ANTINEOPLASTIC

DRUGS
Principles of Cancer
Chemotherapy
ONCOLOGY
Epidemiology OVERVIEW
Leading causes of death

Percentage of Total Deaths, US

Heart Diseases 31.4
Cancer 23.3
Cerebrovascular Diseases 6.9

•Chronic Obstructive Lung Diseases

Accidents
4.7
4.1
Pneumonia & Influenza 3.7
Diabetes Mellitus 2.7
Suicide 1.3
Homicide 0.9
HIV Infection 0.7

Adapted from Greenlee RT, et al. CA Cancer J Clin. 2000:50;22.

 CANCER/NEOPLASIA

• Uncontrolled growth and proliferation of cells

• Benign or Malignant
• Tumor
• Metastasis----distant spread
• PRINCIPLE: Cancer chemotherapy strives to cause a
lethal cytotoxic event or apoptosis in the cancer cell that
can arrest tumor's progression.
• INDICATION: Chemotherapy is indicated when
neoplasms are disseminated and are not amendable to
surgery.
• GOAL : Long term disease free survival.
• TUMOR SUSCEPTIBILITY: Rapidly proliferating cells are
more prone to chemotherapeutic drugs as compared to
slow proliferating cells.
 Principles and Definitions

• Cell cycle kinetics: is the rate at which a cell progresses

through the cell cycle. It is a general indication of how
fast a tissue or cell sample is proliferating.
• Log kill hypothesis: It states that a given dose of
chemotherapy kills the same fraction of tumor cells
regardless of the size of the tumour at the time of
treatment (3-log-kill (99.9%) = 108 – 105 ).
• Growth fraction: Cytotoxic drugs are more effective
against tumours that have a high growth fraction (large
percent actively dividing). Normal cells with high growth
fraction (e.g., bone marrow) are also more sensitive to
anticancer drugs
CELL CYCLE
 Cell Cycle Specificity

• Cell cycle specific drugs (CCS): These are specific to the

cells that are traversing the cell cycle and do not act
against cells in the non proliferating Go phase.

• Cell cycle non-specific drugs(CCNS) : They target both

proliferating (Traversing cell cycle) and non proliferating
(in G0 phase) cells without any discrimination.
 Classification of chemotherapeutic
drugs

• Alkylating agents
• Antimetabolites
• Antibiotics
• Natural products
• Hormonal agents
• Miscellaneous
 Cell Cycle Specificity of Anticancer
drugs

• cycle/phase non-specific
alkylating agents
• phase specific
• G1 phase(RNA synthesis) • G2 phase(RNA,
 L-asparaginase protein synthesis)
 steroids  bleomycin
• S phase(DNA,RNA,  topo I inhibitors

protein synthesis) • M phase(mitosis)

 antimetabolites  Vinca
alkaloids(natural
 anthracyclins products)
 taxanes
 topo II inhibitors
 Principles of combination chemotherapy

• Each drug should be active when used as monotherapy

• Drugs should have different mechanism of action

• Cross-resistance between drugs should be minimal

• Drugs should have different toxic effects

 Rescue Therapy

• Anticancer drugs toxic effects can be alleviated by rescue

therapy
• Leucovorin, readily accumulated by normal cells is
administered
• Mercaptoethanesulfonate (mesna) traps acrolein from
cyclophosphamide and reduces the incidence of
hemorrhagic cystitis
 1. ALKYLATING AGENTS

