RADIOPROTECTORS

Afifah bt Johari 101323044

Nur Ismawani bt Ishak 101323045
 Learning objective
Explain the concept of
radioprotectors.
Describe free radical formation and
damage cause by it.
List the uses of radioprotectors.
 What is radioprotectors ??
Radioprotectors are chemicals that
reduce the biological effects of
radiation EJ Hall, Radiobiology for
the Radiologist.
Compound to protects the normal
tissue without the comparable
reduction in the cytotoxic effect of
the tumor cells T.H Wasserman,
principles and practice of radiation
oncology.
Free radicals
Formation of free radicals
 radiation interacts with other molecules of
the cell that are not critical targets but are
close enough to pass on this damage,
typically in the form of free radicals.
Because mammals are composed of
roughly 80% water, indirect effects involve
the production of radiolysis products of
water, in particular, the hydroxyl free
radical, which is a potent oxidant capable
of breaking chemical bonds, in the nano- to
microsecond timeframe
 Free radicals

Damage on the biological

molecule

Effects on cellular level

Effects on cell kinetics

Cell death.
Damage on the biological molecule
Effects on cellular level
Effects on cell kinetics

Mitotic delay

&
Cell death
Effect of radiation to oral tissues
 Concept of radioprotectors.
Prevents DNA damage
Enhances repair of radiation damage
Enhances repopulation of normal tissue

Mechanisms at chemical level:

Free radical scavenging protects against
O2-based free radicals generated by radiation
Hydrogen atom donation to facilitate
direct chemical repair at sites of DNA damage
List of radioprotectors
Natural Chemical
Vitamin A, C, E
Lipoid acid Cysteine
Garlic Cysteamine
Aloe vera Tempol
Mints Lycopene
Superoxide Dexrazoxane
dismutase Palifermin
Catalase Amifostine (WR-
Glutathione 2721)
 Discovery of
radioprotectors.
1948 Patt ,Cysteine protection against x-irradiation.
1951 Bacq, Discovered that cysteamine can protect
animals from total body irradiation.
1959 -Antiradiation Drug Development Program of the
US Army. Walter Reed Institute in Washington.
Synthesis and testing of more than 4000 compounds
1979 Sweeney, A survey of compounds from the
Antiradiation Drug Development Program of the U.S.
Army Medical Research and Development Command.
Walter Reed Institute of Research.
In Cold war, Soviet Infantry carried radioprotectors for
use of possible nuclear war.
US astronauts carry radioprotectors for solar flare event.
 Amifostine
WR 2721 (most effective in the
Walter Reed series)
Formed by adding phosphate group
to the sulfylhydryl group of
cysteamine.
 Amifostine enter cells, phosphate
group stripped off and SH group will
be scavenging the free radicals.
Hence amifostine is prodrug
Available to be use through
intravenous injection
Adverse effect skin rashes,
hypotension, nausea and vomiting.
 Uses of amifostine
Prevention of xerostomia for head
and neck cancer patient receiving
radiotherapy
Protection against nephrotoxicity,
ototoxicity,neuropathy by cisplatin
Prevent hematologic toxicity by
cyclophosphamide.
Reduce the severity and duration of
mucositis.
 As a cytoprotective agent in chemotherapy
Adult:Initially, 910 mg/m2BSA once daily, as an
infusion given over 15 minutes, 30 minutes before start
of chemotherapy. May reduce to 740 mg/m2if patient is
unable to tolerate the full dose. For patients receiving
cisplatin doses <100 mg/m2, a dose of 740 mg/m2may
be given to reduce renal toxicity.
Intravenous
Prophylaxis ofxerostomiain patients undergoing
radiotherapy for head and neck cancer
Adult:200 mg/m2BSA once daily, as an infusion given
over 3 minutes, beginning 15-30 minutes before
radiotherapy.
 Absorption
Intravenous inj.

Distribution
1)Uptake appears to be high in bone marrow, gastrointestinal mucosa, skin, liver, and
salivary glands. Uptake is low in muscles and nonexistent in brain tissue. Absorption is
minimal or nonexistent in tumor tissues (Tech Info Ethiofos (WR-2721), 1990)

Metabolism
a)Mechanism of selective tissue protection is related in part to higher alkaline
phosphatase activity and higher pH in normal tissue than in malignant cells, resulting in
more rapid and complete conversion and uptake of WR-1065 (Tech Info Ethiosof (WR-
2721), 1990)[114][112][115].

