This document discusses radioprotectors and focuses on amifostine. It provides background on amifostine's development, metabolism, mechanism of action, pharmacokinetics, side effects, and approved uses in radiation oncology to reduce toxicity in head and neck cancer and lung cancer patients. It notes that amifostine does not appear to protect tumors from radiation based on clinical studies. The document concludes by discussing potential new directions for amifostine including using it to enable dose escalation of radiation therapy or combination with novel drugs, and exploring its use to allow hypofractionated radiation schedules.

1. RADIOPROTECTORS
DR BHARTI DEVNANI
MODERATOR:-DR RITU BHUTANI

2. GOAL OF RADIATION THERAPY

3. According to the NCI workshop on normal tissue
protection(Stone et al., 2004), interventions in
the development of radiation effects classified
as
 Prophylaxis/Protection
 Mitigation
 Treatment

4. DEFINITIONS
Prophylaxis or protection
Any measure applied before the threshold dose
for the specific side-effect is reached.
Mitigation
Strategies used before the manifestation of
clinical symptoms(latent phase)
Treatment or management
In the symptomatic phase to reduce the side-
effects

5. WAYS TO IMPROVE THE PROTECTION OF
NORMAL TISSUES

6. Rationales for using Radioprotectors
 Therapeutic ratio (TR) = TCP
NTCP
TCP = Tumor control probability
NTCP= Normal tissue complication probability
 Efficacy/toxicity profile of radioprotector
 Agent R.T. efficacy against tumor
T.R.
 The intrinsic toxicity of the radioprotector

8. IDEAL RADIOPROTECTOR
 Preservation of the anti-tumor efficacy of radiation
 Wide window of protection against all types of toxicity
 High theraputic ratio
 High efficacy/toxicity profile(Low intrinsic toxicity profile)
 Easy and comfortable administration
 Reasonable cost-effectiveness

9. Historically known fact
NH2
HS-CH2-CH
COOH
Problem was their toxicity
nausea and vomiting
General structure:
i. A free SH group at one end
ii. Strong basic function, i.e. an amine or
guanidine at other

10. History of development of radioprotecters

11.  After World War II, a development programme
was initiated in 1959 by the U.S. Army at the
Walter Reed Institute of Research to identify
and synthesize drugs capable of conferring
protection to individuals in a radiation
environment, but without the debilitating toxicity
of cysteine or cysteamine.
 Over 4,000 compounds were synthesized and
tested.

12. Two Radioprotectors in Practical Use
Compound
Dose
(mg/kg)
Dose reduction factor
Use
7 days (GI)
30 days
(Haematopoetic)
WR-638
Cystaphos
500 1.6 2.1
Carried in field pack by
Russian army
WR-2721
Amifostine
900 1.8 2.7
Protector in radiotherapy
and carried by US
astronauts on lunar trips

13.  First breakthrough to reduce toxicity-
covering the SH group with phosphate
 Toxicity of the compound decreased b/c the
phosphate group is stripped inside the cell,
and the SH group begins scavenging for free
radicals.

14. Effect of adding a Phosphate-covering
function on the free SH of Cysteamine
Drug Formula
Mean 50%
lethal dose
(Range) in
mice
Dose
reduction
factor
MEA NH2-CH2-CH2-SH 343 (323-364)
1.6 at
200mg/kg
MEA-PO3
NH2-CH2-CH-
SH2PO3
777(700-864)
2.1 at
500mg/kg

15. CLASSIFICATION
1. Free radical scavenging and cellular detoxification
 Amifostine (WR2721, Ethyol)
 Superoxide dismutase
 Selenium
2. Modification of normal tissue oxygen levels
 Systemic hypoxia
 Local hypoxia
3. Epithelial cell-specific growth factors
 Keratinocyte growth factor (Dorr et al., 2001)

16. 4. Haemopoietic growth factors and cytokines
 Interleukin-7 (Bolotin et al., 1996),
 Interleukin-11 (Van der Meeren et al., 2002),
 Granulocyte-colony stimulating factor (G-CSF) (Russel et al.,
2000),
 Granulocyte, macrophage-colony stimulating factor (GM-CSF)
(Mettler and Guskova, 2001; Vose and Armitage, 1995),
 Stem cell factor (SCF) (Zsebo et al.,1992),
 Antiapoptotic cytokine combinations (Herodin et al., 2003)
5. Angiogenic growth factors
 FGF-1 and FGF-2
6. Vascular endothelial growth factor (VEGF)
7. TNF-α & TGF-β
However, the success with these compounds has also been limited.

17. AMIFOSTINE(WR-2721)

18. Amifostine
 Introduction & History
 Metabolism
 Mec of action
 Pharmakokinetics
 Side effect profile
 Routes of administration
 Use in radiation oncology
1. Head & neck cancer
2. Lung cancer
3. Pelvic cancers

19.  Initially developed at the Walter Reed Army
Research Institute,USA
 Under the Antiradiation Drug Development
Program of the US Army Medical Research
and Development Command (Schuchter and
Glick, 1993; Sweeney, 1979).

