Antineoplastic Agents

DR.dr.Asep Sukohar
Dept. of Pharmacology-Medical Faculty UNILA

Antineoplastic Agents
Antineoplastic medications: drugs used to treat cancer, also called
cancer drugs ,cytotoxic agents and anticancer drugs.

Cancer
Along with heart disease, cancer is the largest cause of death in the
developed world
Cancer affects 1 in 3 people and is responsible for 25% of all deaths
Cancer is an unregulated proliferation of cells due to loss of normal
controls, resulting in unregulated growth, lack of differentiation,
local tissue invasion, and, often, metastasis.
Cancer can develop in any tissue or organ at any age. There is often
an immune response to tumor.
Many cancers are curable if detected at an early stage, and longterm remission is often possible in later stages.
Causes of Cancer:
1. 30 % is due to smoking: lung, mouth, pharynx, larynx, esophagus,
urinary bladder, pancreas, and kidney cancers.
2. Lifestyle diet, alcohol consumption, reproductive behavior, sexual
behavior, exposure to sunlight, etc.
3. At least 15% are related to viruses, e.g. cervical cancer caused by
human papillomavirus.

Types of Tumors:
-Benign: non cancerous and not an immediate threat to
life, even though treatment eventually may be required
for health.
-Malignant: tending to worsen and cause death, invasive
and metastasis
Characteristics of cancer cells:
Persistent cell proliferation
Invasive growth
Metastases (a tumor may shed cells into the circulation. Although most

circulating tumor cells die as a result of intravascular trauma, a tiny number adhere
to the vascular endothelium and penetrate into surrounding tissues, generating
independent tumors (metastases) at distant sites.)

Etiology of Cancer
Genetics
Viruses
Occupational and Environmental Carcinogens
Radiation

Cont.: Etiology of Cancer

Genetic mutations are largely responsible for the
generation of malignant cells. Two major categories
of mutated genes are oncogenes and tumor
suppressor genes.
1-Oncogenes are abnormal forms of normal genes
(proto-oncogenes) that regulate cell growth.
Mutation of these genes may result in direct and
continuous stimulation of the molecular biologic
pathways that control cellular growth and division.
For example, the ras gene encodes the Ras protein,
which regulates cell division. Mutations may result
in the inappropriate activation of the Ras protein,
leading to uncontrolled cell growth and division.

2-Tumor suppressor genes are inherent genes that play a role in cell
division and DNA repair and are critical for detecting inappropriate
growth signals in cells. If these genes, as a result of inherited or
acquired mutations, become unable to function, genetic mutations in
other genes can proceed unchecked, leading to neoplastic
transformation.
Another important regulatory protein, p53, prevents replication of
damaged DNA in normal cells and promotes cell death (apoptosis) in
cells with abnormal DNA. Inactive or altered p53 allows cells with
abnormal DNA to survive and divide. The p53 gene is defective in
many human cancers.
Telomeres are nucleoprotein complexes that cap the ends of
chromosomes and maintain their integrity. Telomere shortening occur
with aging .Telomerase is an enzyme that provides for telomere
synthesis and maintenance, thus telomerase may potentially allow for
cellular immortality. Telomerase activity may promote tumors
through multiple, complex mechanisms, especially by subverting the
normal DNA synthetic checkpoints.

Viruses contribute to the pathogenesis of human malignancies through the

integration of viral genetic elements into the host DNA. These new genes are
expressed by the host; they may affect cell growth or division, or disrupt
normal host genes required for control of cell growth and division.
Alternatively, viral infection may result in immune dysfunction, leading to
decreased immune surveillance for early tumors.
E.G. :Epstein-Barr, nasopharyngeal carcinoma -Hepatitis B virus, hepatocellular
carcinoma -HIV Kaposi's sarcoma.
Immune system dysfunction as a result of genetic mutation, acquired disease,
aging, or immunosuppressants interferes with normal immune surveillance of
early tumors and results in higher rates of cancer. Known cancer-associated
immune disorders include : immune deficiency secondary to
immunosuppressants or HIV infection ( Kaposi's sarcoma)& rheumatologic
conditions, such as Rheumatoid Arrhythrities (B-type lymphoma).
Carcinogenesis can result from ionizing radiation and may develop from 2
different mechanisms;
1. Direct ionization damages DNA and other molecules can cause direct
somatic mutations
2. Secondary effectors such as oxygen radicals can be formed by interaction with
ionizing radiation. Oxygen free radicals can damage and kill cells and also
induce mutations.

Pathogenesis of Neoplasia :
Cancer development can begin with a brief exposure (hours or days)
to a chemical into an activated form and the chemical need not be
present ever again.
However, DNA is altered via mutagens including chemical
carcinogens, viruses, and radiation. This mutations is inherted by at
least one cell division (intiation).
This mutation mainly lead to activation of proto-oncogene into
oncogenes (leading to uncontrolled cell proliferation) and/or
inactivation of tumor suppressor genes (leading to resistance to
apoptosis.)
Upon exposure to other epigenetic factors (hormones, cocarcinogens, immunosuppressantwhich themselves are non
carcinogenic) tumor growth is promoted (promotion)

 Initiation - point at which an irreversible

alteration, usually genetic, is introduced into
a target cell.
Initiation:
(1) is essentially irreversible
(2) caused only by carcinogenic compounds
(3) occurs rapidly after carcinogen exposure
(4) alone does not result in tumor formation

 Promotion is the process whereby an

initiated tissue or organ develop focal
proliferations and it requires the presence
of continuous stimulation.
Promotion
(1) reversible
(2) acts only after exposure to an initiating
agent
(3) requires repeated administration of a
promoter
(4) is not carcinogenic in itself

How long does it take to produce a clinically

detectable neoplasm ?
1. It can be readily calculated tat it takes at least 30 population doublings to
produce 10 9 cells (about 1 gram in weight) from a single, initial transformed cell. It
then takes only about 10 population doublings to produce a neoplasm of 10 12 cells
(weight about 1 Kg, which is the maximal size compatible with life).
2. By the time a solid neoplasm is clinically detected, it has already completed
a major portion of its life cycle (The latent period before which a neoplasm becomes
clinically detectable is quite unpredictably long, usually years).
3. The rate of growth of a neoplasm is determined by the proportion of cells
in the growth fraction and the degree of imbalance between cell proliferation and cell
loss. In the submicroscopic phases of neoplastic growth most cells are in the
proliferative pool (growth fraction). By the time a neoplasm is clinically detectable
most cells in a neoplasm are not in the growth fraction.
4. The growth fraction of neoplastic cells has a profound effect on their
susceptibility to cancer chemotherapy.

There are three basic treatment possibilities for

cancer: surgery, radiotherapy, and
chemotherapy.
Some cancers where chemotherapy works very well:
Childhood leukemia
Retinoblastoma
Osteosarcoma
Testicular cancer
Hodgkins Disease
Some lymphomas
Some early breast cancers
Cancers that are very difficult to treat with chemotherapeutics (need
surgery or radiotherapy first):
Colon
Lung
Late stage breast cancer
Pancreatic cancer

(WHY???).

Problems associated with chemotherapy

1-Resistance to chemotherapy
Resistance to chemotherapy may develop by several
mechanisms:
Decrease in the amount of drug uptake by cancer cells
E.G. Methotrexate
Increase in the amount of drug removed by cancer cells.
(Transporters=P-glycoprotein).
E.G. Vinblastine ,doxorubicin, bleomycin ,etapsoid.
Decrease or alteration in target molecule sensitivity this is
caused by mutation in the molecule targeted by the drug
E.G. Methotrexate,Mercaptopurine,doxorubicin
Increase in DNA repair ability of the cell via an increased
expression of DNA repairing enzymes.
E.G. Alkylating agent

2-Toxicity and side Effects of Antineoplastic Agents:

Normal cells in the body that tend to be

injured the most due to chemotherapy are
those which have a high growth fraction.
Those are bone marrow, GI Tract ,hair
follicles, reproductive organs .Leading to the
followings:
Alopecia- hair loss
Myelosuppression-bone marrow loss
Emetic potential: disruptive to cells in stomach which
causes: Nausea/vomiting
Low WBC count- low immunity

Treatment of Chemotherapy Toxicity

:Injury to

:Results in

:Time Course

Treatment of this
:side effect

:Other

Bone marrow:
Decreased
Neutrophils

Infection

Begins 10-14 days after tmt

initiation. Takes 3-4 wks
.for recovery

Give colony
stimulating factors
(CSFs)

Bone marrow:
Decreased
Platelets

Bleeding,
especially from
nose and gums

Bone marrow:
Decreased
Erythrocytes

Anemia

GI tract

Stomatitis(1
pain and (2
infection
3)Nausea +
vomiting

Hair follicles

Alopecia

Reproductive
tract

Irreversible
sterility in
males,
teratogenic

Platelet infusion

days after therapy is 120

imitated. By this time
therapy has usually stopped,
.so this is a rare effect

erythropoetin

Begins a few days after tmt

initiation and lasts until two
weeks after termination of
. tmt

Treat stomatitis with

anesthetics and
antifungal. Treat
nausea with antiemetics like
ondansetron

Begins 7 10 days after

initiation of tmt and
continues until 1 2
.months post tmt

reversable

You can also use

glucocorticoids&
lorazepam to reduce
.the inflammation

3-Treatment-induced tumor

Many anticancer drugs are mutagens and

can cause the rise of neoplasm ten or
more years after the original cancer was
cured.

