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DR. SWETA SHARMA
DEPT. RADIATION ONCOLOGY
Radiation Induced Cell Death
Radiation directly affects
DNA molecule in the
Single broken strand can
usually be repaired by the
cell, while two broken
strand commonly results
in cell death.
Water is ionized when
exposed to radiation. Free
radicals formed by hydroysis
of water affects DNA.
Negative effect of hydrogen
peroxide on cell nutrition
may be employed as
evidence of indirect effect of
Chronic and Acute Hypoxia
• Hypoxia in tumors can result from two quite different
• Chronic hypoxia : results from the limited diffusion distance of
oxygen through tissue that is respiring.
• Acute hypoxia : the result of the temporary closing of a tumor
blood vessel owing to the malformed vasculature of the tumor.
• Distance to which oxygen can diffuse is about 70µm at the arterial end of
capillary and less at venous end.
Mechansim of Oxygen Effect
•For oxygen effect- O2 to be present
during radiation exposure- during or
within microseconds after radiation
•Free radicals break chemical
bonds, produce chemical changes &
initiate chain of events- final
expression of biological damage.
• If oxygen present it reacts with the
free radicals- produces RO2, an
organic peroxide-a nonrestorable
form of target material.
•Oxygen fixes the radiation lesion.
• Radioprotector: A chemical compound that reduces
the biologic consequences of radiation.
• 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
• Most remarkable group of true radioprotector is the sulfhydrl
• Simplest is cyteine, SH compound containing a natural amino
• Cysteine and Cysteamine, were dicovered early but are toxic.
• If SH group is covered by phosphate group, toxicity is
• Toxicity of the compound decreased b/c the phosphate group is
stripped inside the cell, and the SH group begins scavenging
for free radicals.
Radioprotectors-Mechanism of Action
• SH compounds effective against
sparsely ionizing radiation.
i. Free radical scavenging- O2
based free radical generation or
ii. H2 atom donation to facilitate
direct chemical repair at sites of
• Protective effect of SH
compounds tends to parallel O2
the effect, being maximal for
sparsely ionizing (x and gamma
rays) and minimal for densely
• Dose reduction factor:
Dose of radiation in presence of drug
• DRF= ----------------------------------------------------
Dose of radiation in absence of drug
• The largest possible value of DRF for sparsely ionizing
radiation would equal OER with value 2.5-3
• SH radioprotectors, in reality, have more effect with densely
ionizing radiations than would be expected based on
theoretical mechanism of action. May be other factors
Two Radioprotectors in Practical Use
Dose reduction factor
7 days (GI)
500 1.6 2.1
Carried in field pack by
900 1.8 2.7
Protector in radiotherapy
and carried by US
astronauts on lunar trips
AMIFOSTINE (ETHYOL/WR-2721)---- MOA
Phosphorothioate, non-reactive, does not readily permeate cells becoz of its
terminal phosphorothioic acid group. It is therefore a prodrug.
Dephosphorylated by enzyme alkaline
phosphatase (present in high concentration
in normal tissue and capillaries)
Active metabolite (WR 1065)
Enter in cell by facillited
Scavenges free radicals generated by ionizing radiation
• Phosphorothioate radioprotector floods normal tissue
rapidly after administration but penetrate tumour
much more slowly.
• The strategy is to begin irradiation soon after
administration of drug to exploit a differential effect.
• Amifostine apart from protecting against cell killing this
compound also protect against radiation induced mutagenesis
and oncogenic transformation in cell in culture and against
carcinogenesis in mouse model system.
• A dose of 400 mg/kg is required for optimal cytoprotection
which is toxic with many side effects, but its antimutagenic
effect persists at low nontoxic dose of 25 mg/kg.
• Antimutagenic effect still occurs if the drug is added 3 hrs
• 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
• Well hydrated and in supine position
• B.P. should be measured before and immediately after the 3-
minute amifostine infusion.
• s.c. injection of 500 mg of amifostine
• 1,500 mg intra rectally 20 –30 minutes before each
• Useful for pelvic irradiation
• Benefit demonstrated in a phase I study
• Nausea/ vomiting
• Transient hypotension
• Infusion related :- flushing and feeling of warmth, Chills,
Dizziness, somnolence, hiccups & sneezing
• Hypocalcemia in <1%- clinically asymptomatic by inhibition
of PTH secretion
• Metallic taste during infusion
• Allergic reactions include rash, fever, and anaphylactic
• Incidence and severity of amifostine-related adverse events
vary based on the route of administration.