• Class of anticancer agents comprised of 12 commonly

used drugs and 5 sub-groups/classes:
• Nitrogen Mustards- Mechlorethamine, Cyclophosphamide,
Chlorambucil, Melphalan, Ifosfamide
• Alkyl Sulfonates- Busulfan
• Nitrosoureas- Carmustine, Lomustine
• Ethylenimines- Thiotepa/Triethylenemelamine(TEM)
• Triazenes- Dacarbazine
• Miscellaneous agents- Procarbazine, Hexamethylamine
 ALKYLATING AGENTS
• Any highly reactive drug that binds to certain chemical
groups (phosphate, amino, sulfhydryl, hydroxyl and
imidazole) commonly found in nucleic acids and
macromolecules, bringing about changes in the DNA and
RNA of cells
• Were the first anticancer drugs utilized
• The types of molecular changes induced are :
 cross-linkages between strands of DNA
 loss of basic component (purine) from the breaking of nucleic
acid
 ALKYLATING AGENTS

• Impt targets
• G N7 – strongly nucleophilic
• DNA becomes cross-linked w/ agent
• Intra- or inter-strand
•  Decr’d transcr’n, repl’n
•  Chain scission, so strand breaks
•  Inappropriate base pairing (alkylated G w/ T)
 ALKYLATING AGENTS

• Covalently bind DNA, proteins, nucleic acids

• N7 of Guanine targeted
• DNA cross-linking: intra-strand and inter-strands
• Miscoding
• Excision, ring scission etc.
 ALKYLATING DRUGS RESISTANCE

• Resistance occurs through:

 increased DNA repair

 decrease drug permeability

 production of trapped agents (eg. Thiols-gluthathione)

 a) Nitrogen Mustards

• Mechlorethamine
• Melphalan
• Cyclophosphamide
• Chlorambucil
• Ifosfamide
(MCI)
MECHLORETHAMINE(MUSTINE)

• Deriv. War gas sulphur mustard

• Most rapidly acting and administered rapidly IV
• 1st modern anti-cancer agent and 1940’s discovered to be
effective against human lymphomas
• Disadvantageous due to instability of the 2-chloroethyl
groups , which readily react with H2O & hydroxyl ions
• Several less reactive analogues synthesized
 MECHLORETHAMINE(MUSTINE)

MOA:
• In aqueous sol. It loses a chloride atom and forms a cyclic
ethylenimonium ion. This carbonium ion then interacts
with nucleophilic groups (N7 and O6) of guanine, and leads
to an inter-strand cross-linking of DNA

• Variability exist in the sensitivity of the drug between

normal and tumour tissues; more toxic to proliferating cells
than resting cells
MECHLORETHAMINE(MUSTINE)
DRUG NOTES t1/2 Elimn

MECHLORETHAMN IV admin. > 10 Little or

E Powerful vesicant (blistering agent) mins no intact
Side effects: severe nausea and vomiting, drug is
myelosuppression; leukopenia and excreted
thrombocytopenia occurs 10-14 days after (due to its
admin. Latent viral infections (herpes) appear reactivity)
due to immunosuppression, Extravasation;
areas of the skin accidentally exposed to the
drug should be infiltrated with sodium
thiosulfate to inactivate the drug.
Clinical use: Hodgkin’s disease(MOPP
regimen-mechlorethamine,
vincristine,procarbazine,prednisone), less
reactive nitrogen mustards are now
preferable for non-Hodgkin’s lymphomas,
leukemia and various solid tumors.
 CYCLOPHOSPHAMIDE

• Most versatile and useful nitrogen mustard

• Favourable therapeutic index
• Possesses the broadest spectrum of antitumor activity
• Inactive and enzymatically converted to cytotoxic
metabolites.
 CYCLOPHOSPHAMIDE

MOA:
• similarly results in the cross-linkages of DNA due to the
chloroethyl moieties with adjacent nucleotide bases
• Prodrug- metabolized in the liver by CYP450 enzymes to
phosphoramide and acrolein
DRUG NOTES t1/2 Elimn

CYCLOPHOSPHAMI O, IM, IV admin. 6-7hrs Metaboliz

DE ed in the
50% (metabolite) PPB
liver
Side effects: neutropenia, febrile (CYP450),
neutropenia, fever, alopecia, nausea,
vomiting, diarrhea and Renal
myelosuppression. (renal
Clinical use: Malignant lymphomas(non- failure
Hodgkin’s) ,breast cancer, bladder prolong
cancer, lung cancer, ovarian cancer, their
retention)
solid tumors of children
 Cl
N H
O P N