Cell cycle
Scientists have determined that
cell cycle can be divided into:.
Gap 0 (G0): There are times when
a cell will leave the cycle and
quit dividing. This may be a
temporary resting period or
more permanent. An example
of the latter is a cell that has
reached an end stage of
development and will no
longer divide (e.g. neuron).
Gap 1 (G1): Cells increase in size
in Gap 1, produce enzymes
Mitosis or M Phase: Cell growth
needed for DNA synthesis
and protein production stop at
S Phase: To produce two similar
daughter cells, the complete
this stage in the cell cycle. All of
DNA instructions in the cell
the cell's energy is focused on
must be duplicated. DNA
the complex and orderly
replication occurs during this
division into two similar
S (synthesis) phase.
daughter cells.
Gap 2 (G2): It is the gap between
DNA synthesis and mitosis, the
cell will continue to grow and
produce new proteins & RNA.

Siklus sel,Peran cyclin dan Cdk82

Dipiro

Cancer chemotherapeutic
agents
They are classified into:
Cell-cycle non specific agents(CCNS): are cytotoxic in any phase
of the cycle even on G0 phase and so are more effective against
large slowly growing tumors.
E.G.Bleomycin.

Cell-cycle specific (CCS): are cytotoxic on all phases but not on

cells out of the cycle(at G0 ) and so are more effective against
rapidly growing tumors. Work better in combination than alone
E.G. Mitomycin, doxorubicin,.etc.

Phase specific : act on specific phase of the cycle

E.G.Vinca alkaloids act more in M-phase ,antimetabolites (mainly act on Sphase.)

Anticancer Drugs
There are three Major Groups of Anticancer Drugs:
1) Cytotoxic Drugs (largest group)
-Alkylating agents
-Antimetabolites
-Antitumor antibiotics
-Plant alkaloids
-Miscellaneous cytotoxic drugs
2) Hormones and hormone antagonists
These are among the best-tolerated chemotherapeutics because
they target specific receptors, and thus only specific cell types e.g.
Tamoxifen
3) Immunomodulators
-Immunostimulants, including interferons and interleukins
-Immunosuppressant

1-Cytotoxic

Drugs

I-Alkylating Agents (CCNS)

Mechanism of Alkylating Agents
These drugs work by alkylation with nucleophilic substitution . They
alkylate a variety of cellular constituents, such as cell membranes,
proteins, and most importantly DNA. More specifically, the nitrogenous
bases of DNA are what get alkylated.
The drugs start off as pro-drugs that become activated when a chlorine
atom is extracted. A carbonium ion is thus formed. This carbonium ion
is very electrophilic and will then attack any free pair of electrons (i.e. on
the N7 of guanine). This electrophilic attack results in a bond being
formed between the drug and the guanine of DNA. As a result of this
alkylation, there are a few consequences:
1) Miscoding (In transcription)
2) Cross linking- this only occurs if the drug is bifunctional

The net result is cancer cell undergo apoptosis.

Alkylating Agents(CCNS)

Subgroups of Alkylating Agents

1)
2)
3)
4)

Nitrogen mustards
Nitrosoureas
Alkyl sulfonates
4-Platinum Coordination Compounds

1-Nitrogen Mustards
E.G.: Mechlorethamine, cyclophosphamid, melphalan & chlorambucil
a-Mechlorethamine
- first alkylating agent employed clinically
- bifunctional, thus can crosslink DNA
- extremely unstable and is inactivated within a few minutes following administration.
Thus it is given IV.
Clinical Uses
-Hodgkins Disease
-Non-Hodgkins Lymphoma
Toxicity/ Side Effects
- Dose limiting toxicity is bone marrow depression
- Nausea/ Vomiting
- Alopecia
- Diarrhea
- Sterility

