Anticancer Drugs

Cancer (tumor or neoplasm)

refers to a heterogeneous group of disease
caused by an impairment of the normal
functioning of genes, which leads to genetic
damage.

characteristics of cancer cells:

• Uncontrolled growth
• ability to invade local tissues
• ability to spread (metastasize)
 Characteristics of Cancer Cells
• Cancer involves the development and
reproduction of abnormal cells
• Cancer cells are usually nonfunctional
• Cancer cell growth is not subject to normal
body control mechanisms
• Cancer cells eventually metastasize to other
organs via the circulatory and lymphatic
systems
 Tumor characteristics
• invade and destroy the surrounding tissue.
• The cells are genetically unstable
• loss of normal cell architecture results in cells
that are atypical of their origin.
• lose the ability to perform their usual
functions.
• metastasize, and consequently, recurrences
are common after removal or destruction of
the primary tumor.
 Invasion and metastasis
Two primary pathways of metastasis

• Hematogenous and

• Lymphatic.
 Metastasis
• This process is illustrated in the diverse
patterns of metastasis that are characteristic
of individual types of cancer
• Used to refer to solid tumor only
• E.g. colorectal cancer metastasizes to the
liver and prostrates cancer to the bone
 Metastasis
• 30% of patients will have metastatic tumor
>1 cm at the time of diagnosis
• Another 30% will have microscopic metastases
that are too small to be detected (the proof is
they have cancer recurrence even when the
tumor has been removed or destroyed)
 ETIOLOGY OF CANCER
• Carcinogenesis
– A cancer, is thought to develop from a cell in
which the normal mechanisms for control of
growth and proliferation are altered.
– Current evidence supports the concept of
carcinogenesis as a multistage process that is
genetically regulated
 ETIOLOGY OF CANCER
Genetic and Molecular Basis of Cancer

• Two major classes of genes are involved in

carcinogenesis:
- Oncogenes and
- Tumor suppressor genes
 ETIOLOGY OF CANCER
Oncogenes
• Oncogenes develop from normal genes,
called proto-oncogenes, and may have
important roles in all phases of
carcinogenesis.
• Proto-oncogenes are present in all cells and
are essential regulators of normal cellular
functions, including the cell cycle.
 ETIOLOGY OF CANCER
Oncogenes
• Genetic alteration of the proto-oncogene activates
the oncogene.
• These may be caused by carcinogenics or viruses
(mutations), or may be inherited
• The result is dysregulation of normal cell growth
and proliferation
 ETIOLOGY OF CANCER
Tumor suppressor
• Tumor suppressor genes regulate and
inhibit inappropriate cellular growth
and proliferation.
• Gene loss or mutation results in loss of
control over normal cell growth.
 ETIOLOGY OF CANCER
Tumor suppressor
Two common examples of tumor suppressor
genes are the retinoblastoma and p53 genes.

Mutation of p53 genes is one of the most

common genetic changes associated with
cancer, and is estimated to occur in half of
all malignancies.
Pathology of cancer: tumor origin
• Tumors may arise from any of four basic
tissue types
– epithelial tissue,
– connective tissue (i.e., muscle, bone, and
cartilage)
– Lymphoid tissue
– nerve tissue
 Pathology of cancer: tumor
origin
Malignant cells are divided into those of epithelial
origin or the other tissue types.

• Carcinomas are malignant growths arising

from epithelial cells.
• Sarcomas are malignant growths of muscle
or connective tissue.
• Adenocarcinoma is a malignant tumor
arising from glandular tissue.
 Invasion and metastasis
• Metastasis is the spread of neoplastic cells from
the primary tumor site to distant sites.
• many patients have detectable metastatic disease
at diagnosis.
• Once clinically evident distant metastases are
present, cancers are seldom curable
• microscopic cancer metastases
 Carcinogenesis
Phases :

a. Initiation: Exposure of normal cells to a carcinogen

produces genetic damage to a cell.

b. Promotion: The mutated cells become cancerous.

c. Progression: Invasion into local tissue and metastasis.