IFOSFAMIDE O
Cl

Ifosfamide - Ifex®

• Analogue of cyclophosphamide
• Prodrug: requires CYP450 for activation to 4-
hydroxyifosfamide and acrolein

• Similar metabolism, half-life and excretion to

cyclophosphamide

• Activity against broad spectrum of tumours : germ cell

cancers of the testis, lymphomas, sarcomas, carcinomas
of lung, breast, and ovary
 IFOSFAMIDE
• Side effects: hemorrhagic cystitis (co-administered
with thiol-mesna), confusion, hallucinations

• Urinalysis should be obtained prior to each dose

• Available in vials (1g) for IV injection

• Uroprotective agent mesna (sodium 2-

mercaptoethanesulfonate; mesnex) available in ampules
(1g) for IV injection
DRUG NOTES t1/2 Elimn

IFOSFAMIDE O, IM, IV admin. 6-7hrs Metaboliz

ed in the
50% (metabolite) PPB
liver
Side effects: hemorrhagic cystitis, (CYP450),
neutropenia, febrile neutropenia, fever,
alopecia, nausea, vomiting, and Renal
diarrhea. Less myelosuppression
Clinical use: Malignant
lymphomas,breast cancer, bladder
cancer, lung cancer, ovarian cancer,
solid tumors of children
 Cl
H2N N
Cl

MELPHALAN HO2C

Melphalan - Alkeran®

• Similar mechanism to Mechlorethamine but activation is

not required
• substituted phenyl ring greatly reduces the reactivity of
the molecule
• Dosage reduction may be necessary in renal failure as
measured by BUN.
DRUG NOTES t1/2 Elimn

MELPHALAN O, IV 1-6hrs Metaboliz

Side effects: severe bone marrow ed in the
suppression resulting in infection and liver
bleeding, affects white cells and platelets. (CYP450),
DOES NOT PRODUCE ALOPECIA
Renal
Clinical use: palliative treatment of (renal
multiple myeloma and cancers of the breast failure
or ovary prolong
their
retention)
 CHLORAMBUCIL
• Similar MOA to Mechlorethamine and Melphalan
• Well absorbed orally
• Indications: daily palliative therapy chronic leukemia and
lymphomas
• T ½ 1.5 hrs
• 99% plasma protein bound, extensive hepatic
metabolism to active metabolites
• Least toxic of the nitrogen mustard agents - conduct
weekly blood counts
• Side effects: Bone marrow toxicity, no alopecia, mild
nausea,has immunosuppressive, and teratogenic
properties
 2. ANTIMETABOLITES

• Folic acid analogs e.g. Methotrexate

• Purine analogs: e.g. 6-Mercaptopurine, 6-Thioguanine
• Pyrimidine analogues e.g. 5-Fluorouracil, Cytarabine
• These drugs block enzymes/ pathways involved in DNA
synthesis.
 ANTIMETABOLITES
• Antimetabolites are S-phase specific drugs.

• They generally interfere with the availability of normal

purine and pyrimidine nucleotide precursors, either by
inhibiting their synthesis or by competing with them in
DNA or RNA synthesis.
• Myelosuppression is the dose limiting toxicity for these
drugs.
• Also possess immunosuppressant activity
 FOLATE ANATAGONIST
METHOTREXATE
• Competitively inhibits the binding of folic acid to the
enzyme dihydrofolate reductase which catalyzes the
formation of tetrahydrofolate

dihyfrofolate reductase
Folic acid Tetrahydrofolate
(FH2) (FH4)