b-Cyclophsphamid
-It acts as cytotoxic and immunosuppressor agent.
- Prodrug which must be activated by the cytochrome p450 system, which turns
it into a nitrogen mustard.
- bifunctional agent
-most widely used alkylating agent
Clinical Uses
- Hodgkins Disease
- Non-Hodgkins lymphoma
- Solid tumors of head, neck, ovaries, and breast
- frequently used in combination with methotrexate (anti-metabolite) or
doxorubicin (anti-tumor antibiotic), or fluorouracil as adjuvant therapy post
breast cancer surgery
- Organ transplant recipients (due to immunosuppressive actions)
Toxicity/ Side Effects
- bone marrow depression
- severe nausea and vomiting
- acute hemorrhagic cystitis and renal damage???? (can be minimized via
high fluid intake/infusion and the use of?)
- sterility
- hypersensitivity reactions

Treatment of cyclophsphamid toxicity

2-Nitrosoureas
- bifunctional
- active against broad spectrum of neoplastic disease
- inhibits synthesis of both DNA and RNA, as well as proteins
- These drugs are highly lipophilic, so they can easily cross blood-brainbarrier, and are great for CNS tumors.
- Big problem in this class is that they are highly mutagenic and highly
carcinogenic.
- Major toxicity is DELAYED bone marrow depression & Pulmonary
fibrosis.
Clinical uses
- primary and metastasis tumors of the brain
- Hodgkins Disease
- Non-Hodgkins lymphoma
- Adenocarcinoma of stomach, colon, and rectal cancer
- Hepatocarcinoma
E.G.:
a-Carmustine
b-Lomustine

3-Alkyl Sulfonates
Busulfan
Clinical uses
Great effect on for Chronic granulocytic Leukemia
Toxicity/ Side Effects
- Dose limiting toxicity is bone marrow depression.
- Pulmonary infiltrates and pulmonary fibrosis
- Tonic-clonic seizures in epileptics
- Nausea and vomiting
- Alopecia
- Sterility
- Skin hyper pigmentation
- Cataracts
- Hepatitis

4-Platinum Coordination Compounds

E.G.:
Cisplatin
forms crosslinks within DNA strands. Cis-platin is not really an alkylating
agent, but since it operates via the same mechanism as the alkylating agents,
it is placed within that group.
Clinical Uses
- Very powerful against TESTICULAR CANCER
- Also good for carcinomas of ovary, bladder, head, and neck
Toxicity/ Side Effects
- Renal tubular damage (minimized via massive hydration coupled with antiemetics)
- Ototoxicity and peripheral neuropathy
- VERY SEVER vomiting( Ondanosetron?)

Carboplatin:
is a derivative of cisplatin with less nephero- ,neuro- & ototoxicity.

II-Antimetabolites (CCS)
An antimetabolite is a chemical with a similar structure to a
metabolite required for normal biochemical reactions, yet different
enough to interfere with the normal functions of cells, including cell
division.
All antimetabolites are used in cancer treatment, as they interfere
with DNA production and therefore cell division and the growth of
tumors (mainly in S-phase specific).
They are classified into:
1- Folic acid analogues
2- Purine analogues
3- Pyrimidine analogues
Purin and pyrimidine antagonists are phosphorelated inside the
body into nucleotid form in order to be cytotoxic

Uses
leukemia.
non-Hodgkin's lymphoma
inflammatory bowel disease such as Crohn's Disease and ulcerative
colitis
It is widely used as immunosuppressant in transplantations to
control rejection reactions.

1-Folic acid analogues

Methotrexate:
-A folic acid analogue, prevents the formation of
tetrahydrofolate, essential for purine and pyrimidine
synthesis, by inhibiting dihydrofolate reductase. This
leads to inhibition of production of DNA, RNA and
proteins (as tetrahydrofolate is also involved in the
synthesis of amino acids as serine and methionine).
It is actively taken up into the cells by the same
transport system for folate (resistance..?)
The most common toxicity is nepherotoxicity (pptn of
the drug in renal tubule.)

Cont: Folic acid analogues

1-Methotrexate compete with folic acid for DHFR and inhibits it . Therefore, it inhibits the
synthesis of DNA, RNA and proteins.
2-Also,DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolat which is
needed for the de novo synthesis of the deoxynucleoside thymidine phosphate DTMP
( required for DNA synthesis)

2-Purine analogues
Mercaptopurine (6mercaptopurine, or 6MP) :
-It is immunosuppressive cytotoxic substance. It is widely used in
transplantations to control rejection reactions.
-It is acts as a purine analogue and once enter the cell, it is converted to 6-MPribosephophate and can be incorporated into RNA&DNA resulting in non
functioning RNA & DNA &finally inducing cell cycle arrest and apoptosis.
-It also inhibits purring ring biosynthesis
Adverse reactions
Diarrhea, nausea, vomiting, loss of appetite,
Allergic reaction include rash, itching, swelling, dizziness, trouble breathing.
Mercaptopurine cause myelosuppression. Those taking mercaptopurine
should get permission from a doctor in order to receive immunizations and
vaccinations.