Types of cancer :
Benign tumors :
Slow growing, resemble normal cells, localized, and are not harmful.

Malignant tumors :
Proliferate more rapidly, invade and destroy surrounding tissues, and
harmful

Malignant cancers are further categorized :

a. Solid tumors

Carcinomas are tumors of epithelial cells. e.g., lung, colon, breast.

Sarcomas include tumors of connective tissue (e.g., osteosarcoma)

b. Hematological malignancies
Lymphomas are tumors of the lymphatic system
Leukemias are tumors of blood-forming elements.
Cancer incidence & death
 Causes of cancer
1. Viruses: hepatitis B virus, human papillomavirus

2. Environmental and occupational exposures:

ionizing & ultraviolet radiation
exposure to chemicals (vinyl chloride, benzene, and asbestos)

3. Lifestyle factors: high-fat, low-fiber diets, , alcohol

4. Medications: alkylating agents and immunosuppressants

5. Genetic factors : inherited mutations, cancer-causing genes

(oncogenes), and defective tumor-suppressor genes
 Staging of cancer :
(Categorizing of patients according to the extent of disease)

TNM classification
• T indicates tumor size; classified from 0 to 4 (0
means no tumor)
• N indicates the presence and extent of regional
lymph node spread
( classified from 0 to 3)
0 - no regional lymph node involvement and 3 -
extensive involvement.
• M indicates the presence of distant metastases.
classified as 0 (for absence) or 1 (for presence) of
distant metastases.
What does a value T2N1M0 indicate ?
 Staging and workup
• tumors should be staged to determine the
extent of disease before any definitive
treatment is initiated.
• Staging provides information on prognosis and
guides treatment selection.
• After treatment, the staging is usually repeated
to evaluate the effectiveness.
 Staging and workup
• Some cancers produce tumor markers

• Often nonspecific,

• more useful for monitoring response and

detecting recurrence than as diagnostic tools.
Gradation of toxicity:

I. do not require treatment

II. require symptomatic treatment, not life threatening

III. Potentially life threatening if left untreated

IV. actually life threatening

V. death
 Limit of clinical detection

Cell
number

Time
Tumor growth curve :
Because of the large number of cells required to produce symptoms and be clinically
detectable (approx 109 cells), the tumor may be in the plateau phase of the growth curve
by the time it is detected.
 RNA and the
enzymes produced
to prepare for Mitosis- cell divides into
duplication of the two daughter cells.
cell.

RNA &
protein
produced
to prepare
for DNA
synthesis.

DNA synthesis & replication

occurs
The Cell cycle
 Cell Cycle Specific (CCS) &
Cell Cycle Non-Specific Agents (CCNS)
 Cell-cycle specificity of drugs:
Cell-cycle specific :
Chemotherapeutic agents that are effective only against replicating
cells. Phase specific drugs are :

o M phase: mitotic inhibitors (e.g., vinca alkaloids), Taxane (Paclitaxel)

o G1 phase: asparaginase, prednisone
o S phase: antimetabolites (Methotrexate, 6-Mercaptopurine)
o G2 phase: Antibiotic (bleomycin), etoposide

Cell-cycle nonspecific :
Equally effective against tumors that have a low percentage of
replicating cells.
 Goal of chemotherapy
1. Cure : Requires aggressive therapy for a
prolonged period of time.
- lower the tumor cell burden below 103
- host immunological defenses takes over

2. Palliation : Chemotherapy may be given to

decrease tumor size, control growth, and reduce
symptoms. Given when
- complete eradication of the tumor unlikely
- patient refuses aggressive therapy
 Modalities of cancer treatment
The Major Modalities
• Surgery
• Radiation
• Chemotherapy
• Biological therapy
 Treatment of Cancer
• Surgery to remove solid tumors
• Radiation to kill cancer cells that have
spread to adjacent local or regional tissues
• Chemotherapy to kill cancer cells located
throughout the body
 Treatment protocols