Excretion
A)Kidney

Elimination Half-life
a)8 minutes
 A)MECHANISM OF ACTION
1)Amifostine (WR-2721) is a sulfhydryl-containing compound that
reportedly reduces cytotoxic damage induced by radiation or alkylating
agents in well-oxygenated cells. Protectant effects appear to be mediated
by scavenging of free radicals, competition with oxygen, promotion of
repair of damaged macromolecules, and formation of mixed disulfides to
protect normal cells

2)In animal studies, amifostine is effective in protecting normal tissues

against cytotoxic effects of radiation, cyclophosphamide, nitrogen mustard,
and L-phenylalanine mustard. Cytoprotection has been observed in several
types of normal tissues, including kidney, bone marrow and gastrointestinal
mucosa, but not in brain or spinal cord

3)Protection against cisplatin cytotoxicity has also been reported in animal

models with administration of amifostine, which appears to be related to
capping of the cisplatin adduct on DNA before a cross-link can be formed.
In most instances, malignant cells are not protected from the effects of
radiotherapy or chemotherapeutic agents, and antitumor efficacy is
preserved.

4)HYPOCALCEMIC EFFECTS
amifostine have been reported in cancer patients, which appear related to
inhibition of parathyroid hormone secretion, and possibly to direct
 Cardiovascular Effects - hypotension
Dermatologic Effects- flushing, rash
Endocrine/Metabolic Effects, hypocalcemia
Gastrointestinal Effects, nausea,
vomitting, diarrhea
Immunologic Effects, anaphylactic
Neurologic Effects- dizziness, loss of
consciousness
Respiratory Effects- hiccup, sneezing
 Palifermin
Dosage
Mucositis following chemotherapy, In patients requiring stem cell
transplant; Prophylaxis
a)Dose: 60 mcg/kg/day IV bolus for 3 consecutive days before (the third
dose should be within 24 to 48 hours of starting myelotoxic therapy) and 3
consecutive days after myelotoxic therapy (first of these doses should be
administered after, but on the same day of, hematopoietic stem cell
infusion and more than 4 days after the final dose of the initial dosing
sequence); a total of 6 doses is given

Mucositis following chemotherapy, In patients with solid tumor

malignancies; Prophylaxis
a)Palifermin 40 mcg/kg/day administered intravenously for 3 days before
each 5-day course of fluorouracil and leucovorin in patients with
metastatic colorectal cancer have been used in clinical trials.
Dose-limiting oral and cutaneous toxicities were common at palifermin
doses of 60 mcg/kg/day and higher
 Mechanism of action
Palifermin is a human keratinocyte growth factor,
produced by recombinant DNA technology, that
binds to specific epithelial cell-surface receptors,
resulting in the stimulation of epithelial cell
proliferation, differentiation, and upregulation of
cytoprotective mechanisms. Palifermin targets
the epithelial cells lining the mouth and
gastrointestinal tract
Recent studies
 It is better to advise cancer patients
to take radioprotectors in order to
reduce the post radiation effect in
future.
However, if patient refuse, there is
other alternative of medications that
is available for patients.
 Reference
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076305/
Radiobiology for radiologist, Eric J Hall, 5th edition.
Schuchter LM, Hensley ML, Meropol NJ, et al. 2002 update of recommendations for the use of
chemotherapy and radiotherapy protectants: Clinical practice guidelines of the American Society
of Clinical Oncology. J Clin Oncol. 2002;20:28952903. [PubMed]
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076305/
A randomized study of very accelerated radiotherapy with and without amifostine in head and
neck squamous cell carcinoma. J. Bourhis and Al. Int. J. Radiat. Oncol.. Biol. Phys. 46(5):1105-1108
(2000).
Randomized phase III trial of postoperative radiochemotherapy +/- amifostine in head and neck
cancer. Is there evidence for radioprotection ? ,P. Vach and Al. Strahlenther. Onkol. 179(6):385-389
(2.003).
Prophylactic use of amifostine to prevent radiochemotherapy-induced mucositis and xerostomia in
head-and-neck cancer, D. Antonadou and Al. Int. J. Radiat. Oncol. Biol. Phys. 52(3):739-747
(2.002).
http://www.scribd.com/doc/97280712/Drug-Guidelines,pg 45
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2150001/?page=2
http://www.micromedexsolutions.com/micromedex2/librarian/ND
http://online1.mimsgateway.com.my/Malaysia/drug/info/amifostine/?
q=amifostine&type=brief&mtype=generic#Indications