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CANCER CHEMOTHERAPY

Cancer treatment : 1. Surgery 2. Radiotherapy


3. Chemotherapy. 4. Endocrine therapy.
5. Immunotherapy. 6. Biological therapy

Chemotherapy is used to describe medications that treat cancer. In order to


understand how these medications work, we need to understand a bit about tumor
cells.
Chemotherapy is considered a "systemic" therapy, meaning that it travels throughout
the body, unlike surgery or radiation, which are "local" therapies. The terms used to
terms to describe when chemotherapy is given in the sequence of treatments:

Adjuvant therapy: therapy given after surgery to reduce the likelihood of the
cancer returning.
Neo-adjuvant therapy: therapy given before surgery to shrink the tumor, allowing
the surgery to be more successful.
Concurrent therapy: when 2 or more therapies are given together, such as
chemotherapy and radiation.

The cell cycle: An understanding of the normal cell cycle and the behavior of malignant
or cancerous cells can help one better understand how chemotherapy works to
destroy cancer cells.

Tumors are made up of cells that are reproducing at abnormally high rates. Normal
cells know to stop reproducing (or dividing) when they come into contact with other
cells. In the case of a tumor, this stop mechanism is missing, causing cells to continue
to divide over and over. The RNA or DNA of a cell tell it how to replicate itself, and
chemotherapy works by destroying this RNA or DNA. The more rapidly the tumor
cells are replicating, the better chemotherapy is able to kill the cells

Cell replication occurs in a series of phases, called the cell cycle . The cell cycle is
the sequence of steps a cell goes through in order to copy its genetic material and
divide into two cells. The cell cycle is divided into four phases: the G 1, S, G 2, and
M phases. A chemotherapy agent may work in only one phase of the cycle (called
cell-cycle specific) or be active in all phases (cell-cycle nonspecific.

The cell cycle phases are: resting (G0; nothing is happening), G1 (or gap 1; a growth
phase), S (synthesis; the replication of DNA occurs), G2 (gap 2; another growth phase),
and M (mitosis; the actual division from 1 cell into 2).

The G 1 phase is the phase most active in protein synthesis. The cellular DNA at this
phase is tightly coiled and is not actively being transcribed (copied). Few chemotherapy
agents are active at this phase of the cell cycle.
The S phase is the synthetic phase of the cell cycle. DNA replication is most active in
this phase and many chemotherapy agents work in this phase.

G 2 represents a time when mostly RNA (and some protein) is actively produced.
Mitosis, or actual cell division, occurs during the M phase.

There are major classes of chemotherapy drugs that are most active during this phase of
the cell cycle. By knowing the phase an agent works in, we can combine agents that
work in different phases to achieve the most tumor killing.

Chemotherapy Administration -The most common routes of administration for


chemotherapy are oral and Intravenous and rarely very few agents are given by
intramuscular route.

More recently, other methods have been used to increase the local concentration of
chemotherapy at the tumor site. Chemotherapy can be administered directly into a
specific cavity (intracavitary), the abdomen (intraperitoneal), the lung (intrapleural), the
central nervous system (intra-thecal), or applied directly to the skin (topical).

Because many chemotherapeutic agents also affect healthy cells and organs, the patient's
laboratory data should be checked before chemotherapy administration, including white
blood cell count, hemoglobin/hematocrit, platelet count, renal function tests, and liver
function tests. In addition, assessment for organ specific drug effects will be performed
on a periodic basis. Abnormalities in any of these values may require dose adjustments or
the delay of therapy. Additionally, pretreatment actions, such as increased intravenous
fluids or administration of anti-nausea medicines may be needed to decrease side effects.
Antineoplastic Drugs

Anticancer drugs stop the cancerous activity of malignant cells


Also called antineoplastic agents and chemotherapeutic agents
Characteristics of malignant cells include rapid cell division and growth, different rates of
cellular drug uptake, and increased cellular response to selected anticancer drugs
Some factors present in malignant cells are also found in normal cells
Rapid cell division and growth occur in cells of the GI tract, bone marrow, reproductive
organs, and hair follicles
Antineoplastic agents are often administered in various protocols known as combination
therapy
Calculation of antineoplastic drug doses is based on body surface area in square meters
Great care must be taken while administering antineoplastic agents IV, to avoid
extravasation and infuse unmedicated IV solution before and after administration
of the drug to ensure that antineoplastic drug residues do not remain on the
equipment

