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ANTICANCER DRUGS I
PHARMACOLOGY IV
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Introduction
• Modern cancer chemotherapy originated in the 1940s with the
demonstration that nitrogen mustard possessed antitumor activity
against human lymphomas and leukemias.
• Cancer involves a group of relatively normal cell diving
without controls that usually prevent the cells from growing
beyond their usual size, site and nutritional base.
• Cancer now considered a long-term illness with many subgroup.
• Cancer is a collective term for several disease each with its own
characteristics and natural history according to where it has
started.
• The term cancer is used to describe more than 200 different
disease including those affecting organs (Solid tumors) and
hematological malignancies (which are not localized in the
same way).
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Introduction
• Before treatment, the patient must be carefully staged to
establish the type and extent of disease.
• Depending on the stage of disease, the aim of treatment may
be cure, prolongation of survival or symptom control.
• Treatment options depend on NOT only on the gold standard
of treatment but also patient factors and preference.
• Therapy may include surgery, radiotherapy, chemotherapy
and biological or targeted therapy as single modalities or in
combination.
• Biotherapy (biological therapy or targeted therapy) is a cancer
treatment that restores or boosts the body’s own immune
system to stop or slow the growth of cancer cells and keep
cancer from spreading. Cancer vaccines, and growth factors
are types of biotherapy.
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Etiology
• The incidence, geographic distribution, and behavior of specific
types of cancer are related to multiple factors, including sex,
age, race, genetic predisposition, and exposure to
environmental carcinogens.
• Of these factors, environmental exposure is probably most
important.
• Exposure to ionizing radiation has been well documented as
a significant risk factor for a number of cancers, including acute
leukemias, thyroid cancer, breast cancer, lung cancer, soft
tissue sarcoma, and basal cell skin cancers.
• Chemical carcinogens (particularly those in tobacco smoke)
as well as azo dyes, aflatoxins, asbestos, benzene, and radon
have all been well documented as leading to cancer in animals
and humans.
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Etiology
• Several viruses have been implicated in the etiology of various
human cancers.
• For example,
i. hepatitis B and hepatitis C are associated with the
development of hepatocellular cancer
ii. HIV is associated with Hodgkin's and non-Hodgkin's
lymphomas
iii. human papillomavirus is associated with cervical cancer
iv. Ebstein-Barr virus is associated with nasopharyngeal
cancer
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Etiology
• A number of rare tumors known to be associated with an
inherited predisposition, where an individual is born with a
marked susceptibility to cancer.
• This is due to inheritance of single genetic mutation which
may be sufficient to greatly increase the risk of one or more
types of cancer.
• Examples include:
i. pediatrics malignancies
ii. Wilms’ tumor of kidney
iii. bilateral retinoblastoma, a rare cancer of the eye
iv. Some common cancer such as breast, ovarian and
colorectal cancer may also show a tendency to occur in
families.
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Prevention
Avoiding tobacco use, especially exposure to cigarette smoke
Moderate alcohol consumption
Healthier eating
Limiting to exposure to sunlight and artificial tanning UV
exposure
Encouraging physical exercises
Maintaining a healthy body weight
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Chemoprevention
• Chemoprevention is the prevention of cancer by using
medication.
• The most common example is tamoxifen (pre-monopausal
woman) or an aromatase inhibitor (post menopausal women)
prescribed daily for 5 years to reduce the risk of developing
breast cancer in high risk woman.
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Cancer Chemotherapy
• Cancer chemotherapy remains an interesting area of pharmacology.
• On the one hand, use of anticancer drugs produces high rates of
cure of diseases, which, without chemotherapy, result in
extremely high mortality rates (eg, acute lymphocytic leukemia in
children, testicular cancer, and Hodgkin's lymphoma).
• Furthermore, as a group, the anticancer drugs are more toxic than
any other pharmacological agents, and thus their benefit must be
carefully weighed against their risks.
• Many of the available drugs are cytotoxic agents that act on all
dividing cells, cancerous or normal.
• The ultimate goal in cancer chemotherapy is to use advances in
cell biology to develop drugs that selectively target specific cancer
cells.
• A few such agents are in clinical use, and many more are in
development.
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Cancer Chemotherapy
Cell cycle-nonspecific (CCNS) drug
An anticancer agent that acts on tumor stem cells when they
are traversing the cell cycle and when they are in the resting
phase
Cell cycle-specific (CCS) drug
An anticancer agent that acts selectively on tumor stem cells
when they are traversing the cell cycle and NOT when they are
in the G0 phase
Growth fraction
The proportion of cells in a tumor population that are actively
dividing
Myelosuppressant
A drug that suppresses the formation of mature blood cells
such as erythrocytes, leukocytes, and platelets. This effect is
also known as "bone marrow suppression" .
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Cancer Chemotherapy
Oncogene
A mutant form of a normal gene that is found in naturally
occurring tumors and which, when expressed in noncancerous
cells, causes them to behave like cancer cells .
Tumor suppressor genes
Are normal genes which have a protective effects against
oncogene and also known as anti-oncogenes.
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Cancer at the cellular level