• Greater risk for hypotension
• Higher incidence of fever and cutaneous reactions than with
• Hypotension is less
• Amifostine is useful as a protector for chemotherapy as well as
• It offers protection against nephrotoxicity, ototoxicity and
neuropathy from cisplatin and hematological toxicity from
cyclophosamide without reduction of tumour activity.
Use of amifostine in chemotherapy induced
Use of amifostine in RT induced toxicity
• May be considered to decrease the incidence of acute and late
xerostomia in patients undergoing fractionated radiotherapy
alone for head and neck cancer.
• 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).
• At 1 year, with a median follow-up of 20 months, the LR
tumor control rates did not differ, and DFS & OS were
Use of amifostine in RT induced toxicity
• Current data do not support the routine use of amifostine with
concurrent platinum based CT-RT for head and neck cancer.
• Data are insuffficient to recommend amifostine to prevent
mucositis associated with RT for head and neck cancer.
• Data are insuffficient to recommend routine use of amifostine
to prevent esophagitis in patients receiving Concurrent CT-RT
• Glutamine is a neutral amino acid that acts as a substrate for
nucleotide synthesis in most dividing cells.
• It is the most abundant amino acid in free blood, and
constitutes 60% of the total free amino acid pool in skeletal
• Glutamine metabolism regulated by glutaminase and
glutamine synthetase which occur primarily in skeletal muscle
• States of physiologic stress, including those resulting from the
treatment of malignant disease, are characterized by a relative
deficiency of glutamine.
• Supplementation with this inexpensive dietary supplement
may have an important role in the prevention of
gastrointestinal, neurologic, and possibly cardiac
complications of cancer therapy.
• Glutamine helps to decrease mucous membrane injury induced
by radiation thus it significantly reduces the duration and
severity of oral mucositis during radiotherapy.
• Improve the therapeutic index of both chemotherapy and
• Further study of glutamine supplementation in these areas is
• Chemical or pharmacologic agents that increase the
lethal effects of radiation if administered in
conjunction with it.
Basic Strategy of Radiosensitizers
• Move TCP curve to lower
doses by sensitizing tumour
cells but not affecting NTCP
curve or not altering it as
• Outcome-Increase TCP for a
given level of normal tissue
TYPES OF SENSITISERS
• Non hypoxic cell sensitisers
(Halogenated pyrimidines )
Differential effect is based on the premise that tumor cells
cycle faster and therefore incorporate more of the drug than
the surrounding normal tissues.
• Hypoxic-cell sensitizers
Increase the radiosensitivity of cells deficient in molecular
oxygen(tumors) but have no effect on normally aerated cells
CT can act as radiosensitizing agent by various
• Direct enhancement of initial radiation damage by
incorporating drugs into DNA
• Inhibiting cellular repair mechanisms
• Accumulating cells in radiosensitive phase or eliminating
• Eliminating hypoxic cells
• Inhibiting accelerated repopulation of tumour cells
MECHANISMS OF CHEMOTHERAPY-INDUCED
Hyperbaric oxygen chambers
• An increase in barometric pressure of the gas breathed by the
patient during radiotherapy is termed ‘hyperbaric oxygen
• First Use : Churchill Davidson of St. Thomas Hospital
• Patients were sealed in chambers filled with pure oxygen
raised to a pressure of 3 atm.
• Significant benefit both in LC and survival for Ca Cervix &
advanced H&N but not Ca Urinary bladder
• 6.6% improvement in LC, with suggestion of increase of late
normal tissue damage.
• Feeling of claustrophobia
• Unconventional fractionated schemes
• Increase in late normal tissue damage(damage to laryngeal
cartilage in studies)
• Risk of fire
• Side effects - damage to the ears, sinuses and lungs from the
effects of pressure, temporary worsening of myopia, acute
central nervous system oxygen toxicity (seizures)
Discarded due to introduction of better chemical
radiosensitisers that would achieve same end by simpler
• Pure oxygen if breathed – vasoconstriction - closing down of
some blood vessels – defeats the object
• Carbogen – 95% O2 +5% CO2
• Rationale – addition of CO2 to gas breathing mixture –
shift the oxyHb association curve to right – facilitate
unloading of oxygen into most hypoxic tissues
• Simple attempt to overcome chronic hypoxia
• Can be given under normobaric condition.
• Failed to show significant therapeutic gain.