20. METABOLISM OF AMIFOSTINE

21. Amifostin (WR-2721)
Phosphorothioate prodrug-inactive, does not readily permeate cells.
Dephosphorylation by ALP(expressed on
endothelial cell lining & proximal renal
tubular cells)
Active thiol (WR 1065)
OxidationEnter in cell by facillited
diffusion
WR – 33278(polyamine like disulphide metabolite)
Radioprotection

22. WR-1065
i. Free radical scavenging-
 Protects cellular membranes
and DNA from damage
ii. H2 atom donation
 To facilitate direct chemical
repair at sites of DNA damage

23. WR-33278(Antimutagenic)
RADIOPROTECTION
Prevention of DNA damage
1.Condensation of
DNA, thereby limiting potential
target sites for free-radical
attack
2.Anoxia
Rapid consumption of O2 leads
to induction of cellular anoxia
ACCELARETED RECOVERY
Upregulates the expression
of proteins involved with
DNA repair
Inhibits Apoptosis, by Bcl-2
and hypoxia-inducible
factor-1
Enhanced cellular
proliferation

24. Why selective cytoprotection?
 Diffrential expression of alkaline phosphatase
in tumor tissue
 Hypovascularity & hypoxia
 Acidic environment of the tumor
100 folds decreased concentration in tumor
tissue

25. Absorption- Not orally bioavailable.
 Distribution- Confined primarily to intravascular
compartment.
 Rapidly cleared from Plasma
 Half life <1 min and >90% drug cleared plasma 6 min
after admin. Active metabolite widely distributed in body
tissues.
 Very little amifostine, or the metabolites WR-1065 and
WR-33278, is excreted in urine 1 hour after injection.
 Once amifostine enters the plasma, it is rapidly
metabolized and distributed in the tissues, whereas the
excretion of the metabolic products is very slow

26. Differential uptake
 Extensive uptake is seen in:-
 Salivary glands
 Kidneys
 Intestinal mucosa
 Markedly lower uptake is seen in:-
 Tumour tissues
 Amifostine and metabolites do not cross the
blood-brain barrier

27. Timing of administration
Timely administration of amifostine is necessary.
 Amifostine before 30 min. of RT provide
optimal benefit for cytoprotection of normal
tissues.
 Single morning dose of amifostine provides
superior radioprotection than with a single
afternoon dose

28. >30 min---NO difference

29. <30 min--- Difference present

30. ROUTES OF ADMINISTRATION
 i.v. Amifostine
 At a dose of 200 mg/m2 daily, given as a slow
i.v. push over 3 minutes,15–30 minutes before
each fraction of radiation therapy
 Well hydrated and in supine position
 Antiemetics.
 B.P. should be measured before and
immediately after the 3-minute amifostine
infusion.

31. s.c. Amifostine
 s.c. injection of 500 mg of amifostine
 Nausea
 Fever/rash reaction
 Hypotension is less
Endorectal
 1,500 mg intra rectally 20 –30 minutes before
each radiotherapy session
 Useful for pelvic irradiation
 Benefit demonstrated in a phase I study

32. SIDE EFFECTS
1. Nausea, vomiting & other GI effects
2. Transient hypotension- in 60%. Mean time of
onset is 14 mins into infusion. BP reverts in 5-
15 min.
3. Infusion related :- flushing and feeling of
warmth, Chills, Dizziness, somnolence,
hiccups & sneezing
4. Hypocalcemia in <1%- clinically asymptomatic
by inhibition of PTH secretion
5. Metallic taste during infusion
6. Allergic reactions include rash, fever, and
anaphylactic shock(TEN STS in6-9/100000)

33. Incidence and severity of amifostine-related
adverse events vary based on the route of
administration.
I.V. route
 Greater risk for grade 3 or 4 hypotension
s.c. route
 Higher incidence of fever and cutaneous
reactions than with i.v. route

34. AMIFOSTINE
USE
IN RADIATION THERAPY

35. Head & Neck Cancers
 SCC of H&N
 75% parotid gland was present in the fields
 Dose was 200 mg/m2 daily,15–30 minutes
before each fraction of radiation therapy
(1.8 –2.0 Gy/day, 5 days per week for 5–7
weeks, to a total dose of 50–70 Gy).

37.  Amifostine significantly reduced acute and late
xerostomia and associated symptoms.
 Meaningful saliva production after 1 year was
significantly higher with amifostine (72% versus
49%; p .003).
 At 1 year, with a median follow-up of 20 months,
the LR tumor control rates did not differ, and DFS
& OS were comparable.

