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Hypoxic cell sensitisers


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Hypoxic cell sensitisers

  1. 1. HYPOXIC CELL SENSITIZERS Dr Bharti Devnani Moderator:-Dr Ritu Bhutani
  2. 2.  What is the Hypoxic cell sensitizer? What are the characteristics of an ideal Radio sensitizer? Enumerate all Radio sensitizers.
  4. 4. CONCEPTS  Two concepts fundamental to understanding the rationale for modification of radiation response 1. Therapeutic ratio – defined as NTT/TLD  Both of these parameters have sigmoid dose response curves  As the separation between these curves increases, the likelihood increases that treatment will be effective & not cause an unacceptable level of morbidity 2. Efficacy & toxicity profile of the modifier – directly affect TR  A radiosensitizing agent that exacerbates toxicity to same extent that it improves efficacy – TR unchanged or worsened
  5. 5. RADIOSENSITISERS Physical and Chemical (pharmacological) agents that increase the lethal effects of radiation when administered in conjunction to radiotherapy.
  6. 6. 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.
  7. 7. Oxygen fixes the damage by free radical to DNA. (O2 fixation hypothesis) Why o2 is required?
  8. 8. CHARACTERISTICS OF AN IDEAL HYPOXIC CELL SENSITIZER 1. Selectively sensitize hypoxic cells at concentration that would result in acceptable normal tissue toxicity (differential effect) 2. Chemically stable & not subject to rapid metabolic break down 3. Highly soluble in water or lipids & must be capable of diffusing a considerable distance through a nonvascularized cell mass to reach the hypoxic cell 4. It should be effective at relatively low daily dose /# used in conventional fractