Kampala International University CANCER CHEMOTHERAPY 2017.ppt

CANCER CHEMOTHERAPY
Samuel Baker Obakiro
Dep’t of pharmacology
Kampala International University
samuel baker obakiro

Presentation outline
Introduction to cancer
Review of the cell cycle and its control
Treatment of cancer
Classification of anti-cancers
Discussion of the pharmacology of anti-
cancers (MOA/MOR, PK, INDICATION, SE, DI)

Introduction
• Cancer is a group of disorders that causes cells to escape
the normal controls (check points) of cell division
resulting into abnormal rapid uncontrolled proliferation
of cells.
• It may Involve any tissue of the body and take on many
different forms in each area.
• Cancer is among the leading cause of death globally
Characteristics of Cancer Cells
– Cancer cells divide rapidly (cell cycle is accelerated)
– They are “immortal”
– Cell-cell communication is altered (Lack of differentiation)
– Uncontrolled proliferation
– Invasiveness
– Ability to metastasize (uncontrolled cell division that results
in invasion of previously unaffected organs)

Possible causes of cancers
• Enviromental causes (pollutants,
ozone layer depletion)
• Life styles (smoking, chronic
alcoholism, lack of excrecise, chronic
stress)
• Diet (metallic contaminated foods,
poultry feeds, pesticides)
• Irrational drug use (self medication,
unnecesaary use of drugs)
• Chronic infections ( produce toxins)
• Occupation hazards ( manufacturing,
construction, laboratory, agriculture,
smelting and mining )
• Hereditary factors
• Physical agents (radiation, or injury)
• Chemicals (carcinogens, drugs )
• Mycotoxins (aflatoxins)

Types of cancers
• Carcinoma- cancer of the epithelial tissue
• Lymphoma –cancer of the lymph tissue
• Leukemia- cancer of blood
• Sarcoma- cancer of skelatal tissues (bones &
muscles)

Cancer prognosis
1. Initiation = important change introduced into cell
– Probably through DNA alteration
– leads to an event probably needed for tumor prod’n
– can be reversible unless promoted
2. Promotion = biochemical event encourages tumor
Formation
For cancer to occur there is need for both initiation and
promotion
– Initiators &promoters may be toxins OR radiation OR viruses
3. Progression = More damage resulting into tumors

Stages of cancer development
1. Initiation:
This involves carcinogens binding to DNA and causing heritable
changes in the genetic constitution of the cell.
This results into damage to the DNA.
The agents that bring about initiation are called initiators and
include polycyclic aromatic hydrocarbons, nitrosamines and
viruses, x-rays, ultra violet light.
Initiation is successful if the damaged DNA is not repaired.
However, if the cellular mechanisms repair the damage DNA, then
initiation fails.
Initiation doesn’t result into cancer unless it is promoted. This can
be reversed.
Initiated cells can therefore
1. Remain static in non- dividing state
2. Be cleared from the body by apoptosis
3. Be promoted and develop into neoplasms.
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2. Promotion
• This involves the initiated cells to undergo biochemical
changes that result into formation of pre- neoplastic
lesions.
• Agents that act at this stage are called tumor promoters
e.g. phenobarbital.
• Tumor promoters act by changing gene expression
resulting into sustained cell proliferation or inhibiting
apoptosis.
• However, themselves cannot cause mutations.
• Tumor promotion is reversible because in the event that
the promoting agent is removed, the focal cells may return
to the initiated stage and hence can be repaired.
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3. Progression
Genotoxic agents at this stage cause more irreversible
damage to the DNA.
The number of damaged cells increase rapidly.
This may result into a benign or malignant tumor.
Progressors are capable of causing more serious
chromosome abnormalities.
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THE PROCESS OF CARCINOGENESIS
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Neoplasms /tumours
Two major types: Benign & malignant
• Benign – “noncancerous”
– Local; cells cohesive, well-defined borders
– Push adjacent tissue away
– Doesn’t spread beyond original site
– Often has capsule of fibrous connective tissue
• Malignant – “cancerous” grow more rapidly;
– Not cohesive; seldom have capsule
– Irregular shape; disrupted architecture
– Invade surrounding cells
– Can break away to form second tumor
• Oncogenesis = Process of Tumor Development that involves
DNA sequencing that codes for key proteins in the tumour
• It results into decreased ability to differentiate and control of
replication and growth

