Chemotherapeutic agents and radiation therapy /certified fixed orthodontic courses by Indian dental academy

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Lecture 23

Ahmed Group

Lecture 23

Chemotherapeutic agents and
radiation therapy

Lecture 23

Ahmed Group

Chemotherapeutic agents and
radiation therapy
•
•
•
•
•

Classes of agents
Mechanisms of action
The oxygen effect in chemotherapy
Multiple drug resistance
Interactions of chemotherapeutic agents with
radiation therapy (chemoradiation therapy)
• Photodynamic therapy
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Inspired and developed initially by and for
radiation biologists:
- Many of the techniques and concepts used in
chemotherapy:
• quantitative tumor assay systems

• the concept of cell cycle and sensitivity changes
through the cell cycle;
• population kinetics
- Terms:
• growth fraction,
• dose
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Ahmed Group

Chemotherapy
The term introduced by Paul Erlich
1. Salvarsan, the savior of mankind. Described the use
of chemicals to treat parasites-arsenic compound
effective against trypanosome and syphilis.
2. Penicillin-WWII
3. Alkylating agents-WWI and WWII
4. Anticancer drugs-methotrexate and cyclophosphamide
5. Combination chemotherapy of lymphocytic leukemia
in the early 1960s. Multiple drugs with different
toxicities could be used in combination to cure tumors.
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Chemotherapy
Today a wide variety of anticancer agents are
used in clinical oncology. They have been
proven effective for:
•choriocarcinoma,
•acute lymphocytic leukemia of childhood
•Hodgkin’s disease
•certain non-Hodgkin’s lymphomas,
•some germ cell tumors of testes

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Ahmed Group

Chemotherapy of cancer – is the treatment
and control of metastatic disease, a cancer
that has become systemic and out of control.
There are 13 types of cancer for which cures are claimed
by chemotherapy; this accounts for about 10% of all
cancers.
Comparison: 12.5% of cancers are cured by radiation
therapy

½ x ½ x ½ rule
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Biologic basis of chemotherapy
Anticancer drugs work by affecting DNA synthesis or
function, they do not normally kill resting cells;
The effectiveness of the drug is limited by the growth
fraction of tumor, thus, small rapidly proliferating tumors
are more responsive to chemotherapy than the large ones.
Growth fraction decreases as tumor size increases.

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Ahmed Group


Cell-cycle specific, or phase-specific agents;
Cell-cycle nonspecific or phase-non-specific agents
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Ahmed Group


Lecture 23

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• Classes of agents
• Mechanisms of action
• The oxygen effect in chemotherapy
• Multiple drug resistance
• Interactions of chemotherapeutic agents with
radiation
therapy
(chemoradiation
therapy)
• Photodynamic therapy
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Classes of agents and mode of action
Four categories of most commonly used
chemotherapeutic agents:
•
•
•
•

Alkylating agents;
Antibiotics;
Antimetabolites
Miscellaneous: platinum complexes
procarbazine
plant alkaloids

Lecture 23

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Classes of agents
Alkylating agents
Highly reactive, substitute alkyl groups for hydrogen atoms of
organic compounds (ex. DNA).
Five classes: 1. Nitrogen mustard derivatives
2. Ethylenimine derivatives
3. Alkyl sulfonates
4. Triazine derivatives
5. Nitrozoureas
Most of them contain more than one alkylating group and therefore
considered polyfunctional alkylating agents.
As a class alkylating agents are considered to be cell-cycle nonspecific
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Classes of agents
Antibiotics
The clinically useful antibiotics are natural products
of various strains of the soil fungus Streptomyces.
The directly bind DNA, and inhibit DNA and RNA synthesis
As a class they behave as cell-cycle nonspecific agents.
Examples: Doxorubicin, Actinomycin D,
Bleomycin, Mitomycin C

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Classes of agents
Plant Alkaliods
Vinca alkaloid. Produced from the common periwinkle plant.
The clinically useful alkaloids are large complex molecules that
exert their antitumor effect by binding to cellular microtubular
proteins and inhibiting microtubular polymerization, the
essential compounds of the mitotic spindle.
Effect - mitotic arrest.
Taxanes - products of the yew tree. The toxicity of the leaves or
bark is caused by alkaloids taxanes.
Paclitaxel – is a natuarla product, a new class of antineoplastic
agents, the taxanes, that targets the microtubules.
The taxanes are potent microtubule-stabilizing agents, promoters
of microtubule assemly. This is in contrast to vinca.
They block cells in G2/M phases of the cell cycle.
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Classes of agents
Antimetabolites
Analogues of normal metabolites. The interact with enzymes
and damage cells by:
1. Substituting for a metabolite normally incorporated into a key
molecule
2. Competing successfully with a normal metabolite for
occupation of the catalytic site of a key enzyme
3. Competing with a normal metabolite that acts at an enzyme
regulatory site to alter the catalytic rate of the enzyme

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Classes of agents
Miscellaneous agents
Examples: Methylhydrazine, nitrosoureas, hydroxyurea,
cis-platinum, taxanes
Hydroxyurea. First synthesized in 1869 and was found to be
bone-marrow suppressive in 1928.
Used in treatment of cancer in the 1960s.
It is an inhibitor of ribonucleotide reductase, an enzyme essential
to DNA symthesis, and is consequently specifically cytotoxic
to cells in the S phase;
Cis-platinum. is an inorganic complex-platinum surrounded by
chlorine and ammonium ions. Cell-cycle nonspecific. Binds to
DNA causing cross-linking
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Summary

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Classes of agents
Dose-response relationship for six
commonly used chemotherapeutic
agents

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Classes of agents.

