Transcript Antineoplastic Agents

ANTINEOPLASTIC AGENTS
Edited by:
Israa Eltayib
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 long-term 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: is a gene that has the potential to cause cancer.
– A proto-oncogene: is a normal gene that regulate cell
growth which can become an oncogene due to mutations or
increased expression
– 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.
Cont.: Etiology of Cancer
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.
Cont.: Etiology of Cancer
• 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.
Cont.: Etiology of Cancer
• 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
Cont.: Etiology of Cancer
• 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.
Cont.: Etiology of Cancer
• 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 Arthritis (B-type lymphoma).
Cont.: Etiology of Cancer
• Radiation:
• 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 inherited by at least one cell division
(initiation).
Pathogenesis of Neoplasia
• This mutation 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,
co- carcinogens, immunosuppressant, which
themselves are non carcinogenic) tumor growth is
promoted (promotion)
Pathogenesis of Neoplasia
• Initiation - point at which an irreversible alteration,
usually genetic, is introduced into a target cell.
• Initiation:
– Is essentially irreversible
– Caused only by carcinogenic compounds
– Occurs rapidly after carcinogen exposure
– Alone does not result in tumor formation
Pathogenesis of Neoplasia
• Promotion is the process whereby an initiated
tissue or organ develop focal proliferations and it
requires the presence of continuous stimulation.
• Promotion
– reversible
– acts only after exposure to an initiating agent
– requires repeated administration of a promoter
– is not carcinogenic in itself
Etiology and Pathogenesis of Neoplasia
Initiation and Promotion
How long does it take to produce a
clinically detectable neoplasm ?
1. 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).
How long does it take to produce a
clinically detectable neoplasm ?
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).
How long does it take to produce a
clinically detectable neoplasm ?
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
– Hodgkin’s 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:
1. Decrease in the amount of drug uptake by cancer cells
E.G. Methotrexate
2. Increase in the amount of drug removed by cancer
cells. (Transporters=P-glycoprotein). E.G. Vinblastine
,doxorubicin, bleomycin ,etapsoid….
3. Decrease or alteration in target molecule sensitivity –
this is caused by mutation in the molecule targeted by
the drug E.G. Methotrexate, Mercaptopurine,
doxorubicin
4. 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 suppression
– 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
1)Stomatitis
2) pain and infection
3)Nausea + vomiting
Hair follicles
Alopecia
Reproductive tract
Irreversible sterility in
males, teratogenic
Platelet infusion
120 days after therapy is
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 needed for DNA synthesis
S Phase:
• To produce two similar daughter cells, the complete DNA
instructions in the cell must be duplicated.
• DNA replication occurs during this S (synthesis) phase.
Gap 2 (G2):
• It is the gap between DNA synthesis and mitosis, the cell
will continue to grow and produce new proteins & RNA.
Mitosis (M Phase):
• Cell growth and protein production stop at this stage in
the cell cycle.
• All of the cell's energy is focused on the complex and
orderly division into two similar daughter cells.
Cancer chemotherapeutic agents
They are classified into:
1. 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.
2. 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.
3. Phase specific: act on specific phase of the cycle. E.g.
Vinca alkaloids act more in M-phase ,antimetabolites
(mainly act on S-phase).
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
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
Alkylating Agents(CCNS)
Subgroups of Alkylating Agents
1)
2)
3)
4)
Nitrogen mustards
Nitrosoureas
Alkyl sulfonates
4-Platinum Coordination Compounds
1-Nitrogen Mustards
• Similar to mustard gas
• 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
• Hodgkin’s Disease
• Non-Hodgkin’s Lymphoma
Toxicity/ Side Effects
• Dose limiting toxicity is bone marrow depression
• Nausea/ Vomiting, Diarrhea, Alopecia, 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
• Hodgkin’s Disease
• Non-Hodgkin’s lymphoma
• Solid tumors of head, neck, ovaries, and breast
• Frequently used in combination with methotrexate (antimetabolite) 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-brain-barrier, 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
• Hodgkin’s disease
• Non-hodgkin’s lymphoma
• Adenocarcinoma of stomach, colon, and rectal
cancer
• Hepatocarcinoma
E.g.:
• Carmustine
• Lomustine
3-Alkyl Sulfonates
• Busulfan
Clinical uses
• Great effect on 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 anti-emetics)
• Ototoxicity and peripheral neuropathy
• VERY SEVER vomiting ( ndanosetron)
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
II-Antimetabolites (CCS
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 (6−mercaptopurine, or 6−MP) :
• 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-MP-ribosephophate 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 protein)
• 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
• 5−FU 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 (responsible 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).
• Non−Hodgkin'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-Mitomycin
• Mitomycin−C 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
– mitomycin−C may cause bone marrow suppression.
– Lung fibrosis may occur. If these lung problems do
occur, corticosteroids may provide effective therapy.
Stopping mitomycin−C 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
non−Hodgkin'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 MAOI………hypertension???)
IV-Plant alkaloids (Phase specific)
1-The vinca alkaloids
Vincristine & vinblastine (M-phase)
Mechanism of action
Tubulinmrof ot sesiremylop hcihw nietorp larutcurts a si
microtubules. The cell cytoskeleton and mitotic spindle, amongst
other things, are made of microtubules. Vincristine nilubut ot sdnib
fo notipursiD .serutcurts elubutorcim fo notiaziremylop gntiibihni
sdiolakla acniv ehT .esahpatem ni sisotim stserra selubutorcim eht
,sllec recnac gnidulcni sepyt llec gnidivid yldipar lla tceffa erofereht
.worram enob dna muilehtipe lantisetni osla tub
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 β 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
(L−asparagine) 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
L−asparagine 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-γ, 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-Gonadotropin−releasing hormone analogues
Goserelin Acetate·
Goserelin acetate is a synthetic hormone that acts
similarly to the naturally occurring
gonadotropin−releasing 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 anti−tumor 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
Immunostimulants
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 body’s immune
system fights disease. Your immune system is
your body’s 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 B−cell, 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(25−30% 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 interleukin−2, IL−2
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
,T−lymphocytes, and fibroblasts in response to infection and other
biological stimuli.
The goal of interferon use is to activate tumor−specific cytotoxic
T−lymphocytes. 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 T−lymphocytes. 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 AIDS−related cancer) as
well as many other cancers
Side effects
muscle aches, unusual metallic taste in the mouth, fever and chills, and
general flu−like symptoms such as headache, loss of appetite (anorexia),
nausea and vomiting, and fatigue. To reduce the flu−like 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
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