Cancer versus normal cells
Cancer cells Normal cells
Large in size and have irregular shapes Small in size and have regular shapes
Divide rapidly and uncontrolled Divide slowly and controlled
No check points Check points present
Prone to more mitotic errors Less mitotic errors
No differentiation
Increase in growth factor secretion
Increase in oncogene expression
Loss of tumor suppressor genes
There is differentiation
Intermittent or coordinated growth
factor secretion
Oncogene expression is rare
Presence of tumor suppressor genes

The cell cycle
Involves four phases
1.M-phase (mitosis)
• G0- phase (Some times)
2.G1- phase (Gap one )
3. S- phase (synthesis)
4. G2- phase (Gap two)

Control of the Cell Cycle
Mechanisms for controlling progress through
the cell cycle:
Checkpoints
Length of Telomeres
Chemical Signals from within and outside the
cell

Chemical Signals that Control the Cell Cycle
1. Cyclin and Kinase
-proteins that initiate mitosis
-requires build up of cyclin to pair with kinase
Cyclins
– Proteins produced in synchrony with the cell cycle
- Regulate passage of the cell through cell cycle checkpoints
Cyclin-dependent kinases (Cdks)
– Enzymes that drive the cell cycle
- Activated only when bound by a cyclin
2. Hormones
- chemical signals from specialized glands that stimulate mitosis
3. Growth Factors
- chemical factors produced locally that stimulate mitosis

Check points in the Cell Cycle
The cell cycle is controlled at three checkpoints:
1. G1/S checkpoint: Mitosis complete, the cell checks
if there is no damage to DNA-the cell “decides” to
divide (Restriction check point),
2. G2/M checkpoint: DNA replication complete -the
cell makes a commitment to mitosis, cell ensures
that there is no damage to DNA (apoptosis check
point)
3 Late metaphase (spindle) checkpoint
This ensures that all chromosomes are attached to
spindle

Check points of the cell cycle

Apoptosis
• Programmed cell death (cell
suicide)
• Cascade of proteases initiate
process
Steps
1. Normal cell shrinks due to
condensation of chromatin
2. The cell membrane peels off
3. The nuclear membrane
collapses
4. Apoptotic bodies are formed
which digest the cellular
components
5. Disintegration of the
apoptotic bodies

Approaches in cancer treatment
Surgery Chemotherapy
Radiotherapy Immunotherapy

The Goals of Cancer chemotherapy
• Curative
– Total eradication of cancer cells
– Curable cancers include testicular tumors, Wills tumor
• Palliative
– Alleviation of symptoms
– Avoidance of life-threatening toxicity
– Increased survival and improved quality of life
• Adjuvant therapy
– Attempt to eradicate microscopic cancer after
surgery e.g. breast cancer & colorectal cancer

Cancer Combination Chemotherapy
• Combinations of agents with differing toxicities & mechanisms of
action are often employed to overcome the limited cell kill of individual
anti cancer agents.
• Each drug selected should be effective alone
3 advantages of combination therapy:
1. Suppression of drug resistance - less chance of a cell developing
resistance to 2 drugs than to 1 drug.
2. Increased cancer cell kill - administration of drugs with different
mechanisms of action is always synergistic.
3. Reduced injury to normal cells - by using a combination of drugs
that do not have overlapping toxicities, we can achieve a greater
anticancer effect than we could by using any one agent alone.

