Download Anti-cancer agent

Anticancer Drugs
• Cancer
• Uncontrolled multiplication and spread within the body of abnormal forms of
body's own cells
Cancer chemotherapy not as successful as
antimicrobial chemotherapy
• Metabolism in parasite differs qualitatively from host cells, while
metabolism in cancer cells differ only quantitatively from normal host
cells
• Hence target selectivity is more difficult in cancer
• cancer there is no substantial immune response
• Diagnostic complexity: delay in institution of treatment
Cancer cells differ from normal cells by
• Uncontrolled proliferation
• De-differentiation & loss of function
• Invasiveness
• Metastasis
General toxicity of cytotoxic drugs
• Nausea & Vomiting
• Bone marrow depression
• Alopecia
• Gonads: Oligospermia,
impotence, ↓ ovulation
• Foetus: Abortion, foetal death, teratogenicity
• Carcinogenicity
• Hyperuricemia
• Immunosupression:
• Hazards to staff
Fludarabine
Phases of cell cycle
Modalities of treatment in cancer
1/3 of patients can be cured, effective
• Surgery
when tumor has not metastasized
• Radiotherapy
• Chemotherapy: 50 % of the patients can be treated with
chemotherapy contributing to cure in 15 -20 % of patients
CLASSIFICATION - II:
Depending on mechanism at cell level
• Directly acting cytotoxic drugs:
• Alkylating agents
• Antimetabolites
• Natural products
• Antibiotics
• Vinca alkaloids
• Taxanes
• Epipodophyllotoxins
• Camptothecin analogs
• Enzymes
• Biological response
modifiers
• Miscellaneous: Cisplatin, carboplatin
• Indirectly acting- by
altering the hormonal
mileau :
•
•
•
•
•
Corticosteroids
Estrogens & ERMs
5 alpha reductase inhibitors
Gnrh agonists
Progestins
Alkylating agents
• Nitrogen Mustards
• Meclorethamine, Melphalan, Chlorambucil, cyclophosphamide, ifosfamide
• Ethyleneimine : Thiotepa
• Alkyl Sulfonate: Busulfan
• Nitrosureas
• Carmustine,lomustine, streptozocin
• Triazines
• Dacarbazine, temozolamide
Antimetabolites
• Folate Antagonists
• Methotrexate
• Purine Antagonists
• 6 Mercaptopurine, 6 Thioguanine, Azathioprine
• Pyrimidine antagonists
• 5 Fluorouracil, cytarabine, gemcitabine
Natural Products
• Antibiotics
• Actinomycin D,
Doxorubicin, Daunorubicin,
Bleomycin, Mitomycin C
• Vinca alkaloids
• Vincristine, Vinblastine,
Vinorelbine
• Taxanes
• Paclitaxel, docetaxel
• Enzymes
• L-Asparginase
• Epipodophyllotoxins
– etoposide,
tenoposide
• Camptothecin
analogs
– Topotecan, irinotecan
• Biological response
modifiers
– Interferons,
– Interleukins
Miscellaneous Agents
• Cisplatin
• Carboplatin
• Hydroxurea
• Procarbazine
• Mitotane
• Imatinib
Hormones & antagonists
• Corticosteroids
• Prednisolone
• Estrogens
• Ethinyl Estradiol
• SERM
• Tamoxifene, Toremifene
• SERD
• Fulvestrant
• Aromatase Inhibitors
• Letrozole, Anastrazole,
Exemestane
• Progestins
– Hydroxyprogesterone
• Anti-androgens
– Flutamide,
Bicalutamide
• 5- reductase
Inhibitors
– finasteride,
dutasteride
• GnRH analogs
– Naferelin, goserelin,
leuoprolide
ALKYLATING AGENTS
•Chemically reactive compounds that
combine most readily with nucleophilic
centers.
• The term ‘alkylating agents’ is applied to
compounds which, in a sense, alkylate the
substance with which they react, by joining
it through a covalent bond.
Types of Alkylating agents
Category
Drugs
Nitrogen mustards
Ethyleneimine
Cyclophosphamide,
Mechlorethamine,
Chlorambucil,
Ifosamide, Melphalan
Thiotepa
Alkyl sulfonate
Busulfan
Nitrosoureas
Carmustine, Lomustine
Triazine
Dacarbazine,
temozolamide
MECHANISM OF ACTION
Alkylating Agents
Form highly reactive carbonium ion
Transfer alkyl groups to nucleophilic sites on DNA bases
Results in
Cross linkage
Abnormal base pairing
Alkylation also damages RNA
and proteins
DNA strand breakage
↓ cell proliferation
MECHANISM OF ACTION
• Contain chemical groups that can form covalent bonds
with particular nucleophilic substances in the cell.
• Produce highly reactive carbonium ion intermediates.
• Forms covalent bond with electron donors like amine,
hydroxyl and sulfhydryl groups.
• Alkylating agents are bifunctional, i.e. they have two
alkylating groups.
• The nitrogen at position 7 (N7) of guanine, being
strongly nucleophilic, is probably the main molecular
target for alkylation in DNA.
• N1 and N3 of adenine and N3 of cytosine may also be
affected.
• Being bifunctional they can cause intra- or interchain
cross-linking, abnormal base pairing or chain scission
which causes cell death,gene mutation or carcinogenesis.
• Destroy DNA structure directly, has strong toxicity to both
proliferate or non-proliferate cells—Cell cycle non-specific
agents
• Results in a block at G2 and subsequent apoptotic cell
death.
NITROGEN MUSTARDS
NITROGEN MUSTARDS
• Mechlorethamine
• Melphalan
• Chlorambucil
• Cyclophosphamide
• Ifosfamide
MECHANISM OF ACTION
• Nitrogen mustards inhibit cell reproduction by binding
irreversibly with the nucleic acids (DNA).
• The specific type of chemical bonding involved is
alkylation.
• After alkylation, DNA is unable to replicate and
therefore can no longer synthesize proteins and other
essential cell metabolites.
• Consequently, cell reproduction is inhibited and the cell
eventually dies from the inability to maintain its
metabolic functions.
MECHLORETHAMINE
MECHANISM OF ACTION:-
• Transported into the cell by a choline uptake process.
• Loses a chloride ion and forms a reactive intermediate
• That alkylates the N7 nitrogen of a guanine residue in one
or both strands of a DNA molecule.
• Alkylation leads to cross-linkages that facilitates DNA
strand breakage.
• Occur in both cycling and resting cells (therefore cell-cycle
nonspecific)
• Proliferating cells are more sensitive to the drug, especially
those in G1 and S phases.
PHARMACOKINETICS
• Very unstable, and solutions must be made up just prior to
administration.