• THF is a cofactor for the synthesis of purines,

thymidylate, methionine and glycine
 METHOTREXATE
• FH4 serves as methyl grp donor (1-C unit) to deoxyuridine
(dUMP  dTMP), also regenerating FH2
• The one carbon transfer reactions for purine and
thymidylate synthesis cease, interrupting DNA and RNA
synthesis
• Protein synthesis may also be inhibited
METHOTREXATE-RESISTANCE
 METHOTREXATE-RESISTANCE
• Drug resistance due to transport can be overcome by
increasing extracellular MTX conc.
• MTX enter the cells through membrane folate binding
protein (MFBP).Some tumours lack or have reduced
MFBP
• Under these condition, MTX is transported by passive
diffusion. In high dose MTX therapy, the uptake of MTX
into tumour cells is highly selective
• High dose MTX therapy improves its penetration into
tumour sanctuary sites such as testis, CNS and blood
brain barrier.
• “Folinic acid (Leucovorin) rescue technique”
DRUG NOTES t1/2 Elimn

METHOTREXATE O, IM, IV admin. Biphas Metaboliz

Side effects: myelosuppression, ic: ed in the
3.5hr liver
GIT(diarrhea and ulcerative mucositis),
and (CYP450),
nausea, alopecia and dermatitis are 27hr
common with high-dose therapy,
Renal –
chronic low-dose therapy may result in
80%
cirrhosis of the liver excreted
Clinical use: Non-Hodgkin’s lymphoma, in urine
acute leukemia, breast cancer, head and (renal
neck cancer, bladder cancer failure
prolong
their
retention)
 PURINE ANALOGUES

• 6-Mercaptopurine
• 6-Thioguanine
• Fludarabine Phosphate
• Cladribine
 6-Mercaptopurine, 6-MP

• A purine antagonist (analogue of hypoxanthine)

• First agent active against leukemia

• Currently used as maintenance therapy in acute lymphoblastic

leukemia
 6-Mercaptopurine, 6-MP

• It must be converted to the ribonucleotide by the enzyme

hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
to produce 6-thioinosine-5-phosphate (T-IMP)
HGPRTase
6-mercaptopurine 6-thioguanine-5-
monophosphate
(6-TMP)
• T-IMP can inhibit the first step of de novo purine-ring
biosynthesis (catalyzed by glutamine phosphoribosyl
pyrophosphate aminotransferase)
 6-Mercaptopurine, 6-MP
• T-IMP accumulates and inhibits nucleotide metabolism at
several steps of DNA synthesis

• It can be converted to into thioguanine derivates and can

also be incorporated unto DNA

Resistance
• Decrease drug activation by HGPRTase
• Increase inactivation by alkaline phosphatase
DRUG NOTES t1/2 Elimn

6- O, IV admin. 21min Renal

MERCAPTOPURINE 20% PPB s excretion
Biov. reduced by first pass metabolism in (childr
the liver en)
Widely distributed throughout the body
Do not cross the BBB 47
mins(i
Metabolized to thiouric acid by xanthine n
oxidase adults)
Metabolism inhibited by XANTHINE
OXIDASE INHIBITOR- ALLOPURINOL
Reduced dosage of 6-MP
Side effects: nausea, vomiting, diarrhea
myelosuppression and hepatic toxicity.
Clinical use: acute lymphoblastic
leukemia
 6-Thioguanine, 6-TG

• Also a purine antagonist (analogue of guanine)

HPGRTase
6-Thioguanine 6- thioguaninosine-
(6-TG) 5-monophospahate
(6-TGMP)

• 6-TGMP is converted to deoxy-6-thioguanosine-triphosphate

(dTGTP), which inhibits the biosynthesis of purines

• 6-thioGMP can be further phosphorylated and is incorporated into

DNA and leads to cell-cycle arrest.
• Resistance similar to 6-MP
DRUG NOTES t1/2 Elimn

