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Anticancer Drugs
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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: Fludarabine
• Hazards to staff
Modalities of treatment in cancer
• Surgery
• Radiotherapy
• Chemotherapy: 50 % of the patients can be treated with chemotherapy
contributing to cure in 15 -20 % of patients
(in surgery & radiotherapy 1/3 of patients can be cured, effective when tumor has not
metastasized)
Phases of cell cycle
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.
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 nonproliferate cells—Cell cycle non-specific agents
• Results in a block at G2 and subsequent apoptotic cell death.
NITROGEN MUSTARDS
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)
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Administered only IV, because it can cause severe tissue damage if extravasations
occurs.
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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.
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.
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
• Triethylenephosphoramide
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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 cross-links 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
ANTIMETABOLITES
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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.
METHOTREXATE
• Structurally related to folic acid
• Acts as an antagonist of that vitamin by inhibiting dihydrofolatereductase ,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 DihydrofolateReductase:
• 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 dihydrofolatereductase 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
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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 carrier-mediated 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
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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 intrathecaladministralion, 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
• The drug ,6 mercaptopurine (6-MP) is the thiolanalog 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 6-MP.
SITE OF ACTION:
• a. Formation of nucleotide:
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To exert its antileukemic effect, 6- mercaptopurine must penetrate target cells
and be converted to the corresponding nlucleotide, 6-mercaptopurine 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 guanylateanalogs
generated from the unnatural nucleotides.
• Thio-IMP is dehydrogenated to thio- GMP, which after phosphorylation to di- and
triphosphates, can be incorprated into RNA.
• The deoxyribonucleotideanalogs that are also formed are incorporated into DNA.
MOA
1)
2)
3)
4)
6-mercaptopurine
Converted in the cells to ribonucleotide of 6-mercaptopurine
Suppresses denovo biosynthesis of purines
No DNA synthesis
2. Resistance
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Resistance is associated with
(1) an inability to biotransform6-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
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6-MP is used principally in the mainteinance of remission in acute
lymphoblastic leukemia (ALL).
4. Adverse effects:
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Side effects include nausea, vomiting, and diarrhea.
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Bone marrow depression is the chief toxicity.
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Hepatotoxicity has also been reported.
5. PHARMACOKINETICS
a. administration and metabolism:
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Absorption by the oral route is erratic.
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The drug is widely distributed throughout the body except for the cerebrospinal
fluid.
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6-MP undergoes metabolism in the liver to the 6-methyl mercaptopurine (S-CH3)
derivative or to thiouric acid.
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The latter reaction is catalyzed by xanthine oxidase.
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Because allopurinol, a xanthine oxidase inhibitor, is frequently administered to
cancer patients receiving chemotherapy to reduce hyperuricemia,
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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.
Fludarabine
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Phosphorylates intracellularly to form triphosphate
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Inhibits DNA polymerase and gets incorporated to form dysfunctional DNA
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Effective in slow growing tumors: (apoptosis)
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Use:
– Chronic lymphoblastic leukemia (CLL) and non hodgkins
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Adverse events:
– chills, fever, opportunistic infection, myelosupression
Pyrimidine antagonists
5-FLUOROURACIL (5-FU)
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A pyrimidine analog,
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Fluorouracil is an analogue of thymine in which the methyl group is replaced by a
fluorine atom.
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A stable fluorine atom at position 5 of the uracil ring.
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The fluorine interferes with the conversion of deoxyuridylic acid to thymidylic
acid.
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Depriving the cell of one of the essential precursors for DNA synthesis.
1. Site of action:
- It has two active metabolites: 5-FdUMP and 5-FdUTP.
- 5-FdUMP inhibits thymidylatesynthetases 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.
MOA
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2)
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4)
5)
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:
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Lost the ability to convert 5-FU into active form
Altered or increased thymidylatesynthetase
Increased rate of 5- FU catabolism.
3. Theraputic applications:•
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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:
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Severe toxicity to the GI tract
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Given intravenously or topically.
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Penetrates well into all tissues including the CNS.
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Metabolized in the liver
5. Toxicities:
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Nausea, vomiting, diarrhea, and alopecia, severe ulceration of the oral and GI
mucosa, bone marrow depression and anorexia
Cytarabine
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Cytosine arabinoside, ara-C
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An analog of 2'-deoxycytidine in which the natural ribose residue is replaced by
D-arabinose.
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Acts as a pyrimidine antagonist.
1. Site of action:
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ara-C sequentially phosphorylated to the corresponding nucleotide,
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cytosinearabinoside triphosphate (ara-CTP), in order to be cytotoxic.
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It is S-phase (hence cell-cycle) specific.