Usually identified by an acronym

Eg. A common regimen called POMP( for acute lymphocytic leukemia)
P- prednisone
O- oncovin (vincristine)
M- methotrexate and
P- purinethol (mercaptopurine).
Therapy is scheduled intermittently (approx. 21 days apart)

Allow recovery of the patient's immune system

(reducing the risk of serious infection)

Adjuvant chemotherapy : Given after more definitive therapy, such as

surgery, to eliminate any remaining disease or undetected micrometastasis.
 Administration

• Intravenous (IV) administration is employed most

commonly.
• Other administration techniques include oral,
subcutaneous, intrathecal (spinal canal), intra-
arterial, intraperitoneal, intravesical (within urinary
bladder), continuous IV infusion, and hepatic
artery infusion.
Drugs that may be given intrathecally (spinal
canal) are methotrexate and cytarabine.
 Adverse effects

Common:
o narrow therapeutic index.
o Severe vomiting
o stomatitis, bone marrow suppression, and alopecia

Adverse reactions confined to specific agents

O cardiotoxicity with doxorubicin
O pulmonary fibrosis with bleomycin)
 Common Drug Toxicities
• Drugs affect cells with the fastest growth and
reproductive rates, especially bone marrow and
epithelial cells of the GI tract and skin
• Suppression of bone marrow and blood cell
reproduction leads to anemia, infection, bleeding
• Gastrointestinal disturbances and ulcerations
• Skin ulcerations and alopecia
• Nausea and vomiting is common due to the high
maximally tolerated doses that are required
CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS
A. Alkylating agents:
prototype of this class is mechlorethamine, or nitrogen mustard.
Alkylating agents cause cross-linking and abnormal base pairing of
DNA strands, which inhibit replication of the DNA. This mechanism
is known as alkylation. These are phase-nonspecific agents.
Examples Cisplatin, carboplatin, busulfan, chlorambucil
B. Antitumor antibiotics :
Most of the are obtained from organisms of the Streptomyces
genus. These agents may act by either alkylation (mitomycin) .
These are phase-nonspecific agents.
Examples Bleomycin, Dactinomycin
C. Antimetabolites
are structural analogs of naturally occurring substrates for
biochemical reactions. They inhibit DNA synthesis by acting as false
substitutions in the production of nucleic acids. These are S phase-
specific agents.
Examples 5fluorouracil, azacytidine
D. Mitotic inhibitors.
The taxanes promote microtubule assembly and stabilization, thus
prohibiting cell division. These are M phase-specific agents.
Examples : Vinblastin, vincristin,paclitaxel

E. Topoisomerase inhibitors
Inhibit the enzymes topoisomerase I or II. The topoisomerases are
necessary for DNA replication and RNA transcription. These are G2
phase-specific agents.
Examples : Etoposide, teniposide

F. Enzymes.
It causes the degradation of the essential amino acid asparagine to
aspartic acid and ammonia. Unlike normal cells, tumor cells lack the
ability to synthesize asparagine.This is a G1 phase-specific agent.
Examples : Asparaginase, pegasparaginase
G. Protein tyrosine kinase inhibitors.

These agents are also known as targeted agents because they affect
specific receptors to induce cancer cell death.
Example : Imatinib mesylate, erlotinib.

Imatinib mesylate causes apoptosis or arrest of growth in cells

expressing the Bcr-Abl oncoprotein.
Erlotinib is a selective inhibitor of epidermal growth factor receptor
(EGFR) tyrosine kinase. They blocks the tyrosine kinase signaling
cascade and inhibits cancer cell growth.
 I-Surgery
• The oldest cancer treatment
• The most invasive method
• Requires patient be able to tolerate physical
challenges of surgery
• Was only method that could produce cures
• Still provides the best chance of cure for most
patients with solid tumors.
 I-Surgery
• Uses
– Treat the primary cancer
– To remove isolated metastatic masses
– To make other methods of treatment
possible e.g. providing access for
chemotherapy delivery (implanted
infusion pumps)
 I-SURGERY
• Diagnosis and Staging
• Reconstruct anatomical defects to improve
function, cosmetic appearance, and quality of
life
• Prevention
– Permitting the removal of precancerous lesions
such as abnormal moles or colon polyps.
 I-SURGERY
•Debulking
–Reduce the size of the tumor even though the entire tumor cannot be
resected