• Mechlorethamine is also a powerful vesicant (blistering agent)
• Administered only IV, because it can cause severe tissue damage if
extravasations occurs.
RESISTANCE
• Decreased permeability of the drug
• Increased conjugation with thiols such as glutathione
• Possibly increased DNA repair.
ADVERSE EFFECTS
• Severe nausea and a vomiting.
• Bone marrow depression
• Immunosuppression.
• Extravasation - a serious problem.
THERAPEUTIC APPLICATIONS
• Primarily in the treatment of Hodgkin's disease as part of the MOPP
regimen (Mechlorethamine, Oncovin, Prednisone, Procarbazine)
• Also useful in the treatment of some solid tumors.
CYCLOPHOSPHAMIDE AND IFOSFAMIDE
• Very closely related mustard agents that share most of the same
toxicities.
• They are unique in that
(1) They can be taken orally, and
(2) They are cytotoxic only after generation of their alkylating
species, following their hydroxylation by cytochrome P-450.
MECHANISM OF ACTION
• Most commonly used
• Both cyclophosphamide and ifosfamide are first biotransformed to
hydroxylated intermediates by the cytochrome P-450 system.
• The hydroxylated intermediates undergo breakdown to form the
active compounds, phosphoramide mustard and acrolein.
• Reaction of the phosphoramide mustard with DNA is considered to
be the cytotoxic step.
MECHANISM OF ACTION
MECHANISM OF ACTIVATION:
CYCLOPHOSPHAMIDE
Inactive
Cyclophosphamide
Metabolised in the
liver by P450 mixed
function oxidases
4-hydroxycyclophosphamide
Converted to
phosphoramide
mustard, the actual
cytotoxic molecule
Aldophosphamide is
conveyed to other
tissues
(Reversibly) forms
aldophosphamide.
MECHANISM OF ACTION
Cyclophosphamide
Aldophosphamide
Phosphoramide
mustard

Acrolein
Hemorrhagic cystitis
Cytotoxic effect
Mesna
RESISTANCE
• Increased DNA repair
• Decreased drug permeability
• Reaction of the drug with thiols(for example, glutathione).
• Cross-resistance, however, does not always occur.
PHARMACOKINETICS
• Preferentially administered by the oral route.
• Minimal amounts of the parent drug are excreted into the feces
(after biliary transport), or into the urine by glomerular filtration.
ADVERSE EFFECTS
• Alopecia,
• Nausea,
• Vomiting,
• Diarrhoea
• Bone marrow depression,
• Leukocytosis
• Hemorrhagic cystitis
• Other toxicities on the germ cells resulting in amenorrhea, testicular
atrophy, and sterility.
• High incidence of neurotoxicity in patients on high-dose ifosfamide.
USES OF CYCLOPHOSPHAMIDE
• Neoplastic conditions
•
•
•
•
•
Hodgkins and non hodgkins lymphoma
Multiple myeloma
Burkits lymphoma
Neuroblastoma , retinoblastoma
Breast Cancer, adenocarcinoma of ovaries
• Non neoplastic conditions
• Rheumatoid arthritis
• Nephrotic syndrome
IFOSFAMIDE
• Congener of cyclophosphamide
• Longer half life than cyclophosphamide
• Less alopecia and less emetogenic than cyclophosphamide
• Can cause hemorrhagic cystitis and severe neurological toxicity
• Used for germ cell testicular tumors and adult sarcomas
• Bronchogenic, breast, testicular, bladder, head and neck carcinomas,
osteogenic sarcoma and some lymphomas.
CHLORAMBUCIL
• Slowest acting and least toxic alkylating agent
• Main action on lymphoid tissue
• Drug of choice for long term maintenance therapy of CLL ( chronic
lymphatic leukaemia), Hodgkin's disease and some solid tumours
MELPHALAN
• Very effective in MULTIPLE MYELOMA & advanced ovarian cancer
• Less irritant locally , less alopecia
• Adverse Effects :
• Bone marrow Depression
• Infections , diarrhea and pancreatitis
THIO-TEPA
• Triethylene phosphoramide
• Does not require to form active intermediate
• Active intravesicular agent can also be used topically in superficial
bladder cancer
• Not well absorbed orally given IV
• High toxicity
BUSULFAN
• Highly specific for myeloid elements
• Little effect on lymphoid tissue and G.I.T.
ADVERSE EFFECT:• Hyperuricaemia; Pulmonary fibrosis & Sterility
• Drug of choice for chronic myeloid leukemia.
NITROSOUREA
• Carmustine and lomustine are closely related nitrosoureas.
MECHANISM OF ACTION
• The nitrosoureas exert cytotoxic effects by an alkylation that crosslinks strands of DNA to inhibit its replication and eventually RNA and
protein synthesis.
• Although they alkylate DNA in resting cells, cytotoxicity is expressed
only on cell division; therefore nondividing cells can escape death if
DNA repair occurs.
RESISTANCE
•True nature of resistance is unknown
•Probably results from DNA repair and
reaction of the drugs with thiols.
PHARMACOKINETICS
• In spite of the similarities in their structures,
carmustine - intravenously, lomustine orally.
• Distribute to many tissues,
• Ability to readily penetrate into the CNS.
• The drugs undergo extensive metabolism.
• Lomustine is metabolized to active products.
• The kidney is the major excretory route.
ADVERSE EFFECTS
• Delayed hematopoietic depression
• An aplastic marrow
• Renal toxicity
• Pulmonary fibrosis
THERAPEUTIC APPLICATIONS
• Primarily employed in the treatment of brain tumors.
• They find limited use in the treatment of other cancers.
Triazenes
• Dacarbazine
• Primary inhibitory action on RNA
&
protein synthesis
• Used in malignant melanoma, Hodgkin's disease
• Temozolamide
• New alkylating agent
• Approved for malignant glioma
• Rapidly absorbed after oral absorption & crosses BBB
1. Mechanism of
Action
2. Clinical application
3. Route
4. Side effects
A. Mechlorethamine
DNA cross-links,
resulting in
inhibition of DNA
synthesis and
function
Hodgkin’s and nonHodgkin’s lymphoma
Must be given
Orally
Nausea and vomiting,
decrease in
PBL count, BM
depression, bleeding,
alopecia, skin
pigmentation, pulmonary
fibrosis
B.
Cyclophosphamide
Same as above
Breast, ovarian, CLL, soft
tissue sarcoma, WT,
neuroblastoma
Orally and I.V.
