Anticancer drugs

Introduction
Cancer treatment employs
1- Surgery
2- Radiotherapy
3- Cytotoxic chemotherapy
4- Endocrine chemotherapy
5- Immunotherapy
6- Biological (targeted) Therapy
Principles of cancer chemotherapy

A- Treatment strategies
1- Goal of treatment
2- Indication for treatment
3- Tumor susceptibility and the goal of
treatment
a- Cell-cycle specificity of drugs
b- Tumor growth rate
C- Problems associated with
chemotherapy
1- Resistance
2- Multidrug resistance
3- Toxicity
a- Common adverse effects
b- Minimizing adverse effects
4- Treatment-induced tumors
 Individual anticancer drugs
1- Antimetabolite
A- Methotrexate
B- 6-mercaptopurine
C- 6-thioguanine
D- Fludarabine
E- 5-fluoruracil
F- Cytarabine
 Individual anticancer drugs
continued
2- Antibiotics
A- Dactinomycin
B- Doxorubicin and daunorubicin
C- Bleomycin
 Individual anticancer drugs
continued
3- Alkylating agents
A- Mechlorethamine
B- Cyclophosphamide and ifosfamide
C- Nitrosoureas
 Individual anticancer drugs
continued
4- Microtubule inhibiters
A- Vincristine and vinblastine
 Individual anticancer drugs
continued
4- Steroid hormone and antagonists
A- prednisolone
B- Tamoxifen
C- Aromatase inhibitors
1- Aminoglutethimide
2- Anastazole
D- Progestins
 Individual anticancer drugs
continued
E- Leuprlide and goserelin
F- Estrogens
G- Flutamide and nilutamide
 Individual anticancer drugs
continued
5- Monoclonal antibodies
A- Trastumab
B- Rituximab
C- Bevacizumab
 Individual anticancer drugs
continued
6- Other chemotherapeutic agents
A- Platinium coordination complexes
Cisplatin
Carbplatin
B- procarbazine
C- L-asparginase
D- Interferons
 1- Antimetabolites

They interfere with the availability of normal

pure and pyrimidine nucleotide precursors
either by inhibiting their synthesis or by
competing with them in DNA or RNA
synthesis
 1- Antimetabolites – continued
A- Methotrexate

Mechanism of action
It is structurally related to folic acid, and act as
an antagonist of that vitamin by inhibiting
dihydrofolate reductase - the enzyme that
converts folic acid to its active , coenzme
form, tetrahydrofolic acid
 1- Antimetabolites – continued
A- Methotrexate
Therapeutic uses
 MTX is used in combination with other drugs
against cancer such as lymphocytic leukema,
breast cancer, and head and neck carcenoma.
 MTX in a single dose used against certain
inflammatory diseases as
Sever psoriasis
Rheumatoid arthritis
Crohn disease
 1- Antimetabolites – continued
A- Methotrexate
Adverse effects
Common adverse effects
Nausea, vomiting and diarrhea
Stomitis, mylosupression, erythemia,rash
Renal damage
Hepatic function
 1- Antimetabolites
B- 6-mercaptopurine

Azathioprine is converted to 6-
mercaptopurine to produce its effects
 1- Antimetabolites
B- 6-mercaptopurine
Mechanism of action
1-Nucleotide formation
It must penetrate target cells and be converted
to its nucleotide analog.
2- Inhibition of purine synthesis
It blocks the first step of purine synthesis
3- Incorporation into nucleic acids
It is incorporated in the DNA and RNA lead to
non-functional nucleic acid
 1- Antimetabolites
B- 6-mercaptopurine
Main uses
Acute lymphocytic leukemia

Adverse effects
Bone marrow depression, anorexia,
hepatotoxocity
 1- Antimetabolites
C- 5- Fluorouracil
It is a pyridine analogue
It has a stable fluorine atom instead of hydrogen
atom at 5- position of the uracil ring
Depriving the cell of one of the essential
precursor for DNA synthesis
 1- Antimetabolites – cont
C- 5- Fluorouracil
Mechanism of action
It enters the cell through a carrier mediated
transport system and is converted to
deoxynucleotide (5-FdUMP)
5- FdUMP acts as a pseudosubstrate which
compete with deoxynucleotide monophosphate
for thymidylate synthase. DNA synthsis
decreases due to lack of thymidine
 1- Antimetabolites – cont
C- 5- Fluorouracil
Main uses
Slow growing solid tumor (colorectal, breast,
overian, pancreatic, gastric carcinoma)

Adverse effects
Sever ulceration of the oral and GI mucosa, bone
marrow depression
 2-Antibiotics
A- Dactinomycin
The antitumor antibiotics act on DNA and also
inhibit topoisomerase I and II produce free
radical play a major role in their cytotoxicity.
Mechanism of action
The drug intercalates into the miner grooves of
the double helex between guanine-cytosine
base pairs of DNA, forming a stable
dactinomycin-DNA complex.
 2-Antibiotics
A- Dactinomycin
Clinical uses
Wilms tumor
Gestational choriocarcinoma
Adverse effects
Bone marrow depression is the major limiting
toxicity
 2- Antibiotics
Doxoroubicin and daunorubicin
They are classified as anthracycline antibiotics
Mechanism of action
1- Intercalation in the DNA
2- Binding to cell membrane
3- Generation of Oxygen radicals
Uses
Breast cancer, lung cancer, acute lymphoctic
leukemia, lym.phoma
 2- Antibiotics
Doxoroubicin and daunorubicin
Adverse effects
Irreversible, dose-dependent cardiotoxicity
apparently a result of the generation of free
radicals and lipid peroxidation
Increased skin pigmentation is also seen
 2- Antibiotics
Bleomycin
Mechanism of action
A DNA-bleomycin-Fe2+ complex appears to
undergo oxidation to bleomycin-Fe3+. The
liberated electron react with oxygen to form
superoxide or hydroxyl radical which attack
DNA.
Uses
Testicular cancer-cure, lymphoma-not curative
 3- Antibiotics
Bleomycin
Adverse effects
Pulmonary toxicity, Hypertrophic skin,
hyperpigmentation
 3- Alkalyting agents