Azathioprine:
It is one of the main immunosuppressive cytotoxic substance. It is widely
used in transplantations to control rejection reactions. It is nonenzymatically
cleaved to 6 - M P that acts as a purine analogue and inhibits DNA synthesis

3-Pyrimidine analogues
5-flurouracil (5-FU)
It act as a uracil analogue, it is transformed inside the cell into 5-FU
deoxynucleotide which compete with deoxyuridine monophosphate DUMP
for thymidylate synthase leading to inhibition of deoxythymidine
monophosphate DTMP synthesis
inhibition of DNA synthesis (Not

RNA or protien)

Also it is incorporated into DNA

non functioning DNA .
finally inducing cell cycle arrest and apoptosis by inhibiting the cell's
ability to synthesize DNA.
It is an S-phase specific drug
5FU may be used in combination with other chemotherapy agents to treat
cancers of the breast, stomach,colon, rectum, and pancreas.
Side effect
1- Most unwanted effect is GIT epithelial damage, diarrhea and mouth ulcers.
2-the most dangerous side effect is bone marrow suppression

Cytarabine
It is analogue to 2-deoxycytidine and in the body it is converted into
cytosine triphosphate and inhibit DNA polymerase thus inhibiting DNA
synthesis.

5-flurouracil (5-FU)

Cytarabine

III-Antitumor antibiotics (CCNS) :

1-Dactinomycin
is isolated from soil bacteria of the genus Streptomyces.
It was the first antibiotic shown to have anti-cancer activity and used
in treatment of a variety of cancers.
It inhibits transcription by binding to DNA at the transcription
initiation complex and preventing elongation by RNA polymerase.
As it can bind DNA duplexes, it can also interfere with DNA
replication

2-Doxorubicin (adriamycin)
Mechanism of action
Doxorubicin is anthracyclin antibiotic interferes with the cells'
production of DNA and RNA by inserting itself between adjacent
base pair causing local uncoiling thus blocking DNA and RNA
synthesis.
Also its antitumor effect is related to its inhibition of topoisomerase
II enzyme (responsipole for DNA repair).
CYTP 450 catalyzes the conversion of Dox. into semiquinone free
radicals which produce superoxide ion & H2O2 that mediate single
strand scission in DNA

Uses
Multiple cancers including breast, bone, ovarian & leukemia.
Acute lymphocytic leukemia (ALL).
NonHodgkin's lymphoma
Side effects
A major problem with the use of doxorubicin is that it cause
irreversible heart problems specially heart failure .(why?)
Hypersensitivity, myelosuppression
Nausea, vomiting & diarrhea
Urine and tears may take on a red color.

3-MitomycinC
MitomycinC is an antitumor antibiotic. Mechanistically however, it
belongs to DNA alkylating agents.
Upon bioactivation inside the cell ,it preferentially alkylates O6 of
guanine base in DNA leading to cross linking of DNA.
It also degrade DNA through formation of free radicals.
Side effects
-mitomycinC may cause bone marrow suppression.
-Lung fibrosis may occur. If these lung problems do occur,
corticosteroids may provide effective therapy. Stopping
mitomycinC therapy may also be recommended.

4-Bleomycin
It is cytotoxic in any phase of the cycle even on G0 phase
Bleomycin degrade performed DNA causing chain fragmentation
and release of free bases through the formation of free radicals
(superoxide and hydroxyl radicals).
Uses
-Bleomycin is used in the treatment of a number of different cancers,
including cancer of the head and neck, skin, esophagus, lung, testis,
and genitourinary tract.
-In addition, it is used in the treatment of Hodgkin's disease and
nonHodgkin's lymphomas.
Side effects
Pulmonary fibrosis
Raynaud's phenomenon (which affects the fingers and toes, may
involve pain, pale color, and abnormal sensation as burning)
In addition, headache, and nausea and vomiting may occur.