Same as above
C. Chlorambucil
Same as above
Chronic lymphocytic
leukemia
Orally effective
Same as above
D. Melphalan
Same as above
Multiple myeloma, breast,
ovarian
Orally effective
Same as above
E. Ifosfamide
Same as above
Germ cell cancer, cervical
carcinoma, lung, Hodgkins
and non-Hodgkins
lymphoma, sarcomas
Orally effective
Same as above
a. Nitrogen Mustards
1. Mechanism of Action
2. Clinical application
3. Route
4. Side effects
Atypical alkylating agent.
Chronic granulocytic
leukemia
Orally effective
Bone marrow depression,
pulmonary fibrosis, and
hyperuricemia
b. Alkyl Sulfonates
A. Busulfan
c. Nitrosoureas
1. Mechanism of Action
2. Clinical application
3. Route
4. Side effects
A. Carmustine
DNA damage, it can
cross blood-brain barrier
Hodgkins and non-Hodgkins
lymphoma, brain tumors,
G.I. carcinoma
Given I.V. must be
given slowly.
Bone marrow depression,
CNS depression, renal
toxicity
B. Lomustine
Lomustine alkylates and
crosslinks DNA, thereby
inhibiting DNA and RNA
synthesis. Also
carbamoylates DNA and
proteins, resulting in
inhibition of DNA and RNA
synthesis and disruption of
RNA processing. Lomustine
is lipophilic and crosses the
blood-brain barrier
Hodgkins and non-Hodgkins
lymphoma, malignant
melanoma and epidermoid
carcinoma of lung
Orally effective
Nausea and vomiting,
Nephrotoxicity, nerve
dysfunction
C. Streptozotocin
DNA damage
pancreatic cancer
Given I.V.
Nausea and vomiting,
nephrotoxicity, liver toxicity
d. Ethylenimines
1. Mechanism of
Action
2. Clinical application
3. Route
4. Side effects
A. Triethylene
thiophosphoramide
(Thio-TEPA)
DNA damage,
Cytochrome
P450
Bladder cancer
Given I.V.
Nausea and vomiting,
fatigue
B. Hexamethylmelamine
(HMM)
DNA damage
Advanced ovarian tumor
Given orally after
food
Nausea and vomiting, low
blood counts, diarrhea
d. Triazenes
1. Mechanism of
Action
2. Clinical application
3. Route
4. Side effects
A. Dacarbazine (DTIC)
Blocks, DNA, RNA and
protein synthesis
Malignant Melanoma,
Hodgkins and nonHodgkins lymphoma
Given I.V.
Bone marrow depression,
hepatotoxicity, neurotoxicity,
bleeding, bruising, blood
clots, sore mouths.
ANTIMETABOLITES
• These are analogues related to normal components of
DNA or of coenzymes involved in nucleic acid synthesis.
• They competitively inhibit utilization of the normal
substrate or get themselves incorporated forming
dysfunctional macromolecules.
• They generally interfere with the availability of normal
purine or pyrimidine nucleotide precursors by inhibiting
their synthesis or by competing with them in DNA or RNA
synthesis.
• Their maximal cytotoxic effects are S phase (and-therefore
cell-cycle)specific.
Antimetabolites
• Folate Antagonists
• Methotrexate
• Purine Antagonists
• 6 Mercaptopurine, 6 Thioguanine, Azathioprine
• Pyrimidine antagonists
• 5 Fluorouracil, cytarabine, gemcitabine
METHOTREXATE
• Structurally related to folic acid
• Acts as an antagonist of that vitamin by inhibiting dihydrofolate reductase
,the enzyme that convert folic acid to its active form coenzyme form
tetrahydrofolic acid (THF4).
• It therefore acts as an antagonist of that vitamin.
• Folate plays a central role in a variety of metabolic reactions involving the
transfer of one-carbon units.
MECHANISM OF ACTION
(a) Inhibition Of Dihydrofolate Reductase:
• After absorption of folic acid from dietary sources or
from that produced by intestinal flora, the vitamin
undergoes reduction to the tetrahydrofolate form (FH4)
by the intracellular NADPH-dependent dihydrofolate
reductase.
• Methotrexate enters the cell by an active transport
process, which normally mediates the entry of N5-methyl
FH4.
• At high MTX concentrations, the drug can diffuse into the
cells.
• MTX has an unusually strong affinity for dihydrofolate
reductase, and effectively inhibits the enzyme.
• Its inhibition can only be reversed by a thousand-fold
excess of the natural substrate, dihydrofolate or by
administration of leucovorin, which bypasses the
blocked enzyme and replenishes the folate pool.
(b) Consequences Of Decreased FH4:
• Inhibition of dihydrofolate reductase deprives the cell
of the various folate coenzymes and leads to
decreased biosynthesis of thymidylic acid,
methionine and serine, and the purines (adenine and
guanine).
• Thus eventually to depressed DNA, RNA and protein
synthesis and to cell death.
c. Polyglutamated MTX:
• Like tetrahydrofolate itself, MTX becomes
polyglutamated within the cell, a process that favors
intracellular retention of the compound due to its
larger size and increased negative charge.
Methotrexate
Adenine, guanine,
thymidine ,
methionine, serine
RESISTANCE
• Nonproliferating cells are resistant to methotrexate.
• Due to amplification (production of additional copies) of
the gene that codes for dihydrofolate reductase resulting
in increased levels of this enzyme.
• Enzyme affinity also be diminished.
• Reduced influx of MTX, caused by a change in the carriermediated transport responsible for pumping MTX into
the cell.
THERAPEUTIC APPLICATIONS
• Methotrexate, often in combination with other drugs, is effective against
acute lymphocytic leukemia, choriocarcinoma, Burkitt's lymphoma in
children, breast cancer, and head and neck carcinomas.
• High-dose MTX is curative for osteogerric sarcoma and choriocarcinoma;
treatment is followed by administration of leucovorin to rescue the bone
marrow.
• In addition, low-dose MTX is effective as a single agent against certain
inflammatory diseases, such as severe psoriasis and rheumatoid arthritis.
Pharmacokinetics
• a. Administration and distribution:
• Methotrexate is readily absorbed at low doses from the GI tract, but it can
also be administered by intramuscular (IM), intravenous (IV), and intrathecal
routes.
• High concentrations of the drug are found in the intestinal epithelium, liver
and kidney, as well as in ascites and pleural effusions.
• MTX is also distributed to the skin.
b. Fate:
•Although folates found in the blood have a single
terminal glutamate, most intracellular folates are
converted to polyglutamates.
•Methotrexate is also metabolized to poly-glutamate
derivatives.
•High doses of methotrexate undergo hydroxylatlon
at the 7 position.
•This derivative is less water soluble, and may lead to
crystalluria.
•Therefore, it is important to keep the-urine alkaline
and the patient well hydrated to avoid renal toxicity.
•Excretion of the parent drug and the 7-OH
metabolite occurs via the urine.
5. Adverse effects:
a.
•
Commonly observed toxicities:
Most frequent toxicities are stomatitis, myelosuppression, erythema,
rash, urticaria, alopecia, nausea, vomiting, and diarrhea.
b. Renal damage:
• Although uncommon during conventional therapy, renal damage is a
complication of high-dose methotrexate.
c. Hepatic function:
• Hepatic function should be monitored.
• Long term use may lead to fibrosis.
d. Pulmonary toxicity:
• Children being maintained on methotrexate may develop cough, dyspnea,
fever, and cyanosis.
e. Neurologic toxicities:
• These are associated with intrathecal administralion, and include subacute
meningeal irritation, stiff neck, headache, and fever.
• Seizures, encephalopathy, or paraplegia occur rarely.
• Long-lasting effects, such as learning disabilities.
f. Contraindications:
• Because methotrexate is teratogerlic and an abortifacient it should be
avoided in pregnancy.
Purine antagonists
• 6 Mercaptopurine
• 6 Thioguanine
• Azathioprine
6-MERCAPTOPURINE
• The drug ,6 mercaptopurine (6-MP) is the thiol analog of hypoxanthine.
• It and thioguanine (6-TG) were the first purine analogs to prove benificial for
treating neoplastic disease.
• Azathioprine, an immunosuppressant, exerts its effects after conversion to 6MP.
SITE OF ACTION:
• a. Formation of nucleotide:
• To exert its antileukemic effect, 6- mercaptopurine must penetrate
target cells and be converted to the corresponding nlucleotide, 6mercaptopurine ribose phosphate.
• The addition of the ribose phosphate is catalyzed by the salvage
pathway enzyme, hypoxanthine- guanine phosphoribosryl -transferase
(HGPRT).
b. Inhibition of purine synthesis:
• Inhibit the first step of de novo purine ring biosynthesis as well as formation
of AMP and xanthinylic acid (XMP) from inosinic acid (IMP).
c. Incorporation into nucleic acids:
• Dysfunctional RNA and DNA result from incorporation of guanylate analogs
generated from the unnatural nucleotides.
• Thio-IMP is dehydrogenated to thio- GMP, which after phosphorylation to diand triphosphates, can be incorprated into RNA.
• The deoxyribonucleotide analogs that are also formed are incorporated into
DNA.
6 Mercaptopurine
HGPRT
Ribonucleotide
(HGPRT):
hypoxanthine-guanine
phosphoribosyl transferase
ii. Purine antagonist: 6-mercaptopurine
6-mercaptopurine
Converted in the
cells to
ribonucleotide of 6mercaptopurine
Suppresses denovo
biosynthesis of
purines
No DNA synthesis
2. Resistance
• Resistance is associated with
(1) an inability to biotransform 6-MP to the corresponding
nucleotide because of dcreased level of HGPRT
(2) an increased dephosphorylation; or
(3) increased metabolism of the drug to thiouric acid.
3. Therapeutic applications
• 6-MP is used principally in the mainteinance of remission in acute
lymphoblastic leukemia (ALL).
4. Adverse effects:
• Side effects include nausea, vomiting, and diarrhea.
• Bone marrow depression is the chief toxicity.
• Hepatotoxicity has also been reported.
5. PHARMACOKINETICS
a. administration and metabolism:
• Absorption by the oral route is erratic.
• The drug is widely distributed throughout the body except for the
cerebrospinal fluid.
• 6-MP undergoes metabolism in the liver to the 6-methyl mercaptopurine (SCH3) derivative or to thiouric acid.
• The latter reaction is catalyzed by xanthine oxidase.
• Because allopurinol, a xanthine oxidase inhibitor, is frequently administered
to cancer patients receiving chemotherapy to reduce hyperuricemia,
• it is important to decrease the dose of 6-MP in these individuals to avoid
accumulation of the drug and exacerbation of toxicities.
b. Excretion: The parent drug and its metabolites are excreated by the kidney.
6 Mercaptopurine
6 MP
TPMT
Allopurinol
Xanthine oxidase
6 Thiouric acid
Inactive
metabolite
Fludarabine
• Phosphorylates intracellularly to form triphosphate
• Inhibits DNA polymerase and gets incorporated to form dysfunctional
DNA
• Effective in slow growing tumors: (apoptosis)
• Use:
• Chronic lymphoblastic leukemia (CLL) and non hodgkins
• Adverse events:
• chills, fever, opportunistic infection, myelosupression
Pyrimidine antagonists
• 5 fluoruracil
• Cytosine arabinoside (Cytarabine)
• Gemcitabine
5-FLUOROURACIL (5-FU)
• A pyrimidine analog,
• Fluorouracil is an analogue of thymine in which
the methyl group is replaced by a fluorine atom.
• A stable fluorine atom at position 5 of the uracil ring.
• The fluorine interferes with the conversion of deoxyuridylic acid to
thymidylic acid.
• Depriving the cell of one of the essential precursors for DNA synthesis.
1. Site of action:
• It has two active metabolites: 5-FdUMP and 5FdUTP.
• 5-FdUMP inhibits thymidylate synthetases and
prevents the synthesis of thymidine, a major
building block of DNA.
• 5-FdUTP is incorporated into RNA by RNA
polymerase and interferes with RNA function.
5 fluorouracil
5 FU
FdUMP
Thymidilate
synthetase
dUMP
Uses : stomach , colon,
breast ovaries , liver, skin
cancers
FdUMP = fluorodeoxyuridine
monophosphate
Thymidine
Monophosphate
DNA Synthesis
(Selective failure)
iii. Pyrimidine Antagonist: 5-Fluorouracil (Analogue
of uracil)
5-fluorouracil
Converted to 5-fluoro-2-deoxy uridine
monophosphate
Inhibits thymidilate synthesis
Blocks conversion of deoxyuridilic acid
to deoxythymidilic acid
Inhibition of DNA synthesis
2.Resistance:
• Lost the ability to convert 5-FU into active form
• Altered or increased thymidylate synthetase
• Increased rate of 5- FU catabolism.
3. Theraputic applications:• primarily in the treatment of slowly growing, solid-tumors=(for example:
colorectal, breast, ovarian, pancreatic, and gastric carcinomas)
• Treatment of superficial basal cell carcinomas.
4. Pharmacokinetics:
• Severe toxicity to the GI tract
• Given intravenously or topically.
• Penetrates well into all tissues including the CNS.
• Metabolized in the liver
5. Toxicities:
• Nausea, vomiting, diarrhea, and alopecia, severe ulceration of the oral and
GI mucosa, bone marrow depression and anorexia
Cytarabine
• Cytosine arabinoside, ara-C
• An analog of 2'-deoxycytidine in which the natural ribose residue is replaced
by D-arabinose.