6-THIOGUANINE O admin. Urinary

21min excretion
Metabolized is via thiopurine
methyltransferase-TPMT s
(childr
NOT METABOLIZED BY XANTHINE en)
OXIDASE
No dosage reduction of 6-TG for 47
patients receiving allopurinol mins(i
Side effects: mild nausea, vomiting, n
diarrhea myelosuppression and hepatic adults)
toxicity.
Clinical use: acute myelogenous
leukemia
 PYRIMIDINE ANALOGUES

• Fluorouracil (5-FU)
• Cytarabine
• Gemcitabine
• Capecitabine
 Fluorouracil, 5-FU

• The fluorine interferes with the conversion of

deoxyuridylic acid to thymidylic acid , depriving the
cell of thymidine.
• 5-FU is converted in the cells to 5-fluoro-2-deoxyuridine-
5-monophosphate (5-FdUMP) which inhibits thymidylate
synthase
• Incorporation of 5-FdUMP into DNA inhibits DNA
synthesis

Uridylate thymidylate synthase Thymidylate

(dUMP) (dTMP)
DRUG NOTES t1/2 Elimn

5-FLUOROURACIL- O, IV, topically Mainly

5-FU Widely distributed (including CSF) 10-20 hepatic
mins metabolis
Side effects: mild nausea, vomiting,
m
diarrhea myelosuppression and
20%
alopecia excreted
Clinical use: bladder, breast, colon, in urine
anal, head and neck, liver and ovarian
cancers. Topically the cream has been
use in the therapy of keratosis of the
skin and superficial basal cell carcinoma
 RESISTANCE

• Decreased activation of 5-FU

• Reduced drug sensitivity of thymidylate synthase

 Citarabine

• Most specific for S phase

• Activated by nucleoside kinases to the triphosphate
nucleotide, ara-cytosinetriphosphate (Ara-CTP)
• Ara CTP inhibits DNA polymerase and retards chain
elongation.
Resistance
• Decreased uptake
• Decrease conversion to AraCTP
DRUG NOTES t1/2 Elimn

CYTARABINE IV, IM, SC Metaboliz

Side effects: nausea, mucositis, 10 ed in
mins liver,
myelosuppression
kidney,
Clinical use: chemotherapy of acute intestinal
myelogenous leukemia mucosa,
red blood
cells

80%
excreted
in urine
 NATURAL PRODUCTS

• Typically are plant alkaloids

• Tend to all possess anti-mitotic activity
• Hence all are CCS
• The newer semi-synthetic derivatives of
podophyllotoxins (Epipodophyllotoxins) are classed as
antibiotics based on their anthracycline like activity.
 VINCA ALKALOIDS

Vincristine and Vinblastine

• Periwinkle plant, Vinca rosea/Catharanthus roseus
• Blocks the formation of the mitotic spindle by
preventing the assembly of tubulin dimers into
microtubules
• Depolymerization of the microtubules occurs
• Results in in mitotic arrest at metaphase, dissolution of
the mitotic spindle, and interference with chromosome
segregation( ie, the duplicated chromosomes cannot
align along the division plate.
• M-phase specific
 Resistance
• Decreased rate of drug uptake/Increase drug efflux from
tumour cells
DRUG NOTES t1/2 Elimn

VINCRISTINE & IV Extensive

VINBLASTINE 98-99% PPB Triphasic: liver
Extensively bound to tissues, negligible 35 min, metabolism
amounts in brain or CSF 53 min, with
and 19 conjugates
Toxicity: and
hrs
Vinblastine- gastrointestinal distress, metabolites
alopecia and bone marrow suppression. excreted in
Vincristine- Neurological bile
toxicity(peripheral neurotoxicity),
numbness and tingling of extremities
followed by motor weakness, severe
constipation results with high doses
Clinical use:
Vincristine is used in acute lymphoblastic
leukemia, Wilm’s tumour, neuroblastoma
Vinblastine is used in testicular carcinoma,
Hodgkin’s disease, breast cancer, renal cell
carcinoma
 PODOPHYLLOTOXINS