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Ara-C is also incorporated into DNA and can terminate chain elongation.
2. Resistance:
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Defect in the transport process
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A change in phosphorylating enzymes
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An increased pool of the natural dCTP nucleotide.
3. Therapeutic indications:
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The major clinical use is in acute nonlymphocyticleukemia in combination
with 6-TG and daunorubicin.
4. Pharmacokinetics:
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Given IV
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Distributes throughout the body, but does not penetrate the CNS.
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Injected intrathecally
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Undergoes extensive oxidative deamination
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Excreted by the kidney.
5. Adverse effects:
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Nausea,
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Vomiting,
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Diarrhea
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Severe myelosuppression
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Hepatic dysfunction
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Seizures or altered mental states.
GEMCITABINE
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S-phase specific
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A deoxycytidine antimetabolite
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Undergoes intracellular conversion to gemcitabine monophosphate via the
enzyme deoxycytidine kinase
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it is subsequently phosphorylated to gemcitabine diphosphate and gemcitabine
triphosphate
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Gemcitabine triphosphate competes with deoxycytidine triphosphate (dCTP) for
incorporation into DNA strands
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Due to an addition of a base pair before DNA polymerase is stopped, Gemcitabine
inhibits both DNA replication and repair
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Gemcitabine-induced cell death has characteristics of apoptosis
USES
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variety of solid tumors
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very effective in the treatment of pancreatic cancer
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Small cell lung cancer
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carcinoma of the bladder, breast, kidney, ovary, and head and neck
Plant Alkaloids
Vinca alkaloids
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Obtained from periwinkle plant ( VincaRosea)
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Vincristine, vinblastine, vinorelbine
MECHANISM OF ACTION
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Binds to the microtubular protein tubulin in a dimeric form
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The drug-tubulin complex adds to the forming end of the microtubules to
terminate assembly
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Depolymerization of the microtubules occurs
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Resulting in mitotic arrest at metaphase, dissolution of the mitotic spindle, and
interference with chromosome segregation
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CCS agents- M phase
MOA
1) Vinblastine and Vincristine
2) Bind to β-tubulin (drug tubulin complex)
3) inhibits its polymerization into microtubules
4) No intact mitotic spindle
5) cell division arrested in metaphase
Resistance
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Enhanced efflux of vincristine and vinblastine and several other drugs.
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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
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Given Intravenously
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Concentrated and metabolized in the liver
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Excreted into bile and feces.
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Doses must be modified in patients with , impaired hepatic function or biliary
obstruction.
ADVERSE EFFECTS
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a. Shared toxicities: Vincristine and vinblastine
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Phlebitis or cellulitis, nausea, vomiting, diarrhea, and alopecia.
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b. Unique toxicities:
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Vinblastine is a more potent myelosuppressant.
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Vincristine associated with peripheral neuropathy, Gastrointestinal problems.
TAXANES
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Paclitaxel &docetaxel
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Plant product obtained from bark of Pacific Yew ( TaxusBrevifolia) & European
Yew (TaxusBuccata)
PACLITAXEL
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Better known as taxol,
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Paclitaxel is the first member of ,the taxane family used in cancer chemotherapy.
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A semi-synthetic paclitaxel is now available.
SITE OF ACTION
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Paclitaxel binds reversibly to tubulin
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But it promotes polymerization and stabilization of the polymer rather than
disassembly.
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The overly stable microtubules formed in the presence of paclitaxel are
dysfunctional, thereby causing the death of the cell.
Resistance
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Efflux of the drug
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The mutation in tubulin structure.
Therapeutic indications
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Advanced ovarian cancer and
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Metastatic breast cancer.
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Small-cell lung cancer,
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Squamous-cell carcinoma of the head and neck,
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Several other cancers.
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Combination therapy with other anticancer drugs
PHARMACOKINETICS
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Infused over 3-4 hours.
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Hepatic metabolism and biliary excretion are responsible for elimination of
paclitaxel.