5-Procarbazine
Procarbazine is an anticancer agent inhibits DNA and RNA synthesis
in cells
interfering with mitosis.
Uses
Procarbazine is used in the treatment of various cancers, although
the best established usage is with Hodgkin's disease.
Other cancers in which procarbazine is sometimes used include
lymphomas, brain tumors, skin cancer, lung cancer, and multiple
myeloma.
Side effects
it decreases the white blood cells and the platelet cells.
The most severe side effect is nausea and vomiting.
There may be neurological side effects such as confusion,
sleepiness, depression, nightmares, agitation, and nervousness (it
is weak MAOIhypertension???)

IV-Plant alkaloids (Phase specific)

1-The vinca alkaloids
Vincristine & vinblastine (M-phase)
Mechanism of action
Tubulin is a structural protein which polymerises to form microtubules. The
cell cytoskeleton and mitotic spindle, amongst other things, are made of
microtubules. Vincristine binds to tubulin inhibiting polymerization of
microtubule structures. Disruption of the microtubules arrests mitosis in
metaphase. The vinca alkaloids therefore affect all rapidly dividing cell types
including cancer cells, but also intestinal epithelium and bone marrow.
Side effects
The main side-effects of vincristine are peripheral neuropathy. Accidental
injection of vinca alkaloids into the spinal canal (intrathecal administration) is
highly dangerous, with a mortality rate approaching 100%. (vinblastin is less
neurotoxic)
Uses
Non Hodgkin's& Hodgkin's disease, malignant lymphomas and leukemia.

2-Taxanes
Paclitaxel & docetaxel
it is used for treatment of lung, ovarian and breast cancer.
Mechanism of action
paclitaxel hyper-stabilizes microtubule structure (freez
them). Paclitaxel binds to the subunit of tubulin ,the
resulting microtubule/paclitaxel complex does not have the
ability to disassemble. This adversely affects cell function
because the shortening and lengthening of microtubules is
necessary for their function.
Further research has indicated that paclitaxel induces
programmed cell death (apoptosis) in cancer cells by binding
to an apoptosis stopping protein called Bcl-2 (B-cell leukemia
2) and thus arresting its function.
Side effects
Bone marrow suppression and neurotoxicity

3-Etoposide
Chemically it is deriven from podophyllotoxin, a toxin found
in the mandrake root.
An inhibitor of the enzyme topoisomerase II. cause breaks in
the DNA inside the cancer cells and prevent them from
further dividing and multiplying. Then the cells die.
Side effect
Vomiting & alopecia
Bone marrow suppression
uses
It has been useful for treatment of testicular cancer and
small cell lung cancer.

V-Miscellaneous cytotoxic drugs

1-Crisantaspase
It is a preparation of asparaginase which kills cancer cells by breaking
down certain protein (Lasparagine) that is necessary for survival and
growth of certain tumors incapable of forming such protein e.g. acute
lymphoblastic leukemia ALL.
Fortunately, normal cells are not dependent on Lasparagine for survival.
Asparaginase is mainly given in combination with vincristine and steroids
(either prednisone or dexamethasone).

2-Mitotan
effective in the treatment of adrenocortical carcinoma.
As a chemical, mitotane resembles the insecticides DDD and DDT,
although mitotane does not harm people as these do. Scientists do not
understand why, but the drug causes damage to the adrenocortex in such
a way as to be helpful for some patients with adrenocortical tumors. In
addition, mitotane restricts the ability of the gland to produce steroids.

2- Hormones and hormone

antagonists

1-Corticosteroids
Corticosteroids have broad use in cancer treatment. Some are used to treat
adult leukemias, adult lymphomas, and acute childhood leukemia.
Immunosuppressive mechanism
Glucocorticoids suppress the cell-mediated immunity. They act by inhibiting
genes that code for the cytokines interlukin and TNF-, the most important of
which is the IL-2. The inhibition of cytokine production reduces the T cell
proliferation.
Glucocorticoids also suppress the expansion and antibody synthesis.
Side effects
Hyperglycemia due to increased gluconeogenesis, insulin resistance caution
in those with diabetes mellitus
reduced bone density (osteoporosis, higher fracture risk, slower fracture
repair)
weight gain due to increased visceral and truncal fat deposition (central
obesity) and appetite stimulation
adrenal insufficiency (if used for long time and stopped suddenly without a
taper)
muscle breakdown (proteolysis), weakness; reduced muscle mass and repair
growth failure, pubertal delay
Increased urea formation; negative nitrogen balance
The most common corticosteroids used in cancer treatment are:
dexamethasone (Decadron)
hydrocortisone
methylprednisolone (Medrol)

