Transcript Lecture 24 - biologyofcancer.org

Lecture 24
Radiosensitizers, Bioreductive drugs,
Radioprotectors
Lecture 24
Ahmed Group
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Tumor radiosensitization
Halogenated pyrimidines, nitroimmidazoles
Hypoxic cell cytotoxins: tirapazamine
Normal tissue radioprotection
Mechanisms of action, sulfhydryl compound,
WR series, dose reduction factor (DRF)
• Biological response modifiers
Lecture 24
Ahmed Group
Tumor radiosensitization
Radiosensitizers are chemical or pharmacological agents that
increase the lethal effects of radiation if administered in
conjunction with it. Many compounds that modify the
radiation response do not show a differential effect
between tumors and normal tissues.
There is no point in employing a drug that increases the
sensitivity of tumor and normal cells to the same extent.
Only two types of sensitizers have found practical use in
clinical radiotherapy:
•The halogenated pyrimidines
•Hypoxic cell sensitizers
Lecture 24
Ahmed Group
Tumor radiosensitization
Lecture 24
Ahmed Group
•
•
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Tumor radiosensitization
Halogenated pyrimidines, nitroimmidazoles
Hypoxic cell cytotoxins: tirapazamine
Normal tissue radioprotection
Mechanisms of action, sulfhydryl compound,
WR series, dose reduction factor (DRF)
• Biological response modifiers
Lecture 24
Ahmed Group
The Halogenated Pyrimidines
The halogenated pyrimidines are very similar in structure to
DNA precursos thymidine, having a halogen substituted for
the methyl group.
This “weakens” the DNA chain and makes the cells more
susceptible to damage by gamma-rays or UV light.
These substances are effective as sensitizers only if they
are made available to cells for several cell generations, so
that the analogue may be incorporated into the DNA.
As the percentage of thymidine bases replaced increases,
so does the extent of radiosensitization.
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The Effectiveness of the
Halogenated Pyrimidines
Lecture 24
Ahmed Group
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Tumor radiosensitization
Halogenated pyrimidines, nitroimmidazoles
Hypoxic cell cytotoxins: tirapazamine
Normal tissue radioprotection
Mechanisms of action, sulfhydryl compound,
WR series, dose reduction factor (DRF)
• Biological response modifiers
Lecture 24
Ahmed Group
Hypoxic Cell Radiosensitizers
A search was under way in the early 1960s for compounds
that mimic oxygen in their ability to sensitize biologic
materials to the effects of X-rays.
The approach: use oxygen substitutes that diffuse into
poorly vascularized areas of tumors.
They are not metabolized by the cells in the tumor as rapidly
as oxygen. Because of this, they can penetrate further than
oxygen and reach all of the hypoxic cells in tumor.
Properties essential for a clinically useful hypoxic cell
sensitizer:
selective tumor cell sensitization and acceptable toxicity to the
normal cells;
Chemically stable;
Highly soluble in water or lipids and capable of diffusing a
considerable distance
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Lecture 24
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Hypoxic Cell Radiosensitizers
The first candidate
to satisfy these criteria
was Misonidazole
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Hypoxic Cell Radiosensitizers
Lecture 24
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Hypoxic Cell Radiosensitizers
Misonidazole produces
appreciable sensitization
with cells in culture
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Hypoxic Cell Radiosensitizers
Misonidazole also has a dramatic effect on tumors in
experimental animals
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Hypoxic Cell Radiosensitizers
Lecture 24
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Hypoxic Cell Radiosensitizers
Spurred by the promise of misonidazole in the laboratory compared
with its failure in the clinic, efforts were made to find a better drug
Lecture 24
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Hypoxic Cell Radiosensitizers
An alternative approach to designing drugs that are preferentially
radiosensitize hypoxic cells is to develop drugs that selectively
kill hypoxic cells. They are compounds that can be reduced
preferentially to cytotoxic species in the hypoxic regions of tumors.
Three classes of agents in this category are known:
1. The quinone antibiotics (Mitomycin C)
2. Nitroaromatic compounds (dual function agents)
3. The benzotriazine di-N-oxides (tirapazamine)
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Hypoxic Cell Cytotoxins
Tirapazamine
This compound is believed to be activated by the enzyme
cytochrome p450
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Hypoxic Cell Cytotoxins
Tirapazamine
A transplanted mouse
carcinoma was treated
with X-rays alone,
drug alone or a
combination of the two
The effect of the
combination is much
greater than additive
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Hypoxic Cell Cytotoxins
Tirapazamine
The effect was even more dramatic in vivo scoring regrowth delay
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Markers of hypoxic cells
A major development in the past two decades has been the synthesis
of radioactive-labeled nitroimidazoles for use as markers of hypoxic
cells. Under conditions of reduced oxygen tension, the drug is
metabolized, and broken
down.
In this study patients were
given a tritiated thymidinelabeled drug before tumor
was removed.
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Markers of hypoxic
cells
The interesting result of the
study is that only four of nine
patients had tumors with a
significant proportion of
hypoxic cells. Only melanoma
and small-cell lung cancer
appeared to contain a proportion
of hypoxic cells that would
prejudice the outcome of
radiotherapy
Lecture 24
Ahmed Group
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Tumor radiosensitization
Halogenated pyrimidines, nitroimmidazoles
Hypoxic cell cytotoxins: tirapazamine
Normal tissue radioprotection
Mechanisms of action, sulfhydryl compound,
WR series, dose reduction factor (DRF)
• Biological response modifiers
Lecture 24
Ahmed Group
Normal tissue radioprotectors
Some substances do not directly affect the radiosensitivity of
cells but they may protect whole animals because they
cause vasoconstriction or in some way upset normal processes
of metabolism to such extent that the oxygen concentration in
critical organs is reduced.