PHARMACOLOGY OF ANTICANCER
DRUGS

The Classification of Anticancer Drugs
Anticancers are classified using three criteria:
1. According to chemical structure and source of
Drug
2. According to mechanism of action of
anticancer drug
3. According to the cycle or phase specificity of
the drug

Classification cont’d
According to chemical
structure & source of
drug:
– Alkylating Agents
– Antimetabolite
– Antibiotics
– Plant Extracts
– Hormones
– others
According to mechanism of
action
• Drugs affecting biosynthesis
of nucleic acid
• Drugs destroying DNA
structure and function
• Drugs interfering with
protein synthesis
• Interfering with mitosis
• Hormonal agents
• Miscellaneous actions

According to the cycle or phase
specificity of the drug
1. CELL CYCLE - NONSPECIFIC
(CCNS)
-Cytotoxic in any phase of cell cycle
-Effective against slowly growing
tumors
2. CELL CYCLE - SPECIFIC (CCS)
-Cytotoxic in S phase
-Cytotoxic in M phase
-Effective against rapidly growing
tumors

The log kill hypothesis
• The magnitude of cells killed by anticancer
drugs is a logarithmic function.
• A given dose kills a constant proportion of cell
population rather than a constant number of
cells
• Eg a 3-log-kill dose of an effective drug will
reduce a cancer population of 1012 cells to 109
cells.

Mechanisms of anticancer
resistance
• Increased DNA repair
• Formation of trapping agents eg thiols.
• Changes in target enzymes
• Decreased activation of drugs
• Inactivation of drugs
• Increased drug efflux.

Anticancers
Common side effects
• Alopecia
• Myelosuppresion
• Emesis- prevent with
ondasenteron
• GIT distress
• Mucositis (stomatitis)
• Hyperuricaemia (gout) –
prevent with allupurinol
PK challenges
• Many excreted unchanged
• Others excreted via biliary tract
e.g. doxorubicin
• Metabolism of some creates
active metabolites e.g.
cyclophosphamide
• Cancer patients have pleural
effusions (ascites) that creates a
third space which reduces
plasma levels and aggravates
toxicity
• Many drugs don’t cross the
blood brain barrier

Complete the table below
Drug Mechanism of
action
Specific indications Specific adverse
effects
Cyclophosphamide
Doxorubicin
Cisplatin
Bleomycin
Vincristine
Prednisolone
Methotrexate

1. ALKYLATING AGENTS
• Nitrogen mustards first developed in 1940s
• Most widely used agent, often in combination
with other agents. Interact with DNA causing
substitution reactions, cross-linking reactions
or strand breaks
• CCNS killing ability
• USES: Hodgkin’s disease & lymphomas,
leukemias, lung, breast, ovary, testes, brain,
bladder

ALKYLATING AGENTS
• Nitrogen mustards → chlorambucil,
cyclophosphamide, mechlorethamine.
• Nitrosoureas → carmustine, lomustine.
• Alkylsulfonates → busulfan
• Platinum analogs → cisplatin, carboplatin,
oxaliplatin.
• Triazines →Dacarbazine, temozolomide,

General MOA of alkylating agents
• Transfers an alkyl group (carbon cations) to the
DNA
• 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.

Nitrogen mustards.
• Mechlorethamine.
Mechanism of action
• Converted into a reactive intermediate that
alkylates the N7 of guanine in DNA → cross
linking & depurination, hence DNA breakage.
• Also miscoding mutation.
Resistance
• Decreased drug permeability
• Increased conjugation with thiols
• Increased DNA repair.

MOA of mechlorethamine

• Admistered as freshly prepared solution IV
• Very little is excreted.
Clinical uses
• Hodgkin’s lymphoma
• Some solid tumors.

Adverse effects.
• GIT distress
• Myelosuppression
• Alopecia
• Sterility
• Extravasation → infiltrate area with sodium
thiosulfite.

Cyclophosphamide
• Most common, Prodrug – liver metabolised by
CYP P450 MFO’s
• One of its metabolites is acrolein - Acrolein
causes bladder toxicity with haemorrhagic
cystitis which can be prevent by prior
treatment with Mesna.
• Bladder cancer may develop years after
cyclophosphamide chemotherapy.
• Affects lymphocytes - Also
immunosuppressant
• Cyclophosphamide can also be given orally.