2-Estrogens & Progestons

Mainly used in androgen dependent prostatic tumors

3-Gonadotropinreleasing hormone analogues

Goserelin Acetate
Goserelin acetate is a synthetic hormone that acts similarly to the
naturally occurring gonadotropinreleasing hormone (GnRH). In men, this
results in decreased blood levels of the male hormone testosterone. In
women, it decreases blood levels of the female hormone estrogen.
It is used for treatment of breast and prostatic cancer
Side effects
sweating ,hot flashes, impotence (erectile dysfunction),sterility &
gyncomestia
depression or other mood changes
Other common side effects in women include: light, irregular, vaginal
bleeding & no menstrual period

Hormone antagonists
Tamoxifen
Tamoxifen selectively inhibits the effects of estrogen on breast tissue, while
selectively mimicking the effects of estrogen on bone (by increasing bone
mineral density) and uterine tissues. These qualities make tamoxifen an
excellent therapeutic agent against breast cancer. it is known to compete
with estrogen by binding to estrogen receptors on the membrane of target
cells, thus limiting the effects of estrogen on breast tissue.
Tamoxifen may also has other antitumor activities :affecting oncogene
expression& promotion of apoptosis (cancer cell death)
Adverse Effects
CNS: Depression, light headedness, dizziness, headache, decreased visual
acuity &retinopathy
GI: Nausea, vomiting
Hematological: Hypercalcemia
GU: Vaginal bleeding, vaginal discharge & menstrual irregularities
Dermatologic: Hot flashes, skin rash

3-Immunomodulators

Immune system and cancer

The immune system serves as one of the
primary defenses against cancer. When normal
tissue becomes a tumor or cancerous tissue,
new antigens develop on their surface. These
antigens send a signal to immune cells such as
the T lymphocytes and macrophages, which in
turn directly kill the tumor cells or release
substances like cytokines that may bring about
tumor cell death.

Immunomodulators

Immunosuppressant

a-Immunosuppressant
1 Glucocorticoids
2 Cytotoxic
a- Alkylating agents
b- Antimetabolites
1 Methotrexate
2.Azathioprine and Mercaptopurine

3. Drugs acting on immunophilins

1 Cyclosporin
2. Sirolimus

Drugs acting on immunophilins

Cyclosporin
is a calcineurin inhibitor. is one of the most widely used immunosuppressive
drugs. It is a fungal peptide, composed of 11 amino acids.
Cyclosporin is thought to bind to the cytosolic protein cyclophilin (an
immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes.
This complex of cyclosporin and cyclophilin inhibits calcineurin, which under
normal circumstances induces the transcription of interleukin-2. The drug
also inhibits lymphokine production and interleukin release, leading to a
reduced function of effector T-cells.
Cyclosporin is used in the treatment of acute rejection reactions, but has
been increasingly substituted with newer immunosuppressants, as it is
nephrotoxic.
Sirolimus
Sirolimus is a macrolide lactone, produced by the Streptomyce
hygroscopicus It is used to prevent rejection reactions. Although it is a
structural analogue of tacrolimus, it acts somewhat differently and has
different side effects.
Contrary to cyclosporine that affect the first phase of the T lymphocyte
activation, sirolimus affects the second one, namely the signal transduction
and their clonal proliferation. Therefore, sirolimus acts synergistically with
cyclosporine and, in combination with other immunosuppressants, has few
side effects. Indirectly it inhibits several T lympohocyte kinases and
phosphatases, preventing the transmission of signal into their activity and
the transition of the cell cycle from G1 to S phase. Similarly, it prevents the B
cell differentiation to the plasma cells, which lowers the quantity of IgM, IgG
and IgA antibodies produced. It acts immunoregulatory.

b-Immunostimulants
Biologic therapy, also called immunostimulants,
is a treatment that uses drugs to improve the
way your bodys immune system fights disease.
Your immune system is your bodys natural
defense against disease. A healthy and strong
immune system can detect the difference
between healthy cells and cancer cells. Biologic
therapy attempts to stimulate, or enhance the
immune system so that it can fight the cancer