• To relive pain or other symptoms

• Increase effectiveness of radiation or
chemotherapy
 I-SURGERY
•Surgical removal of a source of
hormone
–A form of hormonal therapy
–Used in to treat tumors whose growth depends on
those hormones
–Most common type: removal of testes in prostate
cancer and removal of ovaries in breast cancer.
 II- Radiation
• It is the destruction of cancer cells by ionizing
radiation
• A component of treatment for ½-2/3 of all
patients with cancer
• Radiation is usually generated by machines
outside the patient (external beam radiation)
 II- Radiation
• Less commonly radiation sources are placed
close to the body surface or within the body
cavity (brachy-therapy)
• Sometimes radiation sources are implanted
into or around cancerous tissue (interstitial
brachytherapy)
 II- Radiation
• Usually administered in small doses over
several weeks (fractionating)
• fractionating permits the administration of
levels of radiation sufficient to kill tumor
cells while allowing normal surrounding
tissue to recover from damage
 II- Radiation
Side Effects
• Radiation can never be directed only at tumor and
normal cells and tissue are also damaged
• The most sensitive tissues are those that undergo
continuous cell renewal such as the skin, hair , GI
mucosa, bone marrow, reproductive tissue, and
sweat glands
• In slowly growing tissue such as lungs, effects of
radiation is seen much later
 II- RADIATION
Side effects:
• the ability to produce a cure with
radiation will depend on the capacity of
normal tissues surrounding the tumor to
withstand the toxic effects
– if the normal tissue are very sensitive, the range of
radiation doses used may be limited
 II- Radiation
• Radiocurability: ability to cure by radiation
• Depends on
– The size and location of the tumor
– Type of tumor
– Tumor’s radiosensitivity

• Curative radiation is limited to localized

tumors like surgery
 II- Radiation
Uses
• Curative for localized tumors
• Total body radiation to prepare for bone
marrow transplant , but highly toxic
• As supplement to surgery
• To destroy micro metasitasis
 II- Radiation
Uses
• Palliatively
– the most common used is to relive pain caused by
skeletal bone metastases
– such as seizures associated with brain metastases
– spinal cord compression caused by growth of
tumors on the spine
 III-CHEMOTHERAPY
• refers to the use of conventional cytotoxic
drugs in addition to hormonal and
endocrine therapy.
• Originally started in 1941, when Goodman
and Gilman first administered nitrogen
mustard to patients with lymphoma
 III-CHEMOTHERAPY
• Now there are > 50 conventional
cytotoxic agents and > 15
hormonal agents for cancer
treatment
 III-CHEMOTHERAPY
Cancer chemotherapy may be
• Primary
• Palliative
• Adjuvant
• neoadjuvant
 Alkylator Drugs
• Irreversibly bind to DNA and interfere with cell
replication and synthesis of essential cell proteins
and metabolites
• Some alkylators are vesicants and will cause
blistering if spilled on the skin
• Dose-limiting toxicity is bone marrow suppression
and resulting susceptibility to infection
• Adverse effects also include nausea, vomiting,
alopecia, and ulcerations of the GI tract and
mucous membranes
 Antimetabolite Drugs
• Inhibit the synthesis of folic acid, purines,
and pyrimidines needed to synthesize DNA
• Antimetabolites are particularly effective in
the treatment of leukemias
• Bone marrow suppression, GI ulcerations,
alopecia, and nausea and vomiting are
common toxicities
 Drugs Derived from Plants
• Vinca alkaloids cause metaphase arrest and inhibit
mitosis; neurotoxicity and leukopenia are the
primary toxicities
• Etoposide and teniposide inhibit the function of
DNA; adverse effects include nausea and
vomiting, leukopenia, and alopecia
• Paclitaxel inhibits mitosis; peripheral neuropathy
and bone marrow suppression are the most serious
toxicities
 Hormone Antagonists
• The female hormone estrogen is a growth factor
for some types of breast cancer
• Tamoxifen is an estrogen receptor blocker that
inhibits the growth of breast cancer cells
• Adverse effects include nausea, hot flashes, rash,
and menstrual irregularities
• Leuprolide and goserelin inhibit the synthesis of
male and female sex hormones and are used in a
variety of hormonally dependent cancers
 IV-ENDOCRINE THERAPY
USES: as adjuvant therapy
 IV-ENDOCRINE THERAPY
• Corticosteroids
– Play important role in managing hematological malignancies
– Also in supportive care of patient with cancer