Metabolism of cyclosphamide

Indications
• Chronic lymphocytic leukemia, Burkitt’s
lymphoma, non-Hodgkin’s lymphomas, breast
and ovarian cancer, and a variety of other
cancers.
• Potent immunosuppressant, it is used in the
management of rheumatoid disorders and
autoimmune nephritis.
Adverse Effects:
• Alopecia, nausea, vomiting,
myelosuppression, and hemorrhagic cystitis

Nitrosoureas
Examples : Carmustine, Lomustine, Semustine
Streptozocin
Mechanism of action
• Nitrosureas (the other alkylators) inhibit the
synthesis of DNA, RNA and proteins through
alkylation of DNA
• All cross the blood brain barrier

PK
• Carmustine IV administered & lomustine
orally
• Penetrates all tissues including CNS due to
lipophilicity
• Metaolised extensively, lomustine
metabolised to active metabolite
• Excreted in urine.

Clinical uses.
• Treatment of brain tumors
• Streptozocin is used to treat insulinoma.
Adverse effects
• Bone marrow depression
• Diabetes with streptozocin.

Alkylsulfonates.
Busulfan.
• Is a bifunctional alkylating agent.
Clinical uses
• Chronic granulocytic leukemias.
Adverse effects
• Pulmonary fibrosis in aged pts
• Can cause leukemia (leukemogenic)

Platinum compounds
• Cell-cycle nonspecific activity
• Kinetics variable based on renal function
– Significant renal excretion
– Significant renal toxicity
Clinical uses.
• Cisplatin → testicular carcinoma, ovarian
carcinoma, bladder carcinoma.
• Carboplatin → for pts who can not tolerate
cisplatin
• Oxaliplatin → advanced colorectal cancer

PK
• Administered IV in saline solution
• Intraperitoneally for ovarian cancer
• Intraarterially to perfuse other organs
• Carboplatin binds 90 % to plsma proteins
• High conc found in liver, kidney, intestine,
testicular & ovarian cells
• Very little reaches the CNS
• Are excreted by renal route.

Toxicities of Platinum cpds
• Cisplatin (CDDP)
– Most nephrotoxic, emetogenic
– Thought to be more efficacious than carboplatin
• Carboplatin
– Less emetogenic and nephrotoxic
– AUC dosing a little tricky sometimes
• Oxaliplatin
– Minimal nephrotoxicity, moderate emetogenicity
– Neuropathy severe

Cisplatin: Case example
Mechanism of Action:
• Cis-platin binds to DNA and proteins & the
interaction is stabilized by hydrogen bonding
– cause unwinding & shortening of DNA helix
• Has a long t1/2 (72 h) due to extensive protein
binding & slow renal elimination

Indications:
• Cisplatin has efficacy against a wide range of
neoplasms.
• Made significant impact on treatment of
testicular teratoma & ovarian tumors.
• Given IV as a first-line drug -testicular, ovarian
& bladder cancer
• Useful in treatment of melanoma & other solid
tumors

Adverse Effect Cisplatin :
• Cisplatin produces relatively little
myelosuppression but can cause severe
nausea, vomiting, and nephrotoxicity.
• Severe nausea and vomiting is ameliorated
with 5-HT3 antagonists
• Nephrotoxicity, ototoxicity, peripheral sensory
neuropthy may also occur

Antimetabolites.
Includes.
• Antifolates →methotrexate
• Purine analogs →6-mercaptopurine,
thioguanine
• Pyrimidine analogs →Fluorouracil, cytarabine,
gemcitabine etc.

Methotrexate
• Is an antifolate
Mechanism of action
• Inhibit conversion of dihydrofolate to tetrahydrofolate
• Deprives the cell of terahydrofolate
• Reduced production of cells requiring methylation
reactions, DNA, RNA, Proteins.
Resistance occur due to;
• Increased production of DHFR enzyme
• Decreased DHFR affinity for methotrexate
• Reduced drug uptake by the cancer cells.