1-Monoclonal Antibodies
Monoclonal antibodies are proteins produced in the laboratory from a
single clone of a Bcell, the type of cells of the immune system that
make antibodies. When used as a treatment for cancer, there are
three general strategies with monoclonal antibodies:
One uses the ability of the antibodies to bind to the cancer cells
having the tumor antigens on their surface. The immune system will
see the cancer cells marked with bound antibodies as foreign and
destroy them.
A second strategy is to use the antibodies to block the binding of
cytokines or other proteins that are needed by the cancerous cells
to maintain their uncontrolled growth. Monoclonal antibodies
designed to work like this bind to the cytokine receptors that are on
the tumor cell surface.
A final strategy involves special antibodies that are linked
(conjugated) to a substance that is deadly to the cancer cells. E.G.
radioactive isotopes, have been successfully conjugated to
antibodies. The antibodies are then used to specifically destroy he
tumor cells with the radioactivity or toxic substance.
Trastuzumab
Trastuzumab is a humanized monoclonal antibody produced by
recombinant DNA technology that binds specifically to the human
epidermal growth factor receptor 2 protein (also known as HER2)
that is found on the cell surface of some cancer tumors, most
notably breast cancer(2530% of breast malignancies) and also
targets it for destruction by the natural killer cells of immune
system.

2-Biological response modifiers

Researchers have been working on stimulating
the immune cells during cancer with
substances broadly classified as biological
response modifiers. Cytokines are one such
substance. These are proteins that are
predominantly released by immune cells upon
activation or stimulation.

Aldesleukin
Aldesleukin is interleukin, that is used to treat metastasis renal cell
carcinoma (a form of kidney cancer) and metastasis melanoma. Aldesleukin
is also known as interleukin2, IL2
When renal cell carcinoma and metastasis melanoma (cancer of the skin that
arises in the pigmented cells of the skin or eyes) do not respond to other
therapies, they are candidates for treatment with aldesleukin.
Aldesleukin is a biological response modifier (BRM). It promotes the
development of T cells, or the cells in the lymphatic system that can fight
cancer cells.

Side effect
Flu-like symptoms (chills, fever, fatigue)
Loss of appetite
Skin problems such as a rash, itchiness, scaling
Cardiac arrhythmias
Gastrointestinal disturbance, such as nausea and vomiting
Neurological effects, such as depression and poor concentration

Interferons
Interferons are small, natural cytokines that are produced by leucocytes
,Tlymphocytes, and fibroblasts in response to infection and other
biological stimuli.
The goal of interferon use is to activate tumorspecific cytotoxic
Tlymphocytes. Thus, tumor cells would be destroyed based on
immunotherapy.
Interferons attach to special receptors on the surface of cell membranes.
Then produce variety of functions including enhancing or inhibiting
enzymes, decreasing cell proliferation, or enhancing the activity of
macrophages and Tlymphocytes. There are several different classes of
interferons, cancer therapy primarily focuses on alpha interferons.
Alpha interferons are used to treat cancers such as hairy cell leukemia,
malignant melanoma, and Kaposi's sarcoma (an AIDSrelated cancer) as
well as many other cancers
Side effects
muscle aches, unusual metallic taste in the mouth, fever and chills, and
general flulike symptoms such as headache, loss of appetite (anorexia),
nausea and vomiting, and fatigue. To reduce the flulike symptoms
physicians may suggest that the patient take acetaminophen before each
dosage.
confusion, trouble thinking and focusing, mental depression, nervousness,
or numbness or tingling of fingers,

Levamisole
Levamisole act to restore depressed immune function.
It increases the response of T cells, or cells belonging to the
lymphatic system that can fight cancer cells. It also seems to
increase the activity of cells that attack and destroy invading
cancer cells, including both monocytes and macrophages.

Side Effects
Allergic reaction.
Decreased bone marrow function, resulting in fatigue
or signs of infection
Problems related to the nervous system, such as
confusion, loss of consciousness, or speech
disturbances

3-Angiogenesis inhibitors
Angiogenesis is the normal process by which the
human body forms new blood vessels.
Angiogenesis is important in the development of
cancer because tumors require blood vessels to
grow and spread to nearby tissue. Once a tumor
reaches a certain size it needs to develop a
blood supply in order to grow. Cancer cells will
secrete certain chemicals to promote
angiogenesis. Angiogenesis inhibitors are drugs
that can stop this process. These antiangiogenesis agents are being investigated as
potential cancer therapies.

Thalidomide
Thalidomide interferes with the growth of rapidly dividing cells.It interferes
with the formation of blood vessels. It is called an antiangiogenic drug
It is used to treat several types of cancers, including kidney, ovarian, and
breast cancer.
Side effects :

Orthostatic hypotension
Thalidomide may cause peripheral neuropathy (numbness, tingling, pain,
or burning sensations in the feet or hands).
Thalidomide may cause severe birth defects or fetal death if taken by
pregnant women (phocomelia).
Rash
Lack of bowel movements