• Prevents the transient fluctuations in tumour blood flow that
lead to the development of acute hypoxia (Horsman et
Benefit has been seen when combined with
• Perfluorochemical emulsions,
• Pentoxifylline and
• High oxygen-content gas breathing
• Accelerated – to overcome proliferation
• Hyperfractionated – to spare late responding normal tissues
• Carbogen breathing – to overcome chronic hypoxia
• Nicotinamide – to overcome acute hypoxia
• Anemia – powerful adverse prognostic factor in pts of Ca
Cervix, H& N cancers & lung cancer
• Investigated in no. of studies
• Transfusion to pts with low Hb levels - ↑ed oxygen tension
• Transfusion to Hb level of 11g/dl or higher – improved
• Not been supported by data from controlled randomized trials
• H & N Cancer pts – 2 phase II trials from DAHANCA study
group –failed to demonstrate any benefit
HYPOXIC CELL SENSITIZER
• Increases radiosensitivity of cell deficient in oxygen (tumour)
but have no effect on normaly aerated cell.
CHARACTERISTICS OF HYPOXIC CELL
• Selective sensitivity to hypoxic cells at a concentration that
would result in acceptable toxicity to normal tissue.
• Chemical stability and not subject to rapid metabolic
• Must be highly soluble in water or lipid and must be capable of
diffusing considerable distance.
• It should be effective at relatively low daily doses of few grays
used in conventional RT
• 1st generation 5-nitroimidazole
• Sensitizer Enhancement ratio - 1.2
• Optimal time for administration - 4 hour before radiation
• Dose limiting toxicity – Gastrointestinal
Sensory peripheral neuropathy
• 2nd generation 2- nitroimidazole
• More active
• Formulations 500 and 100 mg tablets and capsules
• once or twice/wk for 5-6 wks
• Total cumulative dose not to exceed 12 gm/m2
• Optimal time for administration -- 4 hour before radiation
• Dose limiting toxicity
- Sensory peripheral neuropathy that progress to central
nervous system toxicity
• 3rd generation, analog of Misonidazole
• SER- 2.5-3 with dose of 12 g/m2
• Lesser neurotoxic due to Shorter half life
• Lower lipid solubility(less rapidly taken by the neural tissue)
• No significant benefit was observed
• A 5-nitroimidazole of same structural class as metronidazole
• Administered in form of gelatin-coated capsules containing
500 mg active drug
• Given orally 90 min prior to irradiation.
• Daily dose 1200 mg/m2 body surface
• Total dose should not exceed 40g/m2 or 75 g in total.
• Less effective radio sensitizer then Misonidazole or
• Less toxic, no cumulative neuropathy
• Large dose can be given
• Dose-limiting toxicity is nausea and vomiting
• DAHANCA conducted a phase III trial of nimorazole (1.2
g/m2 vs. placebo) for squamous cell cancer of the supraglottic
larynx and pharynx.
• There was a statistically significant improvement in
locoregional tumor control (49% vs. 33% at 5 years; P = .002)
but not for survival.
• The use of nimorazole has become the standard of care in
Denmark but has not been adopted in other countries.
• Alternative to drugs that preferentially radiosensitize hypoixc
cells, eliminates radioresistant hypoxic cells by selectively
• Mitomycin C
• Used as chemotherapy agent
• Acts as an alkylating agent after intracellular activation &
inhibits DNA – DNA cross linking, DNA depolymerization
• But the differential cytotoxicity between hypoxic and
oxygenated cells however is small
• Dose limiting toxicity – cumulative myelosuppression
• Mitomycin C plays an important role in conjunction with
radiotherapy and 5FU, the definitive, chemoradiation
squamous cell carcinoma of the anus.
TIRAPAZEMINE (SR 4233)
• Highly selective toxicity against hypoxic cells both in vivo and
• MOA- Drug is reduced by intracellular reductases to form
highly reactive radical - produces both double & single strand
breaks in DNA
• Efficacy depends on no. of effective doses that can be
administered during course of RT & presence of hypoxic
• S/E – nausea & muscle cramping
• Tirapazamine can also enhance the cytotoxicity of cisplatin
• A mitomycin C derivative
• Provides greater differential cytotoxicity between hypoxic and
oxygenated cells in vitro
• Administration of compounds that mitigate damage caused by
previous radiation exposure constitutes a different approach to
the management of radiation-induced toxicity.
• This strategy contrasts to the classical free radical scavenging
radioprotective mechanism of drugs such as amifostine.
• Recombinant human keratinocyte growth factor that belongs to
the fibroblast growth factor (FGF-7) family of cytokines.
• It stimulates cellular proliferation and differentiation in a
variety of epithelial tissues including mucosa throughout the
alimentary tract, salivary glands, and type II pneumocytes.
• Palifermin also regulates intrinsic glutathion emediated
• FDA approved: prevetion of chemotherapy induced mucositis
• Palifermin is recommended for use for patients undergoing
autologous hematopoietic stem cell transplantation for a
hematologic malignancy with a TBI to decrease incidence of
• The precise role for palifermin in the management of head and
neck cancer remains to be established.