• Administration, oral, IV, IM, Intrathecal.
• Metabolized to 7-hydroxymethotrexate, excreted in
urine.
Clinical uses
• Acute lymphocytic leukemia
• Choriocarcinoma
• Breast cancer
• Burkit’s lymphoma
• Head & neck cancers
• Rhuematoid arthritis
• Chron’s disease
• Etc.

Adverse effects
• Stomatitis
• Alopecia
• Nausea & vomiting
• Erythema
• hepatotoxicity
Administer leucovorin or folinic acid to prevent
adverse effects.

6-mercaptopurine
• Is a thiol analog of hypoxanthine.
Mechanism of action
• Actived by hypoxanthine-guanine
phosphoribosyltransferases to toxic
nucleotides that inhibits enzymes involved in
purine metabolism
• Have low oral bioavailability due to first pass
metabolism.
• Allopurinol inhibit metabolism of 6-MP.

Clinical uses
• Acute leukemias
• Chronic myelocytic leukemias
Side effects
• Bone marrow depression →dose limiting
• Hepatic dysfunction→ cholestasis, jaundice &
necrosis.

Fluorouracil
• An analog of uracil
Mechanism of action
• Converted to 5-fluorodeoxyuridine
monophosphate and competes with
deoxyuridine monophosphate for thymidylate
synthase
• Contains F instead of H at position 5 thus
inhibit formation of thymidine leading to
thymineless death of cells.

• Administered IV or Topically
• Well distributed including CNS
• Metabolised in liver, lungs & kidneys
• Excreted in urine
Clinical uses
• Bladder cancer
• Breast cancer
• Colon cancer
• Head & neck
• Liver & ovarian cancers
• Superficial keratosis
• Basal cell carcinoma

Side effects
• GIT disturbances→ N & V, oral ulceration,
diarrhea, anorexia. Use allopurinal mouth
wash to reduce. (lippincotts, 2010)
• Bone marrow depression → bolus injections
• Alopecia

Plant alkaloids
• Vinca alkaloids →vincristine, vinblastine,
vinorelbine
• Podophyllotoxins →etoposide, teniposide
• Camptothecins → topotecan, irinotecan
• Taxanes → paclitaxel, docetaxel.

Vinca Alkaloids
• Vincristine, vinblastine, vinorelbine
Mechanism of action
• Prevents polymerisation of tubulin to form
microtubules →inhibition of mitosis.
Resistance
• Drug efflux
• Alteration in tubulin structure
samuel baker oakiro

• Administered IV, does not penetrate CNS.
• Cleared by biliary excretion
Clinical uses
Vincristine
• Acute leukemias
• Lymphomas
• Wilm’s tumor
• Choriocarcinomas

Vinblastine
• Lymphomas
• Neuroblastoma
• Testicular carcinoma
• Kaposi’s sarcoma
Vinorelbine
• Non-small cell lung cancer
• Breast cancer

Side effects
Vinblastine vinorelbine
• GIT distress
• Allopecia
• Bone marrow depression
Vincristine
• Neurotoxicity → areflexia, peripheral neuritis
& paralytic illius.

The podophyllotoxins
• Etoposide & teniposide
Mechanism of action.
• Binds to topoisomerase II & leads to
degradation of DNA
• Thought to inhibit mitochondrial electron
transport chain.
Resistance
• Drug efflux
• Mutation in topoisomerase II.

• Etoposide given IV, Orally & teniposide IV.
• Binds plasma proteins highly, Well distributed
but poorly in CNS.
• Metabolised to glucuronides & sulfate &
excreted in urine.
Clinical uses
• Oat cell carcinoma of the lungs
• Testicular carcinoma in combination with
bleomycin & cysplatin.

Toxicity.
• Alopecia
• Anaphylactic reactions
• Nausea & vomiting.