Etoposide and Teniposide

• Semi-synthetic derivatives of podophyllotoxin extracted

from the ROOT OF THE MAY APPLE
•
 MECHANISM

Etoposide and Teniposide

• Forms complex with DNA topoisomerase II, results in
single-strand breakage of DNA
• Most lethal to cells in late S and early G2- phases of the
cell cycle
• No effect on microtubulin
DRUG NOTES t1/2 Elimn

ETOPOSIDE &
TENIPOSIDE Etoposide…can be oral or IV admin Biphasic: Mainly via
Teniposide … IV admin, more potent 11.5 hrs, kidneys
Toxicity: mild nausea, alopecia, allergic 72 hours
reaction, gastrointestinal irritants and bone
marrow suppression
Clinical use:
Etoposide- is used in testicular (in
combination with cisplatin) and ovarian germ
cell cancers, small lung cancers, acute
lymphoblastic leukemia
Teniposide-is used mainly in pediatric
cancers, particularly acute lymhoblastic
leukemia and are used in combination with
citarabine, vincristine and prednisone
 CAMPTOTHECINS
First isolated from the bark and stem of Camptotheca acuminata
(Camptotheca, Happy tree), a tree native to China used as a cancer treatment
in Traditional Chinese Medicine

• Camptothecin(parent)
• Derivatives:
• Topotecan, Irinotecan
 CAMPTOTHECINS-MOA

• Inhibits topoisomerase I activity

• Topoisomerase I cuts and re-ligates single DNA strands
during normal DNA repair process
• Resulting in DNA strand breakage
• S-phase specific
DRUG NOTES t1/2 Elimn

TOPOTECAN &
IRINOTECAN IV 2-3 hrs Topotecan is
35% PPB eliminated
renally
Toxicity: Irinotecan
and its
Topotecan- includes neutropenia, metabolite
thrombocytopenia, anemia are
Irinotecan- Severe diarrhea, eliminated
myelosuppression in bile and
faeces

Clinical use:
Topotecan- Second-line therapy for advanced
ovarian cancer (cisplatin-resistant), and small
cell lung cancer
Irinotecan- Colon and Rectal cancer
 TAXANES
• Paclitaxel (Taxol)
• Docetaxel

• Isolated from the bark of the Pacific yew tree, Taxus

brevifolia
 TAXANES-MOA

• Mitotic “spindle poison” through the enhancement of

tubulin polymerization
• They differ from vinca alkaloids as they bind to different
site on β-tubulin, where they antagonize microtubule dis-
assembly causing mitotic arrest
Resistance
• Increase transport out of the tumour cells (Paclitaxel)
• Mutations in tubulin structure
DRUG NOTES t1/2 Elimn

PACLITAXEL & Extensively

DOCETAXEL Both drugs admin. IV 1-6 hrs metabolized
by the liver
excreted in
Toxicity: urine(10%)
Paclitaxel- includes neutropenia,
thrombocytopenia, peripheral
neuropathy, possible hypertensive rxns
during infusion, alopecia, mild
hypotension and bradycardia
Docetaxel- causes neurotoxicity and
bone marrow suppression

Clinical use:
Paclitaxel- therapy against carcinomas of the
breast, ovary, lung, and head and neck (used
in combination with cisplatin)
Docetaxel- therapy against advanced breast
cancer
 ANTITUMOR ANTIBIOTICS
• Substances of microbial origin that prevent
mammalian cell division

• These are natural products that are produced from

various strains of the soil bacteria, Streptomyces
Examples:
• Anthracyclines: Doxorubicin, Daunorubicin
• Chromomycins: Dactinomycin
• Bleomycin
• Mitomycin
• Newer Anthracycline agents: Epirubicin, Idarubicin
 ANTHRACYCLINES-MOA

Doxorubicin and Daunorubicin

• High-affinity binding to DNA through intercalation,
resulting in blockade of DNA and RNA synthesis
• DNA strand scission occurs via inhibition of
topoisomerase II activity
• Generation of free radicals of oxygen
• S-phase are most sensitive
DRUG NOTES t1/2 Elimn
DOXORUBICIN
& Both drugs admin. IV Biphasic Metaboliz
DAUNORUBICIN (doxorub ed by the
Rapid absorption in all tissues except
CNS icin) : 1 liver
Extensive tissue binding and excreted
17hrs in in bile
Toxicity:
humans and urine
Bone marrow suppression, total
alopecia, Cardiac toxicity-
cardiomyopathy (due to free radical
production)
Clinical use:
Doxorubicin- therapy against
Hodgkin’s & Non-Hodgkin’s lymphoma,
myelomas, sarcomas, breast, lung and
ovarian cancers
Daunorubicin- therapy against acute
leukemia,
Idarubicin- use in acute myelogenous
leukemia
 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 DNA-
bleomycin-Fe(II) complex and leads to chromosomal
aberrations
• CCS (cell cycle specific) drug that causes accumulation of
cells in G2
DRUG NOTES t1/2 Elimn
BLEOMYCIN
Admin. IV, IM, SC, poor O 115 Hepatic
45% systemic absorption mins metabolism
1% PPB Excreted by
Extensive tissue binding the kidneys
Toxicity: Pulmonary dysfunction
(pneumonitis, fibrosis), Hypersensitivity
reactions(chills, fever, anaphylaxis),
alopecia, blister formation

Clinical use: Testicular carcinomas,

Hodgkin’s and non-Hodgkin’s
lymphomas, squamous cell carcinomas
of head and neck, cervix and skin
 MITOMYCIN

• Undergoes metabolic activation to produce a cell-cycle

non-specific DNA alkylating agent

• Potent DNA cross-linking activity.

DRUG NOTES t1/2 Elimn
MITOMYCIN
Admin. IV 8- Hepatic
Toxicity: severe myelosuppression, 48mins metabolis
nephrotoxicity, interstitial pneumonitis m
10%
Clinical use: Carcinomas of the excreted
stomach, pancreas, cervix, colon and unchanged
lung in the
urine
 HORMONAL AGENTS

• Corticosteroids: Prednisone
• Gonadal Hormone Antagonists: Tamoxifen, Flutamide
• Gonadotropin-Releasing Hormone(GnRH) Analogs:
Leuprolide(Lupron, Eligard, Viadur), Goserelin(Zoladex)
and Nafarelin
 Gonadal Hormone Antagonists-
MOA

Tamoxifen
• Selective estrogen receptor modulator(SERM)
• Blocks the binding of estrogen to receptors of estrogen
sensitive cancer cells in breast tissue
• Directly inhibits in vitro growth of human breast cancer
cells that contain estrogen receptors
DRUG NOTES t1/2 Elimn
TAMOXIFEN
(Nolvadex) Admin. O Biphasic: Hepatic
Reaches peak plasma levels after 4–7 7–14 hrs metaboli
hours and 4–11 sm by
Concentrated in estrogen target days CYP 450
tissues(ovaries, uterus, vaginal enzymes
epithelium and breast Excreted
in faeces

Toxicity: Hot flushes and nausea and

vomiting occur in 25% of patients,
occasional vaginal dryness or discharge,
mild nausea in 10% of patients

Clinical use: Breast cancer

 Gonadotropin-Releasing
Hormone(GnRH) Analogs
• Leuprolide acetate (Lupron, Eligard, Viadur)
• Goserelin acetate (Zoladex)
• Histrelin acetate (Vantas)
• Triptorelin pamoate (Trelstar)

 The goal of GnRH therapy for cancer is to suppress the

production of testosterone and estrogen and/or block its
effects at its tissue receptors.

 GnRH agonists suppresses the secretion of LH and slows the

spread of cancerous cells and helps alleviate the symptoms

 Therapy in prostatic carcinomas and breast cancers