RADIOPROTECTORS

Dr. KhaleelMODERATOR:-Dr. Arpitha

6/5/14 Time :2 ;30 pm

GOAL OF RADIATION THERAPY

Interventions in the development of

radiation adverse effects are classified as

Prophylaxis/Protection

Mitigation

Treatment

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

WAYS TO IMPROVE THE PROTECTION OF NORMAL TISSUES

RATIONALES FOR USING RADIOPROTECTORS

Therapeutic ratio (TR) =TCP

NTCP

TCP = Tumor control probability

NTCP= Normal tissue complication probability

Efficacy/toxicity profile of radioprotectordepends on therapeutic ratio

IDEAL RADIOPROTECTOR

Preservation of the anti-tumor efficacy of radiation

Wide window of protection against all types of toxicity

High therapeutic ratio

High efficacy/toxicity profile(Low intrinsic toxicity

profile)

Easy and comfortable administration

Reasonable cost-effectiveness

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

HISTORY OF DEVELOPMENT OF RADIOPROTECTERS

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.

TWO RADIOPROTECTORS IN PRACTICAL USE

CompoundDose

(mg/kg)

Dose reduction factor

Use

7 days (GI)30 days

(Haematopoetic)

WR-638

Cystaphos500 1.6 2.1

Carried in field pack by

Russian army

WR-2721

Amifostine900 1.8 2.7

Protector in radiotherapy

and carried by US

astronauts on lunar trips

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.

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

mercaptoethyl

amine

NH2-CH2-CH2-SH 343 (323-364)1.6 at

200mg/kg

MEA-PO3NH2-CH2-CH-

SH2PO3

777(700-864)2.1 at

500mg/kg

AMIFOSTINE(WR-2721)

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).

METABOLISM OF AMIFOSTINE

Amifostin (WR-2721)

Phosphorothioate prodrug-inactive, does not readily permeate cells.

Active thiol (WR 1065)

WR – 33278(polyamine like disulphide metabolite)

Radioprotection

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

WR-33278(ANTIMUTAGENIC)RADIOPROTECTION ACCELARETED RECOVERY

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

Upregulates the expression of proteins involved with DNA repair

Inhibits Apoptosis, by Bcl-2 and hypoxia-inducible factor-1

Enhanced cellular proliferation

WHY SELECTIVE CYTOPROTECTION?

Differential expression of alkaline phosphatase

in tumor tissue

Hypovascularity & hypoxia

Acidic environment of the tumor

100 folds decreased concentration in tumor tissue

Absorption- Not orally bioavailable.

Distribution- Confined primarily to intravascular

compartment.

Once amifostine enters the plasma, it is rapidly

metabolized and the active metabolites are

distributed in the tissues.

Half life <1 min and >90% drug cleared from

plasma in 6 min after admin.

Amifostine is rapidly cleared from plasma ,

whereas the excretion of the metabolic products

is very slow.

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

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 amifostineprovides superior radioprotection than with a single afternoon dose

>30 min---NO difference

<30 min--- Difference present

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 amifostineinfusion.

s.c. Amifostine

s.c. injection of 500 mg of amifostine

Nausea

Fever/rash reaction

Hypotension

Endorectal

1,500 mg intra rectally 20 –30 minutes before each radiotherapy session

Useful for pelvic irradiation

Benefit demonstrated in a phase I study

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.

AMIFOSTINE

USE

IN RADIATION THERAPY

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).

Amifostine significantly reduced acute and

late xerostomia and associated symptoms.

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.

LUNG CANCER

Factor

studied

Amifostine+

RT

RT alone P value

Pneumonitis 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

MDACC trial (Komaki et al. ):evaluated the

cytoprotective role of amifostine for

esophagitis . 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.

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.

STATUS

The U.S. FDA has approved the i.v. use of amifostinein:-

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)

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 amifostinewith RT achieved higher rates of complete response presumably the result of fewer treatment interruptions because of reduced acute toxicity of the treatment.

HERBAL RADIOPROTECTORS

WHY NOT USEDProtection of salivary glands could also be achieved by using IMRT.

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. 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.