Download Anticancer and Chemotherapy for pharmacy students

Anticancer and Chemotherapy
By:
Mohamed Fahad Al-Ajmi
INTRODUCTION
 Definition:
Under the influence of chemicals in
the environment, radiation or
viruses, the DNA in normal cells
may be transformed, possibly by a
single alteration or substitution of
one of the constituent purine bases,
in such a way that the normal
control mechanisms, which restrict
cell proliferation are removed.
INTRODUCTION
Cancer incidence and death by organ sites

Most common new cancer cases:
Male:
Prostate (29%)
Lung (15%)
Colon/rectum (10%)

Leading cancer deaths:
Male:
Lung (32%)
Prostate (13%)
Colon/rectum (9%)
Female:
Breast (30%)
Lung (13%)
Colon/rectum (11%)
Female:
Lung (25%)
Breast (16%)
Colon/rectum (11%)
INTRODUCTION

Terminology
 Hypertrophy:is the increase in size of
a tissue or organ through increase
in the size of the consistuent cells.
 Hyperplasia:is the increase in organ or
tissue size through increase in
cell number. Both hypertrophy and
hyperplasia are reversible on removal
of the growth stimuli
INTRODUCTION
Nomenclature
CARCINOGENESIS

The process by which a normal
cell is converted to a cancer or
malignant cell.
CARCINOGENESIS
Before discussing the details of molecular
basis of CARCINOGENESIS we need to now
how a normal cell divide (cell cycle).
The eukaryotic cell cycle
M
G1
G2
G0
S
S: Synthesis
M: Mitosis
G1, G2: Gaps between M and S
G0: Quiescent phase
DNA content change in cell cycle
Checkpoints: Point in the eukaryotic cell cycle where
progress through the cycle can be halted until
conditions are suitable for the cell to proceed to the
next stage.
Chromosomes
Unattached to the spindle
Mitotic checkpoint
G1 checkpoint
M
G1
G2
DNA damage
Incomplete
DNA replication
G2 checkpoint
G0
S
DNA damage
Unfavorable
growth conditions
Relationship of antitumor drug action to the
cell cycle
CARCINOGENESIS
Causes of cancer
CARCINOGENESIS
Causes of cancer:


Radiation
 Ionizing radiation
 UV light.
Viruses
 Papelloma virus
 AIDS virus
 Hepatitis virus
Major classes of anti-cancer drugs

Alkylating agents

Antimetabolites

Antibiotics

Antimitotics

Hormones and antagonists

Molecularly-targeted
therapy
Alkylating agents

Damage DNA in resting and cycling
cells




Most toxic to rapidly proliferating cells
Cell-cycle nonspecific.
Toxicities include bone marrow
suppression, acute and delayed GI
effects
Example: cyclophosphamide (Cytoxan)
May cause hemorrhagic cystitis,
particularly in dogs
 Keep well hydrated, encourage drinking

Alkylating agents

Mechanism of action: cross-link 2 strands of DNA leading to
impairment of DNA replication and RNA transcription.
Alkylating agents: examples


cyclophosphamide: creates guanine adducts
that block cell proliferation.
cisplatin and its analogues, such as oxaliplatin: form
DNA adducts and create inter or intrastrand crosslinks
that disrupt DNA synthesis.
Antimetabolites

Analogues of normal metabolites, incorporated
into DNA or RNA, resulting in abnormal nucleic
acids and inhibition of enzymes involved in
nucleotide biosynthesis
Purine
Synthesis
Ribonucleotides
Pyrimidine
Synthesis
Deoxyribonucleotides
DNA
RNA
Antimetabolites


Act in G1, S, G2 or M phases
Effective for high growth fraction
cancers
Antimetabolites


Act the S phase: inhibit DNA synthesis
Example: methotrexate
Mimics folic acid, which is needed for
synthesis of DNA, RNA and some amino
acids
 Toxicities include delayed GI effects and
bone marrow suppression

Antimetabolites: examples



Methotrexate: a folate analog inhibits
dihydrofolate reductase (DHFR), the enzyme
essential for nucleic acid synthesis.
5-fluorouracil (5-FU): a pyrimidine analog that
inhibits thymidylate synthase and also
interferes with RNA synthesis and function.
Gemcitabine: a pyrimidine analog that inhibits
DNA polymerase.
Methotrexate
DNA
5-FU
FH2: dihydrofolate
FH4: tetrahydrofolate
TMP: thymidine monophosphate
dUMP: deoxyuridine monophosphate
Antibiotics


Bacterial or fungal derivatives,
Mechanism of action:
intercalates within the DNA, causes single
and double strand breaks, and inhibits
topoisomerase II.
Damage DNA in cycling and noncycling
cells.
Examples:



1- Bleomycin:
Antibiotics
2- doxorubicin (Adriamycin)
 Rapid IV administration causes
histamine release, severe pruritis and
swelling (facial). Pretreat with H1 and
H2 receptor antagonists


Produces free radicals that damage
heart muscle, particularly in dogs
Vesicant
Inhibitors of topoisomerases
Etoposide
Topoisomerases: Cleavage, unwinding and re-annealing of DNA,
necessary for DNA replication and RNA transcription
Etoposide (VP-16): Inhibits topoisomerase II, leading to doublestrand DNA breaks
Antimitotics

Mechanism of action:



natural products that interfere with
microtubule synthesis and
degradation, leading to inhibition of
cell division.
Cell-cycle specific.
Examples:
1- Paclitaxel (Taxol): stabilizes
microtubules, inhibit the cell cycle during
mitosis.
Antimitotics
2- Vinca (plant) alkaloids





Act in M phase to inhibit mitosis
Vincristine and vinblastine
Both can cause bone marrow
suppression and neurotoxicity
Vesicants: cause blisters on contact
with skin, extravasation causes tissue
necrosis
Protective gear absolutely essential
Mechanism of antimitotics
Vinblastine
Paclitaxel
Hormones and antagonists

Mechanism of action:


inhibits synthesis or effects of the steroid
hormones that are necessary for growth of certain
tumors, such as breast and prostate tumors.
Examples:


Tamoxifen: binds to estrogen receptors (ER) as an
antagonist inhibitor of estrogen.
Anastrozole: inhibits aromatase, the enzyme that
catalyzes the final step in estrogen production.
Mechanisms of Tamoxifen
STI-571 (Gleevec, Imatinib)



A small molecule that inhibits Bcr-Abl tyrosine
kinase
Targets this enzyme which is over-expressed in
CML (chronic myeloid leukemia)
Taken by mouth daily for treatment of
refractory CML
Gefitinib (Iressa)



It inhibits the intracellular tyrosine kinase (TK) domain
of epidermal growth factor receptor (EGFR).
Recent research indicates that it inhibits growth of
cancer cells with mutations of the TK domain of EGFR.
It is approved for treatment of non-small cell lung
cancer refractory to standard chemotherapy. (~10%
patients have EGFR mutations)
Antibodies

Herceptin (Trastuzumab)


A recombinant monoclonal antibody against
epidermal growth factor receptor 2 (Her2); used
for treating refractory breast cancer overexpressing HER2 protein
Avastin (Bevacizumab)

A recombinant monoclonal antibody against
VEGF, which plays an important role in blood
vessel formation (angiogenesis); used for
treatment of colon cancer
Enzymes

L-asparaginase
Breaks down blood asparagine – needed
by some cancer cells for protein synthesis
 Used against lymphomas and some
leukemias
 Antigenic (large protein): hypersensitivity
reactions common

Side effects of chemotherapy
Common toxicities of chemotherapy

Organs with active cell division are
affected:




Bone marrow
GI tract mucosa
Hair follicles
These side-effects are often reversible.
Common toxicities

Bone marrow suppression:


Leukopenia, thrombocytopenia and anemia
Caused by most anti-cancer drugs except:
Bleomycin, vincristine, hormones, and most of
the molecularly-targeted agents.
Common toxicities

Gastrointestinal toxicity:
 Nausea and vomiting: cisplatin and anthracyclines
 Diarrhea: 5-FU, topotecan
 Mucositis: 5-FU

Alopecia (Hair loss): Paclitaxel, carboplatin,
anthracyclines.

Renal toxicity: Cisplatin

Pulmonary toxicity: Bleomycin (pulmonary fibrosis)

Peripheral neuropathy: Cisplatin, oxaliplatin and
paclitaxel
Long-term complications

Cardiomyopathy:


Leukemia:


Anthracyclines (Incidence exceeds
5% for high-dose of doxorubicin)
high-dose etoposide
Infertility:

Alkylating agents
Management of side-effects

Use antiemetics to prevent nausea/emesis


Anemia


Blood transfusion and/or erythropoietin (Epogen)
Neutropenia:



e.g. Zofran; a serotonin antagonist
Granulocyte-colony-stimulating factor (G-CSF,
Neuprogen)
To shorten duration of neutropenia
Thrombocytopenia:

Platelet transfusion and/or thrombopoietin
Guidelines for handling/administering
chemotherapeutic agents


Wear latex gloves, surgical mask, goggles,
protective clothing (eg, lab coat) when
handling
Dilute or mix drugs under laminar flow
hood (if available) or in low-traffic area
without air currents.


This helps prevent aerosolization of particles
Try to use drugs available as preservativefree solutions to avoid having to dilute
them
Guidelines
Guidelines
forfor
handling/administering
handling/administering
chemotherapeutic
chemotherapeutic
agents
agents




If drug must be diluted, use needle guard
(available from manufacturers)
Never “prime” needle by squirting drug into
air
Never use mouth to remove needle cap
Administer drugs through IV catheter to
avoid extravasation

Place carefully and check throughout infusion
Guidelines for handling/administering
chemotherapeutic agents



Pregnant women should not
handle/administer antineoplastic agents
Thoroughly wash hands before and after
handling/administering antineoplastic
agents
Prevent contact of agent with skin or
mucous membranes. If this occurs, wash
area immediately with large volumes of
water, document the contact and seek
medical assistance
Guidelines for handling/administering
antineoplastic agents

Place absorbent pad under patient’s
leg



If drug spills, allows disposal of pad
without contaminating table
Wear latex gloves when disposing of
vomit, urine or feces from animals
receiving antineoplastic agents
Maintain record of all exposure
during preparation, administration,
clean-up and spills