38. LUNG CANCER
Factor
studied
Amifostine+
RT
RT alone P value
Pnemonitis 9% 43% <0.001
Fibrosis 53% 28% <0.05
Esophagitis 4% 42% <0.001
CR or PR 75% 76%
•Antonadou et al.
•Dose:-340 mg/m2 15 minutes before
irradiation.
•No evidence of tumor protection

39.  MDACC trial (Komaki et al. ):evaluated the
cytoprotective role of amifostine for esophagitis
and hematologic and pulmonary toxicities in a
randomized study of patients with stage II or III
non-small cell lung cancer receiving concurrent
chemoradiotherapy.
Did reduce incidence and severity of esophageal,
pulmonary and hematologic toxicity. Did not affect
survival

40. Pelvic malignancies
 Gasrointestinal mucositis
 Various routes of administration of amifostine
(i.v., s.c. and intrarectal) are effective.
 Intrarectal administration was more effective at
reducing radiotherapy-induced rectal toxicities
 s.c. administration was more effective at
reducing radiotherapy-induced urinary toxicities
 Combined route for optimal cytoprotection

41. Dermatitis
 Assessed in a retrospective analysis in which
100 patients with pelvic tumors treated with
radiotherapy and amifostine were compared with
120 historical controls who did not receive
amifostine
 77% lower risk for radiation-induced dermatitis
with amifostine use
 The severity of dermatitis was also significantly
lower
 Among patients who received amifostine, only
grade 1 dermatitis was noted.

42. Status
The U.S. FDA has approved the i.v. use of
amifostine in:-
 Patients with advanced ovarian cancer to
reduce the cumulative renal toxicity associated
with repeated administration of cisplatin. (1996)
 Patients undergoing postoperative radiation
treatment for head and neck cancer, where the
radiation port includes a substantial portion of
the parotid glands to reduce the incidence of
moderate to severe xerostomia.(1999)

43. Issue of tumor protection
A meta-analysis (Sasse et al.,2006) concluded
that
 Amifostine does not affect the efficacy of
radiotherapy
 To the contrary, patients receiving amifostine
with RT achieved higher rates of CR
presumably the result of fewer treatment
interruptions because of reduced acute toxicity
of the treatment.

44. Herbal radioprotectors

45. Why not used
 Protection of salivary glands could also be achieved by
using intensity modulated radiotherapy
 uncertain to what extent amifostine protects against
fibrosis and other dose-limiting late reactions
 the optimal dosage and schedule of amifostine has not
been established.
 major concern related to radioprotectors remains the
potential hazard of tumor protection. However,not even
the trial conducted by Brizel et al,73 which recruited
over 300 patients, has had sufficient statistical power to
detect and quantify a possible tumor protective effect of
amifostine. the lack of statistical power in these studies
hinders any firm conclusions being drawn regarding
tumor protection.
 T/t & toxicites cumbursome repeted puncture &
hypotension

48. New Directions
 Possibility of dose escalation of
radiotherapy
 Combination with novel drugs
 Hypofractionation

49. New Direction:Possibility of
dose escalation of radiotherapy
 Protracted overall treatment time results in a
substantial compromise of RT efficacy because
of rapid tumor repopulation starting within 3
weeks of RT.
 The dose intensity of RT and CCT may be an
imp factor related to the efficacy of such a
regimen in controlling local and disseminated
disease.

50. New Direction:Possibility of
dose escalation of radiotherapy
 In experimental studies (Laaret al, Van der Wilt
et al,Gridelli et al), it has been adequately
proved that it was possible to increase the
dose of chemotherapeutic agent by 1.5-2.2
times with an increase in anti tumor effect and
reduction in toxicity with the use of amifostine.

51. New Direction:Possibility of
dose escalation of radiotherapy
 Koukourakis et al ph I study of 24 pts using
500mg before carboplatin allowed increase in
the dose with sig decrease in the incidence of
esophagitis and diarrhoea (p=.01)

52. New Directions
 Possibility of dose escalation of radiotherapy
 Combination with novel drugs
 Hypofractionation

53. New Direction:Combination with
novel drugs
 Combination of RT with Taxanes in
NSCLC, topo isomerase
inhibitors, irinotecan,liposomal doxorubicin
and gemcitabine in HNC and NSCLC has
resulted in improved local control but at the
cost of severe mucositis leading to
prolongation of treatment time or decrease in
dose and thereby minimising the therapeutic
benefit.
 Addition of Amifostine could increase the
therapeutic index.

54. New Directions
 Possibility of dose escalation of radiotherapy
 Combination with novel drugs
 Hypofractionation

55. New Directions:
Hypofractionation
 Despite established efficacy, it is an
abandoned form of treatment because of high
rate of severe late sequelae.
 Neverthless, large fraction (4-5Gy) may be
more active in certain conditions where tumor
has low radiosensitivity.
 If Amifos c’d maintain a low rate of radiation
toxicity, then hypofractionation c’d become
treatment of choice for certain tumors.