CLASSIFICATION OF ANTINEOPLASTIC AGENTS

1. ALKYLATING AGENTS-( Non cycle specific, act on proliferating cells )


a. Nitrogen mustards- Cyclophosphamide, Melphalan, Chlorambucil,
Mechlorethamine
b. Ethylenimines- Thiotepa
c. Alkylsulphonates-Busulfan , Treosulfan
d. Nitrosoueas- Streptozocin, Carmustine, Lomustine, Semustine
e. Triazines- Dacarbazine

2. ANTIMETABOLITES (active on S phase)


a. Folic acid analogs/antagonists- Methotrexate
b. Pyrimidineanalogs/antagonists-5-Fluorouracil,Cytarabine, Gemicitabine
c. Purine analogs/antagonists- 6-mercaptopurine, Azathioprine,
Thioguanine, Pentostatin

3. NATURAL PRODUCTS ( act on M phase)


a. Antibiotics- Dactinomycin (Actinomycin D), Doxorubicin,
Mitomycin(mitoxantrone), Bleomycin, Daunorubicin
b. Vinca alakaloids- Vinblastine, Vincristine, vinorelbine, vindesine
c. Taxanes- Palcitaxel (Taxol) , Docetaxel
d. Epipodophillotoxins- Etoposide, Teneposide
e. Camptothecins- Topotecan, Irinotecan
f. Enzymes- L Asparaginase
g. Biological response modifiers- Interferons, Interleukin-2, Tumor
necrosis factor, antitumor antibodies(Monoclonal antibodies)

4. HORMONES AND HORMONE ANTAGONISTS


a. Adrenocorticosteroids- Prednisolone, Prednisone, dexamethasone
b. Anti glucocorticoid- Aminoglutethemide
c. Progestins- Hydroxy progesterone, Medroxyprogesterone, Megesterol
acetate
d. Oestrogens- Ethinyl oestradiol, Diethyl stilbesterol(DES)
e. Anti oestrogens- Clomiphene citrate, Tamoxifen, Anastrazole
f. Androgens- Testosterone propionate
g. Anti androgens- Flutamide, Cyproterone acetate, Finasteride
h. GnRH analogs- Goserelin, Leuprolide

5. RADIO ISOTOPES
Iodine-131, Phosphorous-32, Aurus-198

6. MISCELLANEOUS
Cisplatin, Carboplatin, Oxaliplatin(Platinum drugs) Hydroxyurea
Mitotane, Procarbazine

Side/adverse effects of cancer chemotherapy (Antineoplastic agents)

The side effects of chemotherapy are caused by the medication's inability to differentiate
between tumor cells and healthy cells. Chemotherapy kills rapidly dividing cells, and
these are the cells where we see the side effects. Despite this fact, every drug is different
and, while one drug may cause hair loss, another may not, but may cause sores in the
mouth. It is also important to keep in mind that every patient is different and they will
experience different side effects to different degrees.