Another characteristic of
chemotherapy agents is that
the sensitivity to cell killing
varies enormously among cell
types.

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Classes of agents. Mechanisms of action
Sublethal and potentially lethal damage repair
Sublethal damage repair-an increase in survival if a dose of radiation
(or other cytotoxic agent) is divided into fractions. It tends to correlate
with the shoulder of the acute dose-response curve, but this is not
necessarily always true. Repair of potentially lethal damage is
manifested as an increase in survival if cells are held in a
nonproliferative state for some time after treatment.
Similar studies have been performed with a variety of chemotherapeutic
agents.
Next slide: potentially lethal damage repair is a significant factor in the
antibiotics bleomycin and doxorubicin
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Classes of agents.

Sublethal and potentially
lethal damage repair

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The presence or absence of oxygen has a dramatic influence
on the proportion of cells surviving a given dose of X-rays.
Situation with chemotherapeutic agents is more complicated.
Some agents, such as bleomycin, are more toxic to oxygenated
cells than to chronically hypoxic cells.

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Dose-response curves for cells exposed to graded concentrations
of bleomycin in the presence or absence of oxygen

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• Some of the drugs are more toxic to hypoxic that to aerated
conditions;
• Some of the drugs are more toxic to aerated conditions
• A third group of drugs appear to be equally cytotoxic to
aerated or hypoxic cells

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Resistance to chemotherapy and
hypoxic cytotoxins

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Drug resistance
During prolong exposure
to a cytostatic drug cells
become resistant to the
drug and the tumor
becomes unresponsive.

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Drug resistance
Underlying this problem are genetic changes that could be seen
sometimes in chromosome preparations

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Drug resistance
A debatable issue is whether cells that acquired resistance to
chemotherapeutic agents are also resistant to radiation.
Laboratory data show that the acquiring of resistance to a drug does
not necessarily result in radioresistance.

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Comparison of
chemotherapeutic
agents with radiation
There is much greater variation
of sensitivity to chemotherapeutic
agents than there is to radiation.
The response of one cell line to
nine different cytotoxic agents

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Comparison of
chemotherapeutic
There is much greater variation
of sensitivity to chemotherapeutic
agents than there is to radiation.
Figure shows the widely different
response to CCNU of three clones
derived from a common
astrocytoma cell line

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Adjunct use of chemotherapeutic
Spacial cooperation is the rationale for the combination of
radiation and chemotherapy

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Adjunct use of chemotherapeutic

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Photodynamic therapy

Cancer treatment using light to activate a photosensitizing
gent, thereby releasing cytotoxic free radicals.
When photosensitizers are exposed to a specific wavelength
of light, they produce a form of oxygen that kills nearby cells.

Each photosensitizer is activated by light of a specific wavelength.
This wavelength determines how far the light can travel into the body.
Thus, doctors use specific photosensitizers and wavelengths of light to
reat different areas of the body with PDT.

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How is PDT used to treat cancer?
In the first step of PDT for cancer treatment, a photosensitizing
agent is injected into the bloodstream. The agent is absorbed by
cells all over the body, but stays in cancer cells longer than it does
in normal cells. Approximately 24 to 72 hours after injection when
most of the agent has left normal cells but remains in cancer cells,
the tumor is exposed to light. The photosensitizer in the tumor
absorbs the light and produces an active form of oxygen that
destroys nearby cancer cells. In addition to directly killing cancer
cells, PDT appears to shrink or destroy tumors in two other ways.
The photosensitizer can damage to blood vessels in the tumor,
thereby preventing the cancer from receiving necessary nutrients.
In addition, PDT may activate the immune system to attack the
tumor cells.
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The light used for PDT can come from a laser or other sources of
light. Laser light can be directed through fiber optic cables (thin
fibers that transmit light) to deliver light to areas inside the body.
For example, a fiber optic cable can be inserted through an
endoscope (a thin, lighted tube used to look at tissues inside the
body) intothe lungs or esophagus to treat cancer in these organs.
Other light sources include light-emitting diodes (LEDs), which
may be used for surface tumors, such as skin cancer.
PDT is usually performed as an outpatient procedure. PDT may
also be repeated and may be used with other therapies, such as
surgery, radiation or chemotherapy.

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Thank you
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Chemotherapeutic agents and radiation therapy /certified fixed orthodontic courses by Indian dental academy

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Chemotherapeutic agents and radiation therapy /certified fixed orthodontic courses by Indian dental academy