The camptothecin.
• Topotecan & irinotecan
Mechanism of action
• Inhibits topoisomerase I an enzyme necessary for
DNA replication.
• Results in DNA damage.
• Resistance
• Drug efflux
• Inability to convert drug to active metabolite
• Mutation in topoisomeras I enzyme.

• Administered IV
• Metabolised by hydrolysis
• Metabolite excreted in urine.
Clinical uses
• Topotecan →2nd line in advanced ovarian
cancer & small cell lung cancer
• Irinotecan →metastatic colorectal cancer.

The taxanes.
• Paclitaxel & docetaxel.
• Binds to tubulin, causes their polymerisation
& inhibits disassembly of tubulin polymers
• Process leads to inhibition of chromosome
disintegregation.

Resistance
• Drug efflux
• Mutation in tabulin stracture.
• Administered IV
• Large Vd, does not enter CNS.
• Hepatic metabolism, excreted in bile, then
stool.

Clinical uses
• Advance ovarian cancer
• Metastatic breast cancer.
Adverse effects
• Neutropenia →dose limiting
• Peripheral neuropathy
• Transient asymptomatic bradycardia → paclitaxel
• Fluid retension → docetaxel.
• Alopecia
• Serious hypersensitivity rxn → give
dexamethasone, diphenhydramine or H2 blockers
before

ANTIBIOTICS.
• Includes;
• Anthracyclines; Doxorubicin & Daunorubicin.
• Glycopeptide; Bleomycin
• Dactinomycin
• Mitomycin.

Anthracyclines.
• Doxorubicin & Daunorubicin.
• Intercalate between base pairs & inhibit
topoisomerase II
• Generate free radicals
• Blocks DNA & RNA synthesis →DNA strand
scission.
• They are CCNS agents

PK
• Administered IV
• Metabolised in the liver and excreted in bile &
urine.
Clinical uses
• Doxorubicin →Hodgkin’s lymphoma,
myelomas, sarcomas, breast, endometrial,
lung & ovarian cancer and thyroid cancer.
• Daunorubicin →acute leukemia
• Idarubicin → acute myelogenous leukemias

Adverse effects
• Bone marrow supression
• GIT distress
• Severe alopecia
• Cardiotoxicity (distinctive s/e)
Prevention of carditoxicity
• Administer Dexrazoxane inhibit iron mediated
free ion generation.
• Liposomal formulations of doxorubicin may be
less cardiotoxic samuel baker obakiro

Glycopeptide.
• Bleomycin.
• Generates free radicals
• Binds to DNA, causes strand breaks
• Inhibits RNA synthesis
• Active mainly in G2 phase.

PK
• Admisitered parenterally
• Metabolised by tissue aminopeptidases
• Excreted in urine as metabolites and intact
drug.
Clinical uses
• Componet in Hodgkin’s lymphoma (ABVD
regimen→Adriamycin(doxorubicin), bleomycin, vinblastine &
dacarbazine) & testicular cancer (PVB
regimen→platinol (cisplatin), vinblastine & bleomycin)
• Treatment of lymphoma
• Treatment of squamous cell carcinoma.

Adverse effects
• Pulmonay dysfunctions (pneumonitis & fibrosis)
• Hypersensitivity reactions(chills, fever
anaphylaxis)
• Mucocutaneous reactions (alopecia, blisters
formation & hyperkeratosis)

Dactinomycin
• Mechanism of action.
• Binds to DNA and inhibits DNA-dependent
RNA synthesis.
PK
• Given parenterally
• Metabolised and excreted as metabolite &
parent drug in urine.

Clinical uses.
• Treatment of melanoma
• Treatment of Wilm’s tumor(Kidney cancer).
Adverse effects
• Bone marrow suppresssion
• Skin reactions
• GIT irritation.

Mitomycin
Mechanism of action
• Undergoes metabolism in the liver forming a
reactive metabolite that cross link (alkylates)
DNA.
PK
• IV administered
• Cleared by hepatic metabolism.

