Radioprotector & sensitizer

RADIOLOGY ,RADIOTHERAPY

1. RADIOPROTECTOR & RADIOSENSITIZER DR. SWETA SHARMA DEPT. RADIATION ONCOLOGY

2. Radiation Induced Cell Death Radiation directly affects DNA molecule in the target tissue. Single broken strand can usually be repaired by the cell, while two broken strand commonly results in cell death.

3. 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 radiation

4. Chronic and Acute Hypoxia Hypoxia in tumors can result from two quite different mechanisms. 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 .

5. Distance to which oxygen can diffuse is about 70µm at the arterial end of capillary and less at venous end.

6. Mechansim of Oxygen Effect For oxygen effect- O2 to be present during radiation exposure- during or within microseconds after radiation exposure . 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 .

7. GOAL OF RADIOTHERAPY

8. RADIOPROTECTOR Radioprotector : A chemical compound that reduces the biologic consequences of radiation.

9. 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

10. Most remarkable group of true radioprotector is the sulfhydrl (SH) compounds. Simplest is cyteine , SH compound containing a natural amino acid NH 2 HS-CH 2 -CH COOH Cysteine and Cysteamine , were dicovered early but are toxic. If SH group is covered by phosphate group, toxicity is reduced. Toxicity of the compound decreased b/c the phosphate group is stripped inside the cell, and the SH group begins scavenging for free radicals.

11. Radioprotectors -Mechanism of Action SH compounds effective against sparsely ionizing radiation. Mechanism: i . Free radical scavenging- O2 based free radical generation or chemotherapy agents ii . H2 atom donation to facilitate direct chemical repair at sites of DNA damage Protective effect of SH compounds tends to parallel O2 the effect, being maximal for sparsely ionizing (x and gamma rays) and minimal for densely ionizing radiation.

12. 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 involved .

13. 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

14. AMIFOSTINE (ETHYOL/WR-2721)---- MOA Amifostin (WR-2721) 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 diffusion Scavenges free radicals generated by ionizing radiation

15. RATIONALE : 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.

16. 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 following irradiation.

17. 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.

18. s.c . Amifostine s.c . injection of 500 mg of amifostine Endorectal 1,500 mg intra rectally 20 –30 minutes before each radiotherapy session Useful for pelvic irradiation Benefit demonstrated in a phase I study

19. SIDE EFFECTS 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 shock

20. Incidence and severity of amifostine -related adverse events vary based on the route of administration. I.V. route Greater risk for hypotension s.c . route Higher incidence of fever and cutaneous reactions than with i.v . route Hypotension is less

21. Amifostine is useful as a protector for chemotherapy as well as radiotherapy. 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 toxicity

22. 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.

23. 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 ).

24. At 1 year, with a median follow-up of 20 months, the LR tumor control rates did not differ, and DFS & OS were comparable.

25. 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 for NSCLC.

26. GLUTAMINE 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 muscle Glutamine metabolism regulated by glutaminase and glutamine synthetase which occur primarily in skeletal muscle and brain

27. States of physiologic stress, including those resulting from the treatment of malignant disease, are characterized by a relative deficiency of glutamine.

28. 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 . I mprove the therapeutic index of both chemotherapy and radiation Further study of glutamine supplementation in these areas is warranted.

29. RADIOSENSITIZER Chemical or pharmacologic agents that increase the lethal effects of radiation if administered in conjunction with it.

30. Basic Strategy of Radiosensitizers Aim: Move TCP curve to lower doses by sensitizing tumour cells but not affecting NTCP curve or not altering it as much Outcome-Increase TCP for a given level of normal tissue complications

31. 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

32. CT can act as radiosensitizing agent by various mechanisms : Direct enhancement of initial radiation damage by incorporating drugs into DNA Inhibiting cellular repair mechanisms Accumulating cells in radiosensitive phase or eliminating radioresistant phase Eliminating hypoxic cells Inhibiting accelerated repopulation of tumour cells

33. MECHANISMS OF CHEMOTHERAPY-INDUCED RADIATION SENSITIZATION

34. RADIOSENSITIZING HYPOXIC CELLS Hyperbaric oxygen chambers Carbogen inhalation (chronic hypoxia) Nicotinamide (acute hypoxia) Hb correction– Blood transfusion Hypoxic cell sensitizer : Misonidazole;etanidazole;nimorazole Hypoxic cytotoxins ( mitomycin C; tirapazamine ) Other agents Perfluorocarbons

35. Hyperbaric oxygen chambers An increase in barometric pressure of the gas breathed by the patient during radiotherapy is termed ‘hyperbaric oxygen (HBO) therapy. First Use : Churchill Davidson of St. Thomas Hospital Patients were sealed in chambers filled with pure oxygen raised to a pressure of 3 atm .

36. 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 .

37. Problems Feeling of claustrophobia Unconventional fractionated schemes Increase in late normal tissue damage(damage to laryngeal cartilage in studies) Risk of fire Cumbersome 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 means

38. CARBOGEN 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.

39. NICOTINAMIDE(B3) Prevents the transient fluctuations in tumour blood flow that lead to the development of acute hypoxia ( Horsman et al.,1990). Benefit has been seen when combined with Hyperthermia , Perfluorochemical emulsions, Pentoxifylline and High oxygen-content gas breathing

40. ARCON Accelerated – to overcome proliferation Hyperfractionated – to spare late responding normal tissues Carbogen breathing – to overcome chronic hypoxia Nicotinamide – to overcome acute hypoxia

41. BLOOD TRANSFUSION 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 within tumor Transfusion to Hb level of 11g/dl or higher – improved survival 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

42. HYPOXIC CELL SENSITIZER Increases radiosensitivity of cell deficient in oxygen (tumour) but have no effect on normaly aerated cell. INCLUDES Misonidazole , Metronidazole , Benznidazole , Desmethyl-misonidazole Etanidazole , Pimonidazole Nimorazole , Ornidazole Rsu1069

43. CHARACTERISTICS OF HYPOXIC CELL SENSITIZERS 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 breakdown. 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

44. METRONIDAZOLE 1st generation 5-nitroimidazole Sensitizer Enhancement ratio - 1.2 Optimal time for administration - 4 hour before radiation Dose limiting toxicity – Gastrointestinal Sensory peripheral neuropathy

45. MISONIDAZOLE 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 - gastrointestinal - Sensory peripheral neuropathy that progress to central nervous system toxicity

46. ETANIDAZOLE (SR2508) 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

47. NIMORAZOLE 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 Etanidazole Less toxic, no cumulative neuropathy Large dose can be given D ose-limiting toxicity is nausea and vomiting

48. 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.

49. HYPOXIC CYTOTOXIN Alternative to drugs that preferentially radiosensitize hypoixc cells, eliminates radioresistant hypoxic cells by selectively killing them. Mitomycin C Tirapazamine Porfiromycin

50. 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.

51. TIRAPAZEMINE (SR 4233) Highly selective toxicity against hypoxic cells both in vivo and vitro 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 tumor cells S/E – nausea & muscle cramping Tirapazamine can also enhance the cytotoxicity of cisplatin

52. PORFIROMYCIN A mitomycin C derivative Provides greater differential cytotoxicity between hypoxic and oxygenated cells in vitro

53. RADIATION MITIGATORS 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 .

54. Palifermin R ecombinant 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 cytoprotective mechanisms . FDA approved: prevetion of chemotherapy induced mucositis

55. Palifermin is recommended for use for patients undergoing autologous hematopoietic stem cell transplantation for a hematologic malignancy with a TBI to decrease incidence of server mucositis The precise role for palifermin in the management of head and neck cancer remains to be established.

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