1. Hair Loss (alopecia) due to effect on hair bulb, reversible few months after
ceasing the cancertreatment
2. Gut epithelium and other mucosal surfaces, gets damaged , Caused by the
destruction of normal, dividing cells of the gastrointestinal (GI) tract , may result
in stomatitis dysphagia (difficulty in swallowing), mouth ulcers.
3. Nausea and Vomiting - can be extremely severe and prolonged,5HT3
antagonists (Ondansetron, granisetron,) antiemetics or dopamine D2 receptor
antagonist antiemetics (Metoclopramide) are used treating / preventing
emesis/vomition (Chemotherapy Induced Nausea and Vomition)
4. Skin Reactions- Skin reactions can range from dry skin and skin redness to
acne.
5. Bone Marrow and lymhoreticular system- Chemotherapy acts on the rapidly
dividing cells in the bone marrow. Red cell, white cell, and platelet production
may be interrupted when chemotherapy is given. As a consequence, the number
of circulating cells in the bloodstream can become reduced over time, resulting in
anemia (decreased red blood cell count), neutropenia (decreased white blood
cell count), and thrombocytpenia (low platelet count).
6. Immunosuppression- depression of both antibdody and cell mediated immunity
leading to opportunistic infections. The white blood cells (WBC's) help the body
to fight infections. When chemotherapy is introduced into the body, it destroys
both the cancer-producing cells and the healthy, infection-fighting cells,
decreasing the body's ability to fight off infection.
7. Delayed wound healing and clotting of blood, bleeding tendency
8. Local cytotoxicity of the drug if extravasation occurs during administration
9. Specific organ damage on long term therapy- liver, kidney, heart
10. Teratogenic and mutagenic damage the germ calls, reproduction resulting in
permanent sterility
11. Carcinogenicity(second malignancy)

ANTINEOPLASTIC / ANTI CANCER DRUGS

ALKYLATING AGENTS - Alkylating agents are the oldest class of anticancer


drugs.

Almost all of these drugs are active or latent nitrogen mustards.


Nitrogen mustards are various poisonous compounds originally developed for
military use.
Alkylating agents all share a common mechanism of action, but differ in their
clinical activity. They work by attacking the negatively charged sites on the DNA
(oxygen, nitrogen, phosphorous and sulfur atoms). By binding to the DNA, steps
(replication, transcription, and base pairing) leading to duplication of the cell's
genetic material are significantly altered.
In addition, alkylation of DNA leads to DNA strand breaks and DNA strand
cross-linking. By altering DNA in this manner, cellular activity is stopped and
the cell dies.
Chemotherapy drugs in this class are active in every phase of the cell cycle. As a
result, this class of anticancer drugs is very powerful and is used in many types of
cancer, including both solid tumors and leukemias.
In general, prolonged use of these drugs will lead decreased sperm production,
cessation of menstruation, and possibly cause permanent infertility.
This class of chemotherapeutics should never be used in the first trimester of
pregnancy as they have been shown to increase fetal malformations. Use in the
second or third trimester does not seem to carry the same risk
. All alkylating agents can cause secondary cancers although not all agents are
equal in their carcinogenic potential. The most common secondary cancer is a
type of leukemia (AML, or Acute Myeloid Leukemia) that can occur years after
therapy with an alkylating agent.

ANTIMETABOLITES - In general, all antimetabolites interfere with normal metabolic


pathways, including those necessary for making new DNA.
The most widely used antifolate in cancer therapy, with activity against
leukemia, lymphoma, breast cancer, head and neck cancer, sarcomas, colon
cancer, bladder cancer and choriocarcinomas, is Methotrexate.
Methotrexate inhibits a crucial enzyme required for DNA synthesis and
therefore exerts its effect on the S phase of the cell cycle.
5-Fluorouracil (5-FU), another widely used antimetabolite, prevents DNA
synthesis by interfering with the nucleotide ( DNA components) production.
It, too, has a wide range of activity including colon cancer, breast cancer,
head and neck cancer, pancreatic cancer, gastric cancer, anal cancer,
esophageal cancer and hepatomas (primary liver tumor).
A unique and interesting aspect of this drug is its toxicity profile. 5-
Fluorouracil is metabolized by a naturally occurring enzyme in the body
called dihydropyrimidine dehydrogenase, or DPD.
There is a small population of people who are deficient of this particular
enzyme. Lacking DPD does not interfere with normal body function and thus
people are not aware that they are lacking it. However, when these patients
are given this chemotherapy drug, they are unable to metabolize it and
therefore get acute and severe toxicities
The most often seen toxicities include bone marrow suppression, severe GI
toxicities, and neurotoxicities which may include seizures and even coma.
Thymidine is the antidote.
Capecitabine is an oral type of 5-Fluorouracil compound that has similar side
effect potentials