Clinical uses.
• Active against hypoxic tumor cells
• Adenocarcinomas of the cervix, stomach,
pancreas & lung.
Adverse effects
• Severere myelosuppression
• Cardiotoxicity
• Hepatotoxicity
• Pulmonary toxicity
• Renal toxicity

HORMONAL ANTICANCER DRUGS.
• Includes;
• Gonadal hormone antagonists;
Estrogen receptor modulators Tamoxifen, &
antagonist Toremifene.
Androgen receptor antagonist Flutamide
• GnRH analogs; leuprolide, goserelin & nafarelin.
• Aromataze inhibitors; aminoglutethimide,
anastrozole and letrozole.

Gonardal hormone antagonists
TAMOXIFENE
• Is an estrogen antagonist (SERM)
Mechanism of action
• Binds to estrogen receptors on estrogen
sensitive cancer cells and blocks estrogen
effects.
Resistance
• Decreased affinity for the receptors
• Presence of dysfunctional receptors

PK
• Orally administered
• Metabolised by the liver to agonists & antagonist
metabolites
• Excretd in bile as metabolites and unchanged drugs.
Clinical uses
• Breast cancer (estrogen responsive type)
Adverse effects.
• Hot flushes, Nausea & vomiting, Skin rash
• Vaginal bleeding, Hypercalcemia,
Thromboembolism , Visual disturbances

Antiandrogens.
• Flutamide, Nilutamide, Bicalutamide & cyproterone
• Are antiandrogen.
Mechanism of action
• Binds to androgen receptors & prevent their effects.
PK
• Are orally administered
• Cleared by the kidneys
Clinical uses
• Treatment of prostate cancer.
Adverse effects
• Gynecomastia, GIT distress,
• Liver problem with flutamide
• Visual problems with nilutamide

Gonadotropin releasing hormone
analogs.
• Leuprolide, goserelin & nafarelin
Mechanism of action
• Binds to GnRH receptors in the pituitary,
desensitize them and inhibits the release of
FSH & LH which reduces synthesis of androgen
& estrogen
PK
• Leuprolide is available as; sustained release
preparation, subcutaneous or deport injection
formulation.

Clinical uses
• Treatment of prostate cancer
• Metastatic cancer of the prostate
→leuprolide.
Adverse effects.
• Impotence
• Hot flushes
• Tumor flare. But these are minimal than with
estrogen. samuel baker obakiro

Aromataze inhibitors (Adrenal
hormone synthesis inhibitors)
• Aminoglutethimide
Mechanism of action
• Inhibit both the adrenal & extra-adrenal synthesis
of pregnenolone (precursor of estrogen) from
cholesterol
• Also inhibit hydrocortisone synthesis →give
together with hydrocortisone.
• NB: not commonly used due to better drugs
available.

Exemestane and formestane
• A steroidal irreversible inhibitor of aromataze.
PK
• Orally active & well distributed
• Metabolised by CYP3A4 isozymes
• Metabolites excreted in urine.
• Dose adjustment required in renal failure.

Anastrozole & Letrozole.
• Are imidazole aromataze inhibitors.
Mechanism of action
• Inhibits aromataze, an enzyme that converts
androstenedione (an androgenic precursor)to
estrone (an estrogen)
• Cause almost total inhibition of estrogen
synthesis.

PK
• Are orally active
• Cleared by liver metabolism
Clinical uses
• Treatment of breast cancer.
Adverse effects
• Nausea & Diarrhea
• Hot flushes
• Bone & back pain
• Dyspnea
• Peripheral edema.

MONOCLONAL ANTIBODIES.
• Genetically engineered antibodies that attack cancer cells
• Commonly used ones include; Trastuzumabs, Rituximabs,
Bevacizumab & Cetuximab, Gemtuzumab & Ozogamicin,
Alemtuzumab & Tositumumab.
Mechanism of action
• Not know but thought to be through;
• Down regulation of HER2- receptor expression (important
in breast cancer devt)
• Induction of antibody dependent cytotoxicity
• Decrease in angiogenesis due to an effect on vascular
endothelial growth factors.

PK
• Administered IV, does not cross the BBB
Clinical use
• Treatment of breast cancer
Adverse effects
• Congestive heart failure (most serious)
• Infusion related effects: fever, chill, headache,
dizziness, nausea & vomiting, abdominal pain
& back pain.

Rituximab
• It is a genetically engineered, chimeric
monoclonal antibodies directed against the
CD20 antigen expressed on surface of normal
& malignant B lymphocytes.
Mechanism of action
• Its Fab domain binds to the CD20 antigen on B
lymphocytes and its Fc domain recruits
immune effectors, inducing complement, cell-
mediated cytotoxicity of B cells

PK
• Administered IV
• Causes rapid depletion of both normal &
malignant B cells.
Clinical uses
• Treatment of post-transplant lymphoma.
• Treatment of chronic lymphocytic leukemia.

Adverse effects
• Hypotension
• Bronchospasm angioedema
• Fever & chills with first infusion in pts with
high circulating levels of neoplastic cells.
Prevented by pretreatment with
diphenhydramine.
• Tumor lysis syndrome (renal failure,
hyperkalemia, hypocalcemia, hyperuricemia &
hyperphosphatemia)
• Leukopenia, thrombocytopenia, &
neutropenia. samuel baker obakiro

Bevacimab.
• It is an anti-angiogenesis agent.
• It attaches to & stops vascular endothelial
growth factor from stimulating the formation
of new blood vessels in tumor cells.
PK
• Its infused IV

Clinical uses.
• Treatment of metastatic colorectal cancer with
5-FU.
Adverse effects.
• Hypertension
• Stomatitis
• GIT bleeding
• Proteinuria
• Heart failure.
• Bowel perforation, opening of healed wounds
& stroke are rare serious adverse effects.

Cetuximab.
• Is a chimeric monoclonal antibody.
• Targets the epidermal growth factor receptor
on the surface of cancer cells & interfering
with their growth.
PK
• Administered IV.

Clinical uses.
• Treatment of colorectal cancer in combination
with irinotecan.
Adverse effects.
• DIB
• Hypotension
• Interstitial lung disease.
• Rash, fever, constipation & abd pain also
occurs. samuel baker obakiro

ENZYMES
• L-Asparaginase
• It hydrolyses blood asparagine making it
unavailable for tumor cells that require it for
their growth.
Resistance
• Increased synthesis of asparagine.

PK
• Administered IV or IM
Clinical uses
• Treatment of childhood acute lymphocytic
leukemia.
Adverse effects.
• Hypersensitivity reactions.
• Decrease in clotting factors.
• Liver abnormalities
• Pancreatitis
• Seizure
• Coma due to ammonia toxicity

Interferon.
• Commonly used forms include; interferon α-
2a and α-2b.
Mechanism of action
• Exact mechanism unknown but thought to act
through;
• Synthesis of enzymes
• Suppression of cell proliferation
• Activation of macrophages
• Increased cytotoxicity of lymphocytes.

PK
• Administered either IM subcutaneous or IV.
• Filtered in kidneys & degraded during
reabsorption with minimal liver metabolism.
Clinical uses
• Interferon α-2a: hairy cell leukemia, chronic
myeloid leukemia Karposi’s sarcoma in AIDS.
• Interferon α-2b: hairy cell leukemia,
melanoma, follicular lymphoma and AIDS
related Kaposi’s sarcoma

Anticancer drugs

References.
• B G Katzung. Basic & Clinical pharmacology
11th edition
• Goodman & Gilman’s. pharmacological Basis
of Therapeutics 11th edition.
• Lippincott’s illustrated review pharmacology
4th edition
• Katzung & Trevor. Examination & Board
Review Pharmacology 9th edition.

Kampala International University CANCER CHEMOTHERAPY 2017.ppt

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