• Acts as a pyrimidine antagonist.
1. Site of action:
•
ara-C sequentially phosphorylated to the corresponding nucleotide,
•
cytosine arabinoside triphosphate (ara-CTP), in order to be cytotoxic.
•
It is S-phase (hence cell-cycle) specific.
•
Ara-C is also incorporated into DNA and can terminate chain elongation.
2. Resistance:
• Defect in the transport process
• A change in phosphorylating enzymes
• An increased pool of the natural dCTP nucleotide.
3. Therapeutic indications:
• The major clinical use is in acute nonlymphocytic leukemia in combination
with 6-TG and daunorubicin.
4. Pharmacokinetics:
• Given IV
• Distributes throughout the body, but does not penetrate the CNS.
• Injected intrathecally
• Undergoes extensive oxidative deamination
• Excreted by the kidney.
5. Adverse effects:
• Nausea,
• Vomiting,
• Diarrhea
• Severe myelosuppression
• Hepatic dysfunction
• Seizures or altered mental states.
GEMCITABINE
• S-phase specific
• A deoxycytidine antimetabolite
• Undergoes intracellular conversion to gemcitabine monophosphate
via the enzyme deoxycytidine kinase
• it is subsequently phosphorylated to gemcitabine diphosphate and
gemcitabine triphosphate
GEMCITABINE
• Gemcitabine triphosphate competes with deoxycytidine triphosphate
(dCTP) for incorporation into DNA strands
• Due to an addition of a base pair before DNA polymerase is stopped,
Gemcitabine inhibits both DNA replication and repair
• Gemcitabine-induced cell death has characteristics of apoptosis
GEMCITABINE
Therapeutic Uses
• variety of solid tumors
• very effective in the treatment of pancreatic cancer
• Small cell lung cancer
• carcinoma of the bladder, breast, kidney, ovary, and head and neck
C. Antimetabolites
1.
Methotrexate
1. Mechanism of Action
2. Clinical application
3. Route
4. Side effects
inhibits formation of FH4
(tetrahydrofolate) from folic
acid by inhibiting the enzyme
dihydrofolate reductase
(DHFR); since FH4 transfers
methyl groups essential to DNA
synthesis and hence DNA
synthesis blocked.
Choriocarcinoma, acute
lymphoblastic leukemia
(children), osteogenic sarcoma,
Burkitt's and other nonHodgkin‘s lymphomas, cancer of
breast, ovary, bladder, head &
neck
Orally
effective
as well as
given I.V.
bone marrow depression,
intestinal lesions and interference
with embryogenesis.
Drug interaction: aspirin and
sulfonamides displace
methotrexate
from plasma proteins.
2. Pyrimidine Analogs:
Cytosine Arabinoside
1. Mechanism of
Action
2. Clinical application
3. Route
4. Side effects
inhibits DNA
synthesis
most effective agent for induction of
remission in acute myelocytic
leukemia; also used for induction of
remission acute lymphoblastic leukemia,
non-Hodgkin's lymphomas; usually used in
combination chemotherapy
Orally
effective
bone marrow
depression
3. Purine analogs:
6-Mercaptopurine
(6-MP) and
Thioguanine
1. Mechanism
of Action
2. Clinical application
3. Route
4. Side effects
Blocks DNA
synthesis by
blocking
conversion of
AMP to
ADP; also blocks
first step in
purine
synthesis.
Feedback
inhibition
blocks DNA
synthesis by
inhibiting
conversion of
GMP to GDP;
also blocks first
step in purine
synthesis by
feedback
inhibition
most effective agent for
induction of remission in acute
myelocytic
leukemia; also used for
induction of remission acute
lymphoblastic leukemia,
non-Hodgkin's lymphomas;
usually used in combination
chemotherapy
Orally
effective
bone marrow
depression,
Plant Alkaloids
Vinca Alkaloids
Podophyllotoxins
Camptothecins
Taxanes
VINCA ALKALOIDS
• Vinblastine
• Vincristine
• Vinorelbine
Vinca alkaloids
• Obtained from periwinkle plant ( Vinca Rosea)
• Vincristine, vinblastine, vinorelbine
MECHANISM OF ACTION
• Binds to the microtubular protein tubulin in a dimeric
form
• The drug-tubulin complex adds to the forming end of
the microtubules to terminate assembly
• Depolymerization of the microtubules occurs
• Resulting in mitotic arrest at metaphase, dissolution
of the mitotic spindle, and interference with
chromosome segregation
• CCS agents- M phase
Vinblastine and Vincristine
Bind to β-tubulin (drug tubulin complex)
inhibits its polymerization into microtubules
No intact mitotic spindle
cell division arrested in metaphase
Mechanism of action
Resistance
• Enhanced efflux of vincristine and vinblastine and several other
drugs.
• Alterations in tubulin structure
Therapeutic applications
Vincristine - Acute leukemias, lymphomas, Wilm’s Tumor and
Neuroblastoma
Vinblastine – Lymphomas, Neuroblastomas,Testicular cancer and
Kaposi’s sarcoma
Vinorelbine – non-small cell lung carcinoma and breast Cancer
PHARMACOKINETICS
• Given Intravenously
• Concentrated and metabolized in the liver
• Excreted into bile and feces.
• Doses must be modified in patients with , impaired hepatic function
or biliary obstruction.
ADVERSE EFFECTS
• a. Shared toxicities: Vincristine and vinblastine
• Phlebitis or cellulitis, nausea, vomiting, diarrhea, and alopecia.
• b. Unique toxicities:
• Vinblastine is a more potent myelosuppressant.
• Vincristine associated with peripheral neuropathy, Gastrointestinal
problems.
Comparison between
Vincristine
• Alopecia more common
• Peripheral & autonomic
neuropathy & muscle
weakness (CNS)
• Constipation
• Uses: (Childhood cancers)
• ALL , Hodgkins, lymphosarcoma,
Wilms tumor, Ewings sarcoma
Vinblastine
• Less common
• Less common, temp.
mental depresssion
• Nausea, vomiting,
diarrhoea
• uses
• Hodgkins disease & other
lymphomas , breast cancer, testicular
cancer
TAXANES
• Paclitaxel & docetaxel
• Plant product obtained from bark of Pacific Yew ( Taxus Brevifolia) &
European Yew (Taxus Buccata)
PACLITAXEL
• Better known as taxol,
• Paclitaxel is the first member of ,the taxane family used in cancer
chemotherapy.
• A semi-synthetic paclitaxel is now available.
SITE OF ACTION
• Paclitaxel binds reversibly to tubulin
• But it promotes polymerization and stabilization of the polymer
rather than disassembly.
• The overly stable microtubules formed in the presence of paclitaxel
are dysfunctional, thereby causing the death of the cell.
Mechanism of action
Cell cycle arrested in G2 and M phase
Resistance
• Efflux of the drug
• The mutation in tubulin structure.
Therapeutic indications
• Advanced ovarian cancer and
• Metastatic breast cancer.
• Small-cell lung cancer,
• Squamous-cell carcinoma of the head and neck,
• Several other cancers.
• Combination therapy with other anticancer drugs
PHARMACOKINETICS
• Infused over 3-4 hours.
• Hepatic metabolism and biliary excretion are responsible for
elimination of paclitaxel.
ADVERSE EFFECTS
• Hypersensitivity
• Neutropenia
• Peripheral neuropathy
• Transient asymptomatic bradycardia
• Alopecia
• vomiting
• Diarrhea
Epipodophyllotoxins
• Etoposide & tenoposide
• Semisynthetic derivatives of podophyllotoxins podophyllum peltatum
(plant glycoside)
MECHANISM OF ACTION
Etoposide and Teniposide
forms complex with DNA and topoisomerase ІІ
prevent resealing of broken DNA strand
Cell death
• Act in S & G2 phase
Etoposide& Teniposide
• Teniposide is an analogue with similar properties
• PK- orally well absorbed and distributes to most body tissues.
Elimination is mainly via kidneys
• Clinical use – Testicular and lung ca. in combination with cytotoxic
agents. Non-hodgkin’s lymphoma and AIDS related Kaposi’s Sarcoma
• Toxicity – Etoposide and Teniposide are GI irritants and cause alopecia
and bone marrow suppression
CAMPTOTHECINS
• Topotecan
• Irinotecan
Camptothecin analogs
TOPOTECAN and IRINOTECAN:• Derived from camptotheca accuminata
• Inhibit Topoisomerase I: No resealing of DNA after strand has untwisted
TOPOTECAN and IRINOTECAN
PK• Irinotecan – prodrug – converted to active metabolite in liver
• Topotecan is eliminated renally
• Irinotecan and its metabolite eliminated in bile and faeces
• Topotecan:
• Used in metastatic ovarian cancer
• Major toxicity is bone marrow depression
• Irinotecan
• Used in metastatic cancer of colon/rectum
• Toxicity: diarrhoea, neutropenia, thrombocytopenia, cholinergic side effects
ANTIBIOTICS
1. ANTHRACYCLINES(DOXORUBICIN & DAUNORUBICIN)
2. DACTINOMYCIN(ACTINOMYCIN D)
3. PLICAMYCIN(METHRAMYCIN)
4. MITOMYCIN (MITOMYCIN C)
5. BLEOMYCIN
6. MITOZANTRONE
Dactinomycin
Mechanism of Action
• Intercalates into the minor grooves of double helix between G-C base
pairs of DNA ad interferes with the movement of RNA polymerase along
the gene preventing transcription.
• May also cause strand breaks and stabilise DNA topoisomerase II
complex.
Dactinomycin
• Uses:
• Wilms tumor,
• gestational choriocarcinoma
• Adverse effects
• bone marrow supression
• Irritant like meclorethamine
• sensitizes to radiation, and inflammation at sites of
prior radiation therapy may occur
• Gastrointestinal adverse effects
Anthracyclines
• Doxorubicin
• Daunorubicin
Mechanism of Action
• High-affinity binding to DNA through intercalation, resulting in
blockade of DNA and RNA synthesis
• DNA strand scission via effects on Top II
• Binding to membranes altering fluidity
• Generation of the semiquinone free radical and oxygen radicals
Doxorubicin & Daunorubucin
Toxicity
• Bone marrow depression
• Total alopecia
• Cardiac toxicity
Therapeutic Uses
• Doxorubicin- carcinomas of the breast, endometrium, ovary, testicle,
thyroid, and lung, Ewing’s sarcoma, and osteosarcoma
• Daunorubicin- acute leukemia
Bleomycins
• Group of metal-chelating glycopeptide antibiotics obtained from
Streptomyces verticullus.
• Produces chelation of copper or iron ions which produces superoxide
ions that interacts with DNA.
• Degrade preformed DNA, causing chain fragmentation and release of
free bases.
Bleomycin
•Acts through binding to DNA,
which results in single and
double strand breaks following
free radical formation and
inhibition of DNA synthesis
•The DNA fragmentation is due
to oxidation of a DNAbleomycin-Fe(II) complex and
leads
to
chromosomal
aberrations
•Cell cycle specific
•Active in G2 phase
127
Bleomycin
• Uses :
• Epidermoid cancers of skin, oral cavity, genitourinary tract, esophagus
• Testicular tumors
• Hodgkins lymphoma
• Adverse effects:
•
•
•
•
Pneumonitis
Fatal pulmonary fibrosis
Hyper pigmentation
spares bone marrow
Mitomycin
• CCNS , given intravenously and is rapidly cleared by hepatic metabolism
Mechanism of Action
• Bioreductive alkylating agent that undergoes metabolic reductive activation
through an enzyme-mediated reduction to generate an alkylating agent that
cross-links DNA
Toxicity
• Severe myelosuppression
• Renal toxicity
• Interstitial pneumonitis
Therapeutic Uses
• Squamous cell carcinoma of the cervix
• Adenocarcinomas of the stomach, pancreas, and lung
• 2nd line in metastatic colon cancer
Plicamycin
Mechanism of Action
• Binds to DNA through an antibiotic-Mg2+ complex
• This interaction interrupts DNA-directed RNA synthesis
Toxicity
• Bleeding disorders
• Liver toxicity
Therapeutic Uses
• Testicular cancer
• Hypercalcemia
Mitoxantrone
• Analogue of doxorubicin with lower cardiotoxicity
• It has a narrow range of utility: in acute nonhaemolytic leukaemia,
chronic myelogenous leukaemia, non-hodgkin lymphoma and
carcinoma breast.
• Major toxicity is marrow depression and mucosal inflammation.
MISCELLANEOUS
• Cisplatin
• Carboplatin
• Hydroxyurea
• Procarbazine
• L-Asparaginase
• Imatinib
CISPLATIN
Cl
NH3
Pt
Cl
NH3
• A member of the platinum coordination complex class
• Because of cisplatin's severe toxicity, carboplatin was developed.
• The therapeutic effectiveness of the two drugs is similar but their
pharmacokinetics, patterns of distribution and dose-limiting toxicities
differ.
MECHANISM OF ACTION
• Similar to that of the alkylating agents.
• Cisplatin enters the cell and binds to the N7 of guanine of DNA, forming
inter- and intra-strand crosslinks.
• The resulting cytotoxic lesion inhibits both DNA and RNA synthesis.
• Both drugs can also bind to proteins and other compounds containing
SH groups.
• Cytotoxicity can occur at any stage of the cell cycle, but the cell is most
vulnerable to the actions of these drugs in GI and S.
Mechanism of action of cisplatin
Cisplatin enters cells
ClForms highly reactive platinum complexes
Intra strand & interstrand cross links
DNA damage
Inhibits cell proliferation
2.Resistance
• Elevated glutathione levels
• Increased DNA repair
3. Therapeutic applications
• Treatment of solid tumors such as metastatic testicular carci noma in
combination with vinblastine and bleomycin
• Ovarian carcinoma in combination with cyclophosphamide
• Alone for bladder carcinoma
4. Pharmacokinetics
• Cisplatin and carboplatin are administered IV
• Given intraperitoneally for ovarian cancer.
• Over 90% is bound to serum proteins.
• Highest concentrations are found in liver, kidney, intestinal, testicular
and ovarian cells, but little penetrates into the CSF.
• The renal route is for excretion.
5. Adverse effects
• Severe vomiting
• Nephrotoxicity
• Hypomagnesemia
• Hypocalcemia
• Ototoxicity and tinnitus
• Mild bone marrow suppression
• Neurotoxicity
• Hypersensitivity reactions.
• Myelosuppression.
CARBOPLATIN
• Better tolerated
• Nephrotoxicity , ototoxicity , neurotoxicity low
• Less emetogenic
• But thrombocytopenia and leukopenia may occur
• Less plasma protein binding
• Use:
• primarily in ovarian cancer of epithelial origin
• Squamous cell carcinoma of head and neck
L-Asparaginase
• Catalyzes the deamination of asparagine to aspartic acid and
ammonia.
• Enzyme used chemotherapeutically
• Derived from bacteria.
1. Mechanism of action
• Some neoplastic cells require an external source of asparagine
• Because of their limited capacity to make sufficient L-asparagine to
support growth and function.
• L-Asparaginase hydrolyzes blood asparagine and thus deprives the
tumor cells of this nutrient required for protein synthesis.
L-asparaginase
2. Resistance:
• Increased capacity of tumor cells to synthesize asparagine
3. Therapeutic application:
• Childhood acute lymphocytic leukemia in combination with vincristine and
prednisone.
4. Pharrnacokinetics:
• Administered either IV or IM
• Because it is destroyed by gastric enzymes.
5. Adverse effects:
• Hypersensitivity reactions
• Decrease in clotting factors
• Liver abnormalities,
• Pancreatitis,
• Seizures and coma
Procarbazine
• MOA: forms hydrogen peroxide, which generates free radicals that cause
DNA damage
• Inhibits DNA and RNA synthesis.
• Used in the treatment of Hodgkin's disease as part of the "MOPP regimen
and also other cancers.
• Procarbazine rapidly equilibrates between the plasma and the CSF after oral
or parenteral administration.
• Drug are excreted through the kidney.
Toxicity
• Bone marrow depression
• Nausea
• vomiting
• Diarrhea
• Neurotoxic, causing symptoms drowsiness to hallucinations to
paresthesias.
• A disulfiram-type reaction
• Procarbazine is both mutagenic and teratogenic.
HYDROXYUREA
MOA:• It blocks the conversion of ribonucleotides to deoxyribonucleotides by
inhibiting the enzyme ribonucleoside diphosphate reductase-thus
interferes with DNA synthesis.
• Exerts S-phase specific action.
Therapeutic value:• chronic myeloid leukaemia, psoriasis and in some solid tumours.
• Myelosuppression is the major toxicity.
Hydroxyurea
Ribonucleotides
Ribonucleoside diphosphate
reductase
Deoxyribonucleotides
Hydroxyurea
• Uses:
• CML, Polycythemia,
psoriasis
• Dose:
• 20-30 mg/kg /day
orally
• Adverse effects
• Myelosuppression
(Minimal)
• Hypersensitivity
• Hyperglycemia
• Hypoalbuminemia
IMATINIB
• Selective anti-cancer drug whose development was guided by knowledge
of specific oncogene
• MOA:
• specific anticancer drug acts on specific oncogene.
• Inhibits tyrosine kinase activity of protein product of B cr-Abl oncogene
that is expressed in chronic myelogenous leukemia→ as result
proliferation of oncogene inhibited→ apoptosis results.
IMATINIB
RESISTANCE:• Due to mutation in Bcr-Abl tyrosine kinase
PK:• well absorbed orally , metabolized in liver , metabolites excreted in faeces
through bile.
T1/2 – 18 hrs
• A/Es- Abdominal pain, vomitting, fluid retention,myalgia and CHF
USE:
• (1) CML
• (2) GI stromal tumors ( C-kit tyrosine kinase)
Hormonal therapy
Hormonal therapy is one of the major modalities of
medical treatment for cancer
It involves the manipulation of the endocrine
system through exogenous administration of
specific hormones, particularly steroid hormones, or
drugs which inhibit the production or activity of such
hormones
•Used for several types of cancers derived from
hormonally
responsive
tissues,
including
the breast, prostate, endometrium, and adrenal cortex.
•Most familiar example of hormonal therapy
in oncology is the use of the selective estrogenresponse modulator tamoxifen for the treatment
of breast cancer, although another class of hormonal
agents, aromatase inhibitors, now have an expanding
role in that disease.
Hormones & antagonists
• Corticosteroids
– Prednisolone
• Estrogens
– Ethinyl Estradiol
• SERM
– Tamoxifene, Toremifene
• SERD
– Fulvestrant
• Aromatase Inhibitors
– Letrozole, Anastrazole,
Exemestane
• Progestins
– Hydroxyprogesterone
• Anti-androgens
– Flutamide,
Bicalutamide
• 5- reductase
Inhibitors
– finasteride,
dutasteride
• GnRH analogs
– Naferelin, goserelin,
leuoprolide
Glucocorticoids
• Marked lympholytic effect so used in acute leukaemias & lymphomas,
• They also
•
•
•
•
•
•
•
•
Have Anti-inflammatory effect
Increase appetite, prevent anemia
Produce sense of well being
Increase body weight
Supress hypersensitivity reaction
Control hypercalcemia & bleeding
Non specific antipyretic effect
Increase antiemetic effect of ondansetron
Estrogens
• Physiological antagonists of androgens
• Thus used to antagonize the effects of androgens in androgen
dependent prostatic cancer
• Fofesterol
• Prodrug , phosphate derivative of stilbesterol
• 600-1200mg IV initially later 120-240 mg orally
Anti-Estrogens
• Tamoxifen (SERMs)
• Raloxifene (SERMs)
• Faslodex
Tamoxifen
• Selective estrogen receptor modulator (SERM), have both
estrogenic and antiestrogenic effects on various tissues
• Binds to estrogen receptors (ER) and induces conformational
changes in the receptor
• Has antiestrogenic effects on breast tissue.