ADVERSE EFFECTS
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Hypersensitivity
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Neutropenia
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Peripheral neuropathy
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Transient asymptomatic bradycardia
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Alopecia
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vomiting
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Diarrhea
Epipodophyllotoxins
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Etoposide&tenoposide
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Semisynthetic derivatives of podophyllotoxinspodophyllumpeltatum (plant
glycoside)
MOA
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2)
3)
4)
Etoposide and Teniposide
forms complex with DNA and topoisomerase ІІ
prevent resealing of broken DNA strand
Cell death
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Act in S & G2 phase
Etoposide&Teniposide
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Teniposide is an analogue with similar properties
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PK- orally well absorbed and distributes to most body tissues. Elimination is
mainly via kidneys
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Clinical use – Testicular and lung ca. in combination with cytotoxic agents. Nonhodgkin’s lymphoma and AIDS related Kaposi’s Sarcoma
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Toxicity – Etoposide and Teniposide are GI irritants and cause alopecia and bone
marrow suppression
CAMPTOTHECINS
TOPOTECAN and IRINOTECAN:•
Derived from camptothecaaccuminata
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Inhibit Topoisomerase I: No resealing of DNA after strand has untwisted
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Irinotecan – prodrug – converted to active metabolite in liver
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Topotecan is eliminated renally
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Irinotecan and its metabolite eliminated in bile and faeces
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Topotecan:
– Used in metastatic ovarian cancer
– Major toxicity is bone marrow depression
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Irinotecan
– Used in metastatic cancer of colon/rectum
– Toxicity: diarrhoea, neutropenia, thrombocytopenia, cholinergic side
effects
ANTIBIOTICS
Dactinomycin
Mechanism of Action
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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.
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May also cause strand breaks and stabilise DNA topoisomerase II complex.
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Uses:
– Wilms tumor,
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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
Mechanism of Action
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High-affinity binding to DNA through intercalation, resulting in blockade of
DNA and RNA synthesis
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DNA strand scission via effects on Top II
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Binding to membranes altering fluidity
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Generation of the semiquinone free radical and oxygen radicals
Toxicity
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Bone marrow depression
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Total alopecia
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Cardiac toxicity
Therapeutic Uses
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Doxorubicin- carcinomas of the breast, endometrium, ovary, testicle, thyroid, and
lung, Ewing’s sarcoma, and osteosarcoma
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Daunorubicin- acute leukemia
Bleomycins
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Group of metal-chelating glycopeptide antibiotics obtained from Streptomyces
verticullus.
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Produces chelation of copper or iron ions which produces superoxide ions that
interacts with DNA.
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Degrade preformed DNA, causing chain fragmentation and release of free bases.
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Acts through binding to DNA, which results in single and double strand breaks
following free radical formation and inhibition of DNA synthesis
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The DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) complex
and leads to chromosomal aberrations
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Cell cycle specific
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Active in G2 phase
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Uses :
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Epidermoid cancers of skin, oral cavity, genitourinary tract, esophagus
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Testicular tumors
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Hodgkins lymphoma
Adverse effects:
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Pneumonitis
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Fatal pulmonary fibrosis
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Hyper pigmentation
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spares bone marrow
Mitomycin
CCNS , given intravenously and is rapidly cleared by hepatic metabolism
Mechanism of Action
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Bioreductive alkylating agent that undergoes metabolic reductive activation
through an enzyme-mediated reduction to generate an alkylating agent that crosslinks 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
•
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.
MOA
•
Similar to that of the alkylating agents.
•
Cisplatin enters the cell and binds to the N7 of guanine of DNA, forming interand 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.
MOA
1)
2)
3)
4)
5)
6)
Cisplatin enters cells
(Cl-goes out)
Forms 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 carcinoma 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 externalsource of asparagine
- Because of their limited capacity to make sufficient L-asparagine to support
growth and function.
- L-Asparaginasehydrolyzes blood asparagine and thus deprives the tumor cells of
this nutrient required for protein synthesis.
2. Resistance:
•
Increased capacity of tumor cells to synthesize asparagine
3. Therapeutic application:
•
Childhoodacute 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.
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.
RESISTANCE:•
Due to mutation in Bcr-Abl tyrosine kinase
PK:•
wellabsorbed 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 estrogen-response 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
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
•
Toxicity
Hot flashes, Fluid retention, nausea
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
1)) Flutamide
– Antagonizes androgenic effects
– approved for the treatment of prostate cancer
•
MOA: bind to androgen receptor inhibit androgen effects.
•
USE: prostatic carcinoma.
•
ADR: hot flushes, Hepatic dysfunction, Gynecomastia.
2)) 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
•
Letrozole
•
Orally active non steroidal compound
•
MOA : Inhibits aromatisation of testosterone &androstenedione to form
estrogen.
•
Uses : Breast Ca
Gonadotropoin-Releasing Hormone Agonists
•
Leuprolide
•
Goserelin
MOA
•
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 AGONIST
•
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
TOXICITY
•
Gynecomastia, Edema, thromboembolism
USES
•
Metastatic carcinoma of the prostate
•
Hormone receptor-positive breast cancer
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)
•
TAMOXIFEN-
Anti-oestrogen mainly used in the palliative treatment in hormone dependent breast ca
•
PROGESTINS –
Medroxyprogesterone acetate, hydroxyprogesteronecaproate 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
•
GnRHantagonist –
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, letrozoleetc
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