on the surface of a particular type of cancer cell.
 attracted directly to the cancer cell, without any appreciable affect on healthy tissues.
 Once it has reached the cancerous cell, monoclonal antibodies exert several complex effects that
limit cell function, inhibit mitosis, and can possibly result in the cell’s death.
Newer monoclonal agents
 bispecific antibodies may also contain a second antibody that produces an additionalbeneficial
effect such as stimulating production of cytotoxic T lymphocytes or other immune system
components that attack the tumor.
 Bevacizumab (Avastin) can also be used as angiogenesis inhibitors; that is, these agents inhibit
the formation of new blood vessels in growing tumors.
 binds specifically to vascular endothelial growth factor (VEGF), and prevents it from stimulating
the formation of blood vessels in the tumor.

 Alemtuzumab (Campath)
 Bevacizumab (Avastin)
 Cetuximab (Erbitux)
 Gemtuzumab (Mylotarg)
 Rituximab (Rituxan)

This intervention can be used along with other more traditional anticancer drugs to treat specific cancers such as
advanced colorectal cancer.

Heavy Metal Compounds

 act like the alkylating agents
 they form strong cross-links between and within DNA strands; thereby preventing DNA translation and
replication.
 are especially important in treating certain epithelial cancers, including testicular cancer, ovarian cancer,
bladder cancer, and others
 used to treat cancer include cisplatin, carboplatin, and oxaliplatin These drugs, which contain platinum,
are also known as platinum coordination complexes.
Specific agents:
 Carboplatin (Paraplatin) - Carcinoma of the ovaries
 Cisplatin (Platinol) - Carcinoma of bladder, ovaries, testicles, and other tissue
 Oxaliplatin - Colorectal cancer

Adverse effect:
 Carboplatin - Blood disorders (anemia, leukopenia, neutropenia, thrombocytopenia); unusual tiredness; GI
distress (nausea, vomiting)
 Cisplatin - Nephrotoxicity; GI distress (nausea, vomiting); neurotoxicity (cranial and peripheral nerves);
hypersensitive reactions (e.g., flushing, respiratory problems, tachycardia)
 Oxaliplatin- Blood disorders (anemia, leukopenia, neutropenia,thrombocytopenia); joint pain,chest pain

Aspirin and Other NSAIDs

 can prevent colorectal cancer, and that these drugs might also decrease malignancies in other tissues such
as the stomach, esophagus, breast, bladder, and lungs.
 increased protection occurring in people who use aspirin on a regular basis.
 exact reason for this anticancer effect is unknown
 reduce the risk of colorectal cancer and other cancers by inhibiting the synthesis of certain prostaglandins
 aspirin and similar drugs inhibit the cyclooxygenase enzyme that synthesizes prostaglandins in various
cells in the body.
 Hence, aspirin and other NSAIDs may. In addition, the COX-2 form of the cyclooxygenase enzyme seems
to be prevalent in certain tumors, and inhibition of this enzyme using COX-2 selective drugs may
ultimately provide optimal results in certain cancers.

Prostaglandins such as:

 prostaglandin E2 may promote the growth and proliferation of certain tumors.

Tyrosine Kinase Inhibitors

Tyrosine kinase is an enzyme found in many cells and is responsible for transmitting signals from the cell
membrane to other functional components throughout the cell. In certain types of cancer, defective function of
tyrosine kinases leads to abnormal cell function and proliferation. Hence, drugs that inhibit tyrosine kinase activity
will be especially useful in some cancers.11 Several tyrosine kinase drugs are currently available including erlotinib
(Tarceva), geftinib (Iressa), and imatinib (Glivec). These drugs are gaining acceptance as a part of the treatment of
certain leukemias, as well as cancers affecting other tissues such as the lungs, stomach, and pancreas. Use of these
drugs is fairly new, however, and more information about optimal use of tyrosine kinase inhibitors will surely be
forthcoming.
Miscellaneous Agents

Arsenic trioxide
Arsenic is a heavy metal that can exert toxic, poisonous effects. Therapeutic dosages of arsenic trioxide (Trisenox),
however, may limit the growth of certain leukemias such as acute promyelocytic leukemia. However, because of its
potential toxicity, arsenic trioxide is not usually an initial treatment, but is reserved for patients who relapse or
who are resistant to other treatments. Although the exact mechanism of action is unclear, this drug apparently
induces several cytotoxic effects by directly damaging DNA and proteins that regulate DNA synthesis and
replication.

Asparaginase.
Asparaginase (Elspar) is an enzyme that converts the amino acid asparagine into aspartic acid and ammonia. Most
normal cells are able to synthesize sufficient amounts of asparagine to function properly. Some tumor cells
(especially certain leukemic cells) must rely on extracellular sources for a supply of asparagine, however. By
breaking down asparagine in the bloodstream and extracellular fluid, asparaginase deprives tumor cells of their
source of asparagine, thus selectively impairing cell metabolism in these cells. Asparaginase is used primarily in the
treatment of acute lymphocytic leukemia.

Bortezomib
Bortezomib (Velcade) inhibits proteasome activity in mammalian cells. Mammalian proteasome is responsible for
degrading certain cellular proteins affecting cell function and division. By prolonging the activity of these proteins,
bortezomib brings about complex changes in cell function that lead to cell dysfunction and death. Certain types of
cancer, such as multiple myeloma, are more sensitive to impaired proteasome regulation, hence the use of this
drug in these cancers.

Denileukin Diftitox
Denileukin Diftitox (Ontak) is formulated by combining interleukin-2 with diphtheria toxin. Certain leukemia and
lymphoma cells have a surface receptor that has a high affinity for interleukin-2, thus attracting this drug directly to
these cells. Upon binding with the receptor, the diphtheria toxin component of the drug inhibits cellular protein
synthesis, which ultimately results in cell death.

Estramustine
Estramustine (Emcyt) is a chemical combination of mechlorethamine (an alkylating agent) and estrogen. It is not
clear, however, how this drug exerts antineoplastic effects. The beneficial effects of this drug are probably not
related to any alkylating effects. Rather, they may be the direct result of its estrogenic component, or its inhibitory
effect on the microtubules that comprise the mitotic apparatus. This drug is typically used for the palliative
treatment of advanced prostate cancer.

Hydroxyurea
It is believed that hydroxyurea (Hydrea) impairs DNA synthesis by inhibiting a specific enzyme (ribonucleoside
reductase) involved in synthesizing nucleic acid precursors.

Mitotane
Although the exact mechanism of this drug is unknown, mitotane (Lysodren) selectively inhibits adrenocortical
function. This agent is used exclusively to treat carcinoma of the adrenal cortex.

Thalidomide
Thalidomide (Thalomid) was originally developed as a sedative and antinausea drug, but was withdrawn from the
market because it caused severe birth defects when administered to pregnant women. This drug, however, has
reemerged as a potential treatment for cancers such as multiple myeloma. Although the exact reasons for its
anticancer effects are not clear, thalidomide exerts a number of complex effects on immune function, including the
suppression of tumor necrosis factor alpha.40 This drug also inhibits angiogenesis, and may therefore limit the
growth of solid tumors by inhibiting vascularization and nutrient supply.

Tretinoin
Tretinoin (Vesanoid), also known as all-trans-retinoic acid, is derived from vitamin A (retinol). This drug is not
cytotoxic, but it may help cells differentiate and replicate at a more normal rate. However, the exact way that this
agent affects cell differentiation is not known. Tretinoin is used primarily to treat certain forms of leukemia.

Combination Chemotherapy
Frequently, several different anticancer drugs are administered simultaneously. This process of combination
chemotherapy increases the chance of successfully treating the cancer because of the additive and synergistic
effect of each agent. Often, different types of anticancer drugs are combined in the same regimen to provide
optimal results.11 For instance, a particular drug regimen may include an alkylating agent, an antineoplastic
antibiotic, a hormonal agent, or some other combination of anticancer drugs. These drug combinations are often
indicated by an acronym of the drug names. For instance, “FAC” indicates a regimen of fluorouracil, doxorubicin
(Adriamycin), and cyclophosphamide. These abbreviations are used to summarize drug therapy in a patient’s
medical chart, so therapists should be aware of the more common chemotherapy combinations.

Use of Anticancer Drugs with Other Treatments

Cancer chemotherapy is only one method of treating neoplastic disease. The other primary weapons in
the anticancer arsenal are surgery and radiation treatment. The choice of one or more of these techniques
depends primarily on the patient, the type of cancer, and the tumor location. In many situations, chemotherapy
may be the primary or sole form of treatment in neoplastic disease, especially for certain advanced or inoperable
tumors, or in widely disseminated forms of cancer, such as leukemia or lymphoma. In other situations,
chemotherapy is used in combination with other techniques, such as an adjuvant to surgery and radiation
treatment. Primary examples of adjuvant cancer chemotherapy include using anticancer drugs following a
mastectomy or surgical removal of other carcinomas.
Whether anticancer drugs are used as the primary treatment or as adjuvant therapy, a common general strategy is
upheld. To achieve a total cell kill, all reasonable means of dealing with the cancer must be employed as early as
possible. Cancer is not the type of disease in which a wait-and-see approach can be used. The general strategy is
more aligned with the idea that a barrage of anticancer modalities (i.e., surgery, radiation, and a combination of
several different antineoplastic drugs) may be necessary to achieve a successful outcome. In addition, a
multimodal approach (combining chemotherapy with radiation or using several drugs simultaneously) may
produce a synergistic effect between these modalities. For instance, certain drugs may sensitize cancer cells to
radiation treatment.

SUCCESS OF ANTICANCER DRUGS

 Some forms of cancer (choriocarcinoma, Wilms tumor) can be cured in more than 90 percent of affected
patients.
 In other neoplastic disorders, chemotherapy may not cure the disease but may succeed in mediating
remission and prolonging survival in a large patient percentage.
 Several types of cancer do not respond well to treatment. For example, the majority of metastatic cancers
cannot be cured by current chemotherapeutic methods or by any other type of treatment.

RESISTANCE TO CANCER CHEMOTHERAPY DRUGS

 Cancers can become resistant to drugs through several different mechanisms. One common mechanism
occurs when the cancer cell synthesizes a glycoprotein that acts as a drug efflux pump.
 Cancer cells also use other mechanisms to induce drug resistance, including the production of specific
substances (glutathione, glutathione-S-transferases) that inactivate anticancer drugs within the cancer
cell, or the development of mechanisms that repair DNA that is damaged by anticancer drugs.
  Hence, various strategies are being explored to prevent or overcome multiple-drug resistance during
cancer chemotherapy.
 These strategies include altering the dosage, timing, and sequence of administration of different
medications and using different combinations of medications to combat resistance.

FUTURE PERSPECTIVES
 Several new strategies are being explored to increase the effectiveness and decrease the toxicity of anti-
cancer drugs.
o Use of monoclonal antibodies
o encapsulating the drug in a microsphere or liposome that becomes lodged in the tumor
o Drugs that selectively impair the chemistry or metabolism of cancerous tissues
o Drugs that limit the metabolism and proliferation of cancerous cells
o Drugs that can protect healthy cells from the more traditional anticancer agents
o Finally, important advances have been made in understanding how the body’s immune system
can be recruited to help prevent and treat certain cancers.