Because cells are less sensitive to X-rays under hypoxia, this
provides a radioprotection of the normal tissues.
Examples: sodium cyanide, carbon monoxide, epinephrine,
histamine and serotonine.
Such compound are not really radioprotectors per se.
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Normal tissue radioprotectors
Sulfhydryl compounds
True radioprotectors are the sulfhydryl compounds. The simplest is
cysteine, a sulfhydryl compound containing a natural amino acid.
Structure of cysteine
SH – CH2 – CH
Structure of cysteamine
NH2
SH – CH2 – CH2 – NH2
COOH
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Normal tissue radioprotectors
Sulfhydryl compounds, DRF
Animals injected with cysteamine require doses of X-rays 1.8 times
higher that control animals to produce the same mortality rate.
This factor of 1.8 is called the dose-reduction factor, defined as:
Dose of radiation in the
presence of drug
DRF =
Dose of radiation in the
absence of drug
to produce a given level of lethality
Lecture 24
Ahmed Group
•
•
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Tumor radiosensitization
Halogenated pyrimidines, nitroimmidazoles
Hypoxic cell cytotoxins: tirapazamine
Normal tissue radioprotection
Mechanisms of action, sulfhydryl compound,
WR series, dose reduction factor (DRF)
• Biological response modifiers
Lecture 24
Ahmed Group
Normal tissue radioprotectors
Mechanism of action
Most efficient radioprotectors have a
certain features in common:
a free SH group at one end of the
molecule, and
a strong basic function such as amine
or guanidine at the other end.
The mechanism of SH-mediated
cytoprotection include:
1. Free radical scavenging
2. Hydrogen atom donation to facilitate
direct chemical repair at sites of
DNA damage
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Normal tissue radioprotectors
Mechanism of action
If the free radicals can be scavenged
before they can interact with biologic
molecules, the effect of radiation is
reduced.
The protective effect of sulfhydryl
compound tends to parallel the oxygen
effect, being maximal for sparsely
ionizing radiations (e.g., X- or gammarays ) and minimal for densely
ionizing radiations (e.g. low-energy alpha
particles)
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Development of more effective compounds
Cysteine is a radioprotector, but it’s also toxic and induces nausea
and vomiting at the dose levels required for radioprotection.
A development program was initiated in 1959 by the US Army
to identify and synthesize less toxic drugs.
Over 4,000 compounds were synthesized and tested.
The toxicity is reduced if:
sulfhydryl groups are covered by a phosphate group:
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Development of more effective compounds
WR series
The structures of three typical compounds out of more than
4,000 synthesized are shown in the table:
WR-638 – cystaphos, protects only against sparsely ionizing radiations;
WR-2721 – amifostine, protects blood-forming organs
WR-1607 – structure similar to other two WRs. It’s much more
effective but also very toxic (rat poison), so it’s not usable.
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WR series
WR-2721 – amifostine
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WR series
WR-2721 – amifostine
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WR series
WR-2721 – amifostine
Mouse is given a radioactive-labeled amifostine. The tumor has not taken up the drug at
all, whereas the bone marrow and salivary glands show high uptake of the drug
Lecture 24
Ahmed Group
•
•
•
•
•
Tumor radiosensitization
Halogenated pyrimidines, nitroimmidazoles
Hypoxic cell cytotoxins: tirapazamine
Normal tissue radioprotection
Mechanisms of action, sulfhydryl compound,
WR series, dose reduction factor (DRF)
• Biological response modifiers
Lecture 24
Ahmed Group
Biological Response Modifiers
Biological response modifiers, used to treat cancer exert their
antitumour effects by improving host defense mechanisms
against the tumor. They enhance the ability of the host to tolerate
damage by toxic chemicals that may be used to destroy the cancer.
They can target the pathways tumor cells use to curcumvent
normal growth regulation and may inhibit signals that protect
tumor cells from radiation damage thus acting as radiosensitizers.
Therefore, an increased tumor cell response to radiation
might be observed, despite of the lack of direct cytotoxicity
of these drugs.
A possible synergistic effect of biological modifiers with radiation
treatment is the basis and subject of ongoing studies.
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Biological Response Modifiers
Biologic Response Modifiers (BRM), also called immunotherapy,
is a type of treatment that mobilizes the body's immune system
to fight cancer. BRMs consist of vitamins, hormones,
and other natural drugs. The examples include:
» Ascorbic Acid Mixture
» Vitamin E
» Cimetidine
» Selenium
» Inteferon beta
» Interleukin-2 (IL-2)
» Melatonin
» Low Dose Bromocriptine (Parlodel)
» Vitamin C
» Cyclical Ginadal Hormones
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Biological Response Modifiers
The therapy mainly consists of stimulating
the immune system to help it do its job more effectively.
Biological response modifiers are substances that are able to
trigger the immune system to indirectly affect tumors.
These include cytokines such as interferons and interleukins.
This strategy involves giving larger amounts of these
substances by injection or infusion in the hope of stimulating
the cells of the immune system to act more effectively.
Lecture 24
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