• The ability to produce both estrogenic and antiestrogenic affects is
most likely due to the interaction with other coactivators or
corepressors in the tissue and the binding with different estrogen
receptors, ER and ER
• Subsequent to tamoxifen ER binding, the expression of estrogen
dependent genes is blocked or altered
• Resulting in decreased estrogen response.
• Most of tamoxifen’s affects occur in the G1 phase of the cell cycle
Selective Estrogen Receptor Modulators (SERMs)
• Tamoxifen : Non steroidal antiestrogen
Antagonistic:
Breast and
blood vessels
Agonistic:
Uterus,
bone, liver,
pitutary
Tamoxifen
Toxicity
• Hot flashes
• Fluid retention
• nausea
Tamoxifen
Therapeutic Uses
• Tamoxifen can be used as primary therapy for
metastatic breast cancer in both men and
postmenopausal women
• Patients with estrogen-receptor (ER) positive tumors
are more likely to respond to tamoxifen therapy, while
the use of tamoxifen in women with ER negative
tumors is still investigational
• When used prophylatically, tamoxifen has been shown
to decrease the incidence of breast cancer in women
who are at high risk for developing the disease
Selective Estrogen Receptor Down regulator
(fulvestrant)
• Pure estrogen antagonist
• USES: Metastatic ER+ Breast Ca in
postmenopausal women
• MOA:
• Inhibits ER dimerization & prevents interaction of
ER with DNA
• ER is down regulated resulting in more complete
supression of ER responsive gene function
Anti-Androgen
• Flutamide
• Antagonizes androgenic effects
• approved for the treatment of prostate cancer
Anti-androgen
FLUTAMIDE
• MOA: bind to androgen receptor inhibit androgen effects.
• USE: prostatic carcinoma.
• ADR: hot flushes
• Hepatic dysfunction
• Gynecomastia.
Anti androgens
• BICALUTAMIDE :
• Androgen Receptor antagonists
• Palliative effect in metastatic Prostatic Ca
Aromatase Inhibitors
• Aminogluthethimide
• Anastrozole
Aminogluthethimide
Mechanism of Action
• Inhibitor of adrenal steroid synthesis at the first step, conversion of
cholesterol of pregnenolone
• Inhibits the extra-adrenal synthesis of estrone and estradiol
• Inhibits the enzyme aromatase that converts androstenedione to
estrone
Aminogluthethimide
Toxicity
• Dizziness
• Lethargy
• Visual blurring
• Rash
Therapeutic Uses
• ER- and PR-positive metastatic breast cancer
AROMATASE INHIBITOR:
ANASTRAZOLE:
• Inhibit aromatase w/c catalyses conversion of androstenedione
(androgenic precursor) to estrone ( estrogenic hormone)
• USE: advanced breast cancer
• ADR: hot flushes, bone and back pain,Dyspnea
• DOSE: 1mg orally daily
Aromatase Inhibitors
• Letrozole
• Orally active non steroidal compound
• MOA : Inhibits aromatisation of testosterone &
androstenedione to form estrogen.
• Uses : Breast Ca
Gonadotropoin-Releasing Hormone
Agonists
• Leuprolide
• Goserelin
Gonadotropoin-Releasing Hormone Agonist
Mechanism of Action
• Agents act as GnRH agonist, with paradoxic effects on the pituitary
• Initially stimulating the release of FSH and LH, followed by inhibition of
the release of these hormones
• Resulting in reduced testicular androgen synthesis
GnRH agonists
• NAFERELIN : nasal spray / SC inj
• ↓FSH & LH release from pituitary- ↓ the
release of estrogen & testosterone
• USE : Breast Ca, Prostatic Ca
• PROGESTINS:
• Hydroxyprogesterone – used in metastatic
endometrial Ca.
• A/E: bleeding
Gonadotropoin-Releasing Hormone Agonist
Toxicity
• Gynecomastia
• Edema
• thromboembolism
Gonadotropoin-Releasing Hormone Agonist
Therapeutic Uses
• Metastatic carcinoma of the prostate
• Hormone receptor-positive breast cancer
5- reductase inhibitors
Finasteride
• Orally active
• DHT levels ↓
• Benign prostatic
hyperplasia
Dose: 5mg/day
Prostate volume
Symptom score
Peak urine flow rate
DHT level in prostate
Also used for prevention of hair loss
Side effects: Loss of libido & impotence in 5 % pts.
Hormones and related agents • GLUCORTICOIDS –
Prednisolone - most commonly used glucorticoid in Ca.chemo. Used for
combination chemotherapy in leukemia and lymphomas
• ESTROGEN –
Physiological antagonists of androgens
Antagonizes the effects of androgens in androgen dependent prostatic
tumors- fosfestrol ( prodrug) – stilboestrol (prostatic tissue)
• TAMOXIFENAnti-oestrogen mainly used in the palliative treatment in hormone
dependent breast ca
• PROGESTINS –
Medroxyprogesterone acetate, hydroxyprogesterone caproate and
megestrol
2nd line hormonal therapy for metastatic hormone dependent breast ca
and endometrial ca
• ANTI-ANDROGENS –
Flutamide and bicalutamide – bind to androgen receptor – inhibit
androgen actions
Prostatic ca, used along with GNRH agonist – strategy known as ‘complete
androgen blockade’
Flutamide can cause – hot flushes, hepatic dysfunction and gynaecomastia
• GnRH agonists Goserelin, Nafarelin and leuprolide act as agonist of GnRH
used in advanced prostatic ca
• GnRH antagonist –
Cetrorelix, ganirelix and abarelix are antagonist of GnRH
Decrease the release of gonadotropins without causing initial
stimulation
Can be used in prostatic ca without the risk of flare up reaction
• AROMATASE Inhibitors – Anastrozole, letrozole etc
Aromatase is the enzyme responsible for conversion of androstenedione (
androgen precursor) to estrone (estrogenic hormone)
1st gen.- aminoglutethimide
2nd gen.- formestane, fadrozole,rogletimide
3rd gen.- exemestane,letrozole,anastrozole
Aromatase inhibitors – useful in advanced breast ca.
Adverse effects – hot flushes, arthralgia and fatigue
THANK YOU
-PHARMA STREET