ahmed group lecture 24 radiosensitizers, bioreductive drugs, radioprotectors lecture 24

Ahmed GroupAhmed GroupLecture 24Lecture 24

Radiosensitizers, Bioreductive drugs, Radioprotectors

Lecture 24


• 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


Tumor radiosensitization

Radiosensitizers are chemical or pharmacological agents thatincrease the lethal effects of radiation if administered inconjunction with it. Many compounds that modify theradiation response do not show a differential effectbetween tumors and normal tissues.There is no point in employing a drug that increases thesensitivity 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


Tumor radiosensitization


The Halogenated Pyrimidines

The halogenated pyrimidines are very similar in structure toDNA precursos thymidine, having a halogen substituted forthe 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 theyare made available to cells for several cell generations, sothat the analogue may be incorporated into the DNA.

As the percentage of thymidine bases replaced increases, so does the extent of radiosensitization.


The Effectiveness of the Halogenated Pyrimidines


Hypoxic Cell RadiosensitizersA search was under way in the early 1960s for compoundsthat mimic oxygen in their ability to sensitize biologicmaterials 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 rapidlyas oxygen. Because of this, they can penetrate further thanoxygen and reach all of the hypoxic cells in tumor.

Properties essential for a clinically useful hypoxic cellsensitizer: selective tumor cell sensitization and acceptable toxicity to thenormal cells;Chemically stable;Highly soluble in water or lipids and capable of diffusing a considerable distance


Hypoxic Cell Radiosensitizers

The first candidate to satisfy these criteriawas Misonidazole



Misonidazole producesappreciable sensitizationwith cells in culture


Hypoxic Cell RadiosensitizersMisonidazole also has a dramatic effect on tumors inexperimental animals



Spurred by the promise of misonidazole in the laboratory comparedwith its failure in the clinic, efforts were made to find a better drug



An alternative approach to designing drugs that are preferentiallyradiosensitize hypoxic cells is to develop drugs that selectivelykill hypoxic cells. They are compounds that can be reducedpreferentially 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)


Tirapazamine

Hypoxic Cell Cytotoxins

This compound is believed to be activated by the enzymecytochrome p450


Hypoxic Cell CytotoxinsTirapazamine

A transplanted mousecarcinoma was treatedwith X-rays alone,drug alone or acombination of the twoThe effect of thecombination is muchgreater than additive


Hypoxic Cell CytotoxinsTirapazamine

The effect was even more dramatic in vivo scoring regrowth delay


Markers of hypoxic cellsA major development in the past two decades has been the synthesisof radioactive-labeled nitroimidazoles for use as markers of hypoxic cells. Under conditions of reduced oxygen tension, the drug is

metabolized, and brokendown.In this study patients weregiven a tritiated thymidine-labeled drug before tumorwas removed.


Markers of hypoxic cells

The interesting result of thestudy is that only four of ninepatients had tumors with asignificant proportion ofhypoxic cells. Only melanomaand small-cell lung cancer appeared to contain a proportionof hypoxic cells that wouldprejudice the outcome of radiotherapy


Normal tissue radioprotectors

Some substances do not directly affect the radiosensitivity ofcells but they may protect whole animals because theycause vasoconstriction or in some way upset normal processesof metabolism to such extent that the oxygen concentration incritical organs is reduced.Because cells are less sensitive to X-rays under hypoxia, thisprovides a radioprotection of the normal tissues.Examples: sodium cyanide, carbon monoxide, epinephrine,histamine and serotonine.Such compound are not really radioprotectors per se.



True radioprotectors are the sulfhydryl compounds. The simplest iscysteine, a sulfhydryl compound containing a natural amino acid.

Structure of cysteine

NH2

SH – CH2 – CH COOH

Structure of cysteamine

SH – CH2 – CH2 – NH2

Sulfhydryl compounds



Sulfhydryl compounds, DRF

Animals injected with cysteamine require doses of X-rays 1.8 timeshigher 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 drugDRF = Dose of radiation in the absence of drug

to produce a given level of lethality


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 scavenging2. Hydrogen atom donation to facilitate direct chemical repair at sites of DNA damage

Normal tissue radioprotectors Mechanism of action


Normal tissue radioprotectors Mechanism of action

If the free radicals can be scavengedbefore they can interact with biologicmolecules, the effect of radiation is reduced.The protective effect of sulfhydrylcompound tends to parallel the oxygeneffect, being maximal for sparselyionizing radiations (e.g., X- or gamma-rays ) and minimal for denselyionizing radiations (e.g. low-energy alphaparticles)


Development of more effective compounds

Cysteine is a radioprotector, but it’s also toxic and induces nauseaand vomiting at the dose levels required for radioprotection.A development program was initiated in 1959 by the US Armyto 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:


Development of more effective compounds

The structures of three typical compounds out of more than4,000 synthesized are shown in the table:WR-638 – cystaphos, protects only against sparsely ionizing radiations;WR-2721 – amifostine, protects blood-forming organsWR-1607 – structure similar to other two WRs. It’s much more effective but also very toxic (rat poison), so it’s not usable.

WR series


WR-2721 – amifostine

WR series


WR-2721 – amifostine

WR series

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


Biological Response Modifiers

Biological response modifiers, used to treat cancer exert theirantitumour effects by improving host defense mechanisms against the tumor. They enhance the ability of the host to toleratedamage 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 protecttumor 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 cytotoxicityof these drugs. A possible synergistic effect of biological modifiers with radiationtreatment is the basis and subject of ongoing studies.


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



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 totrigger 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 stimulatingthe cells of the immune system to act more effectively.


ahmed group lecture 24 radiosensitizers, bioreductive drugs, radioprotectors lecture 24

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