• Corticosteroids are lymphocytotoxic

• Useful in malignancies in which lymph
tissue are involved such as lymphocyetic
leukemia, lymphoma
 IV-ENDOCRINE THERAPY
• Hormone receptor tests measures the amount
of hormone receptors in cancer tissue.
• Hormones (such as estrogen and
progesterone) can attach to these receptors.
• If the test is positive, it is indicating that the
hormone is probably helping the cancer cells
to grow.
 V- BIOLOGICAL THERAPY
The immune system is an effective antitumor
defense
• Malignant cells occasionally arise in healthy bodies
as a result of mutations but Not all these cells give
rise to clinically evident cancer
• There are rare cases of spontaneous remission from
metastatic cancer
• An intact immune system can identify malignant
cells and destroy them without negative effects on
normal cells.
 V- BIOLOGICAL THERAPY
What are the different types of
biological therapies?
1-Nonspecific immunomodulating agents:
Drugs that stimulate the immune system,
causing it to produce more cytokines and
antibodies to help fight cancer and
infections in the body.
 V- BIOLOGICAL THERAPY
2-Biological response modifiers (BRMs):
They change the way the body's defenses interact
with cancer cells.
• boost the body's ability to fight the disease.
• direct the immune system's disease fighting powers
to disease cells.
• strengthen a weakened immune system.
 V- BIOLOGICAL THERAPY
1-Interferons (IFN)
• A type of BRM that naturally occurs in the body.
• They have been shown to improve the way a
cancer patient's immune system acts against
cancer cells.
– INFs may work directly on cancer cells to slow their growth,
– they may cause cancer cells to change into cells with more normal behavior.

• Some INFs may also stimulate natural killer cells,

T cells, and macrophages.
V- BIOLOGICAL THERAPY
2-Interleukins (IL): (Aldesleukin)
–Proteins (cytokines) that occur naturally in the
body
–stimulate the growth and activity of immune cells,
such as lymphocytes, which work to destroy cancer
cells
 Antibiotic Drugs
• Inhibit the synthesis of DNA and other
essential cell functions
• Drugs are too toxic for treatment of
common bacterial infections
• The dose-limiting toxicity is usually bone
marrow suppression and cardiac toxicity
• Doxorubicin is widely used to treat
leukemias and a variety of solid tumors
 Combination chemotherapy
• administration of multiple agents to
overcome factors for decreased patient
response
• Drugs that possess minimally overlapping
mechanisms of action and toxicities are
combined
• Combination of chemotherpay with bioligical
therapy
 Combination chemotherapy
more effective than single-agent therapy

The reasons for administering combination chemotherapy include:

a. Overcoming or preventing resistance
b. Cytotoxicity to resting and dividing cells
c. Biochemical enhancement of effect
d. Rescue of normal cells

When combining chemotherapy agents, factors to consider include

a. Antitumor activity
b. Different mechanisms of action
c. Minimally overlapping toxicities