• Cancer arises from the changes in genes that regulate cell
growth.
• For normal cell to transform into cancer cell, genetic changes
must occur to the genes that regulate cell growth and
differentiation.
• The nature of genetic changes may be a single point change
to DNA nucleotide or the complete loss/gain of an entire
chromosome.
• However, the most important factor is that genes which
regulate cell growth and or differentiation must altered to allow
the cell to grow in an uncontrolled manner.
• Most cancers require a series of genetic mutation in an cell
before invasive tumor results.
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The cancer cell

• Cancer cells differ from normal cells in that they function
differently.
• Inherently unstable, the may display different protein or
enzyme content and chrosomal abnormalities such as
deletion or translocation which may be associated with
difference in their susceptibility to chemotherapy or
radiotherapy.
• The changes in in internal structure and function lead to
changes in their appearance which are visible under light
microscopy, for example, larger and more varied appearance of
nuclei and loss of appearance of cell function such as gland
formation. This allowed them to be easy detected .
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Concepts in tumor cell biology

• The normal cell cycle consists of a definable sequence of events that
characterize the growth and division of cells and can be observed by
morphological and biochemical means.
• Two of the four phases of the cell cycle can be studied directly:
• The M-phase, or mitosis, is easily visible using light microscopy
because of chromosomal condensation, spindle formation, and cell
division.
• The S-phase is the period of DNA synthesis and is observed by
measuring the incorporation of titrated thymidine into cell nuclei.
• The duration of the S-phase in human tumors is 10 to 20 hours.
• This period is followed by the G2-phase, or period of preparation for
mitosis, in which cells contain a tetraploid number of chromosomes.
• The G2-phase lasts only 1 to 3 hours for most cell types, with mitosis
itself lasting approximately 1 hour.
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Concepts in tumor cell biology

• The two daughter cells enter the G1-phase, whose duration
varies from several hours to days.
• The G1-phase also can give rise to a resting state, termed G0,
in which cells are relatively inactive metabolically and are
resistant to most chemotherapeutic drugs.
• The generation time, or Tc, is the time required to complete
one cycle of cell growth and division.
• The factors that influence daughter cells to enter the G0, or
resting stage, are not well understood.
• Proliferating cells generally are more sensitive to
chemotherapy than are resting cells.
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Cancer Cell Cycle Kinetics

Cell Cycle Kinetics
• Cancer cell population kinetics and the cancer cell cycle
are important determinants of the actions and clinical uses of
anticancer drugs.
• Some anticancer drugs exert their actions on cells
undergoing cycling (cell cycle-specific [CCS] drugs), and
others (cell cycle-nonspecific [CCNS] drugs) kill tumor
cells in both cycling and resting phases of the cell cycle
(although cycling cell are more sensitive).
• CCS drugs are usually most effective when cells are in a
specific phase of the cell cycle .
• Both types of drugs are particularly effective when a large
proportion of the tumor cells are proliferating (ie, when the
growth fraction is high).
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Cancer Cell Cycle Kinetics

• Phases of the cell cycle that are
susceptible to the actions of cell
cycle-specific (CCS) drugs.
• All dividing cells—normal and
neoplastic—must traverse these
cell cycle phases before and
during cell division.
• Tumor cells are usually most
responsive to specific drugs (or
drug groups) in the phases
indicated.
• Cell cycle-nonspecific (CCNS)
drugs act on tumor cells while
they are actively cycling and
while they are in the resting
phase (G0).
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The log cell kill hypothesis

• Cytotoxic drugs act by first-order kinetics; that is, at a given dose,
they kill a constant fraction of the tumor cells rather than a fixed
number of cells.
• For example, a drug dose that would result in a three-log cell kill
(i.e.,99.9% cytotoxicity) would reduce the tumor burden of an animal
that has 108 leukemic cells to 105 cells.
• This killing of a fraction of cells rather than an absolute number per
dose is called the log cell kill hypothesis.
• The earliest detectable human cancers usually have a volume of at
least 1 cc and contain 109 (1 billion) cells.
• This number reflects the result of at least 30 cycles of cell division, or
cell doublings, and represents a kinetically advanced stage in the
tumor’s growth.
• Most patients actually have tumor burdens that are greater than 109.
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The log cell kill hypothesis

• Since the major limiting factor in chemotherapy is cytotoxicity to
normal tissues, only a limited log cell kill can be expected with each
individual treatment.
• Even in the absence of tumor regrowth, several cycles of
therapy would be required for eradication of the tumor,
assuming it was sensitive to the drugs employed.
• When a tumor has decreased in size to approximately 108
cells, it is generally no longer detectable clinically and is
considered a clinically complete remission.
• Regrowth of residual cells is the obvious cause of relapse in
patients who have achieved clinically complete remissions.
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