ANTITUMOR CYTOTOXIC ANTIBIOTICS

Bleomycin -isolated form the fungus Streptomyces verticullus


Its mechanism of action is similar to that of the anthracyclines, in that free
oxygen radicals are formed that result in DNA breaks leading to cancer cell death.
This drug is rarely used by itself rather in conjunction with other
chemotherapies.
Bleomycin is an active agent in regimens for testicular cancer and Hodgkin's
lymphoma.
The most concerning side effect of this drug is lung toxicities due to oxygen free
radical formation.
Dactinomycin/Actinomycin D induces alkylation of guanine residue on
opposite strands and inhibition of topoisomerase II
Mitomycin is dreduced in cells, act as bifunctional alkylating agent
Anthracyclines
Many of the currently effective anti-cancer drugs are developed from natural
sources.
The drug daunorubicin was isolated from Streptomyces, a soil-dwelling
fungus. Doxorubicin, another anthracycline drug, was isolated from a
mutated strain of the same fungus.
Both of these drugs have a similar mechanism of action, but the latter is
more effective in the treatment of solid tumors.
This class of chemotherapeutics works by the formation of free oxygen
radicals. These radicals result in DNA strand breaks and subsequent
inhibition of DNA synthesis and function.
Anthracyclines also inhibit the enzyme topoisomerase by forming a complex
with the enzyme and DNA. Topoisomerases are a class of enzymes that
serve to unwind the DNA double strand helix to allow for DNA repair,
replication and transcription.
This class of chemotherapeutics is also not cell cycle specific.
The most important side effect of this group of drugs is cardiac toxicity. The
same free radicals that serve to damage the DNA of the cancer cell may
damage the cells of the heart muscle. One has to monitor heart function very
carefully when patients are on these medications.

PLANT ALKALOIDS - Plant alkaloids are a group of chemotherapy agents derived


from plant materials , . They are classified into four groups: topoisomerase inhibitors,
epipodophyllotoxins, taxanes and vinca alkaloids.
Plant alkaloids are cell-cycle specific, but the cycle affected varies from drug to drug.
Camptothecan analogs (also called Topoisomerase I inhibitors) act by forming
a complex with Topoisomerase and DNA resulting in the inhibition and
function of the Topoisomerase enzyme. The presence of Topoisomerase is
required for on-going DNA synthesis.
These drugs are used in many solid and liquid tumors. Unlike other classes of
chemotherapy, the side effects of this class of drugs vary from drug to drug.
Camptothecins include both irinotecan and topotecan. The parent compound of
these agents, first identified in the late 1950's, is a naturally occurring alkaloid
found in the bark and wood of the Chinese tree Camptotheca accuminata, also
called the Happy Tree
Etoposide and Teniposide are epipodophyllotoxin chemotherapy agents (also
called topoisomerase II inhibitors) that work by similar mechanisms. They are
isolated from the May Apple (Podophyllum perlatum)plant and work in the late
S and G 2 phases.
The leave extract of a periwinkle plant, Vinca rosea, killed cells found in
leukemias. Isolation and chemical characterization lead to the currently used
chemotherapy drugs: vincristine, vinblastine, and vinorelbine.
These chemotherapeutics bind to the tubulin and lead to the disruption of the
mitotic spindle apparatus.
The disruption of mitosis implies that these drugs are active specifically during
the M phase of the cell cycle.
They have a wide application to many different malignancies and cause
neurotoxicity as the most prominent and dose limiting side effect
Commonly used to treat TVT in canines
Taxanes -The taxanes include paclitaxel and docetaxel.
specific for the M phase of the cell cycle
They bind with high affinity to the microtubules and inhibit their normal
function. This class of drugs has a broad range of clinical activity including breast
cancer, lung cancer, head and neck cancer, ovarian cancer, bladder cancer,
esophageal cancer, gastric cancer and prostate cancer.
The most common side effect of these drugs is the lowering of the blood counts.
These compounds were first isolated from the bark of the Pacific yew tree Taxus
brevifolia and paclitaxel was identified as the active component

PLATINUMS
Natural metal derivatives were also shown to have some activity in the fight
against cancer. These agents work by cross-linking DNA subunits. (The cross
linking can happen either between two strands or within one strand of DNA .)
The resultant cross-link acts to inhibit DNA synthesis, transcription and function
. The platinum compounds can act in any cell cycle.
Cisplatin is used most often in lung cancer and testicular cancer.
The most significant toxicity of cisplatin is kidney damage.
A second-generation platinum, called carboplatin, has fewer kidney side effects,
and at times may be an appropriate substitute for regiments containing
cisplatinum.
Oxaliplatin is a third-generation platinum that is active in colon cancer and has
no renal (kidney) toxicities, however, it can cause severe neuropathies

ENZYMES
L-asparaginase is an example of an enzyme used in the treatment of
cancer
L-asparaginase works by hydrolyzing asparagines into aspartic acid and
ammonia
Cancer cells need an exogenous source of asparagine for survival; normal
cell can synthesize asparagine
Side effects of L-asparaginase include pain at the injection site,
hypotension, and diarrhea

BIOLOGIC RESPONSE MODIFIERS (BRMS):


used to enhance the bodys immune system; used in conjunction with
antineoplastic protocols
Interferons (alpha, beta, and gamma) are a group of proteins that have
antitumor and antiviral effects; used to treat tumors and viral infections in cats
Colony stimulating factors (CSFs) stimulate the growth, maturation, and
differentiation of bone marrow stem cells; have been used to treat neutropenia
in dogs and cats - An example is filgrastim
Interleukins are a group of chemicals that play various roles in the
immune system and promote the replication of antigen-specific T cells
Acemannan is a potent stimulator of macrophage activity and is used to
treat fibrosarcomas and mast cells in dogs and cats
Monoclonal antibodies have cytotoxic effects on tumor cells and are used
in conjunction with other antineoplastic agents
HORMONES AND HORMONE ANTAGONISTS

a. Adrenocorticosteroids- Prednisolone, Prednisone, dexamethasone


i. Anti-inflammatory action
ii. Antileucucytic action
iii. suppress bone marrow cells, reduce edema, and suppress tumor
growth
b. Progestins- Hydroxy progesterone, Medroxyprogesterone, Megesterol
acetate
For estrogen dependent endometrial cancers

c. Oestrogens- Ethinyl oestradiol, Diethyl stilbesterol(DES)


Oppose action of androgens
In androgen dependent prostatic tumors

d. Anti oestrogens- Clomiphene citrate, Tamoxifen, Anastrazole


Used in estrogen dependent tumors -mammary tumors /breast
cancers
e. Androgens- Testosterone propionate
Used in estrogen dependent tumors
f. Anti androgens- Flutamide, Cyproterone acetat, Finasteride (5 alpha
reductase inhibitor)
Used in BPH- benign prostatic hyperplasia, prostatic tumor,
g. GnRH analogs- Buserelin, Goserelin, Leuprolide
Used in androfen dependent and metastatic prostatic cancer
h. Anti glucocorticoid- Aminoglutethemide, trilostane.
Inhibit the conversion of androgens to estrogens, are used in estrogen
dependent breast cancer

RADIO ISOTOPES


Act by virtue of physical property-radiation, ionizing of cells resulting
in damaged cellular integrity
Iodine-131(131I ) indicated in metastatic thyroid tumors ( radiation)
Phosphorous-32 ( 32P) used in leukaemia, polycythemia vera (
radiation )
Aurus-198( 198Au) used in prostatic, pelvic cancer ( and
radiation)
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IMMUNOSUPPRESSIVE DRUGS
work by interfering with one of the stages of the cell cycle or by affecting cell
messengers
Cyclosporine inhibits the proliferation of T-lymphocytes; used for managing
KCS in dogs and immune-mediated skin disorders
Azathioprine affects cells in the S phase of the cell cycle and also inhibits T- and
B-lymphocytes; used mainly in dogs for immune-mediated disease
Cyclophosphamide interferes with DNA and RNA replication, disrupting
nucleic acid function; has been used for immune-mediated diseases
Tacrolimus a macrolide immunosuppressant, acts like cyclosporine, used
during liver and kidney grafts