They bind covalently to nucleophilic groups on

various cell constituants.
Alkylation of DNA is probably the crucial
cytotoxic reaction that is lethal to the tumor
cell. Alkylating agents so not discriminate
between cycling and resting cells.
 3- Alkalyting agents
A- cyclophosphamide and Ifosfamide
They are very closely related to mustard agents.
They can be taken orally
 3- Alkalyting agents
A- cyclophosphamide and Ifosfamide
Mechanism of action
They are biotranformed to hydroxylated
intermediates by cytochrome p450 system. The
intermediate undergo break down to form the
active compounds, phosphoramide mustard
and acrolein. Phosphoramide mustard react
with DNA.
 3- Alkalyting agents
A- cyclophosphamide and Ifosfamide
Clinical uses
Broad spectum as a single or as a part of the
regimens to treat wide variety of neoplastic
diseases
Non-neoplastic disease such as nephrotic
syndrome and intractable rheumatoid arthrits
 3- Alkalyting agents
A- cyclophosphamide and Ifosfamide
Adverse effects
Bone marrow depression especially leukocytosis
Hemorrhagic cystitis which can lead to fibrosis
of the bladder
 4- Microtubule inhibitors
Vincrestine and vinblastine
These drugs are referred as vinica alkaloids,
since they are derived from the plant vinica
rosea.
Although they are similar in structure but they
are different in therapeutic use.
 4- Microtubule inhibitors
Vincrestine and vinblastine
Mechanism of action
They are both cell cycle specific and phase
specific, because they block mitosis in
metaphase (M phase).
Their binding to the microtubular protein,
tubulin, is GTP dependent and blocks the
ability of tubulin to polymerize to form
microtubules. The result dysfunctional spindle
apparatus
 4- Microtubule inhibitors
Vincrestine and vinblastine
Uses
Acute lymphocytic leukemia
Hodgkin and non- hodgkin lymphomas
Adverse effects
Phlebitis and cellulitis, if the drugs extravasate
during injection
Peripheral neuropathy
 5- Steroid hormone and their antagonists

1- Hormone-responsive
2- Hormone-dependent
3- Both
 5- Steroid hormone and their antagonists

A- Prednisone
uses: Lymphocytic leukemia, Hodgkin and
non- hodgkin lymphomas
B- Tamoxifen
Selective estrogen receptor modulator
Uses: Breast cancer in patients with positive
estrogen receptors
 5- Steroid hormone and their antagonists

C- Progestins
Megestrol
Uses:
Hormone responsive breast cancer and
endometrial neoplasm
However. Aromatase inhibitors are replasing
it in therapy
 5- Steroid hormone and their antagonists

D- Leuprolide and goserelin

They are synthetic nonapeptide analogs of
gonadotropin releasing hormone (GnRH).
They occupy GnRH receptor in the pituitary
and lead to its desensitization and
consequently inhibition of release of LH and
FSH. Thus both androgen and estrogen are
reduced.
Uses: Prostate cancer
Adverse effects: Impotence, hot flashes
 5- Steroid hormone and their antagonists

E- Flutamide, nilutamide
They are non steroidal antiandrogens. They
compete with the natural hormone for binding
to androgen receptor and prevent its
translocation into the nucleus
 5- Steroid hormone and their antagonists

Flutamide blocks the inhibitory effect of

testosterone on gonadotrophin secretion
causing increase in LH and testosterone
secretion. Therefore, it should always
administer with leuprolide or gasorelin which
can desensitize the hypothalamus pituitary axis
uses: Prostate cancer
Adverse effects: Gynecomastia, GI disturbance,
liver failure
 5- Steroid hormone and their antagonists

F- Aromatase inhibitors
The aromatase reaction is responsible for the extra-
adrenal synthesis of estrogen which take place in the
liver, fat and muscle and breast tissue, including
breast malignancies. Peripheral aromatization is an
important source of estrogen in postmenopausal
women.
Aminoglutethimide
Uses: Metastatic breast cancer in postmenopausal
women
Adverse effects: inhibition of hydrocortisone
 6- Monoclonal antibodies

They are created from B lymphocytes (from

immunized mice or hamster) fused with
immortal B lymphocyte tumor cells. The
resulting hybrid cells can be individually
cloned and each clone will produce antibodies
directed against single antigen type.
Recombinant technology has led to the
creation of humanized antibodies overcome
the immunologic problems observed in mouse
antibodies
 6- Monoclonal antibodies

Trastuzumab
Uses
In patients with metastatic breast cancer,
overexpression of transmembrane human
epidermal growth factor-receptor protein 2
(Her 2)
Adverse effects
Congestive heart failure is the most serious
toxicity, fever, chill, nausea, vomiting
 7- Other chemotherapeutic agents

Platinium coordination complex

Cisplatin, Oxaliplatin and carboplatin
Uses: solid tumor, bladder carcinoma,
Testicular carcinoma, ovarian carcinoma
 7- Other chemotherapeutic agents

Interferons
Recommbent DNA techniques in bacteria
produce interferons including interferon-α-2α
and -2β that are employed in treating
neoplastic diseases
 Interferons

After binding interferon, a series of complex

intracellular reactions take place including
enzyme synthesis, suppression of proliferation
activation of macrophage and increased
cytotoxity of lymphocyte.
Uses
Hairy cell leukemia, melanoma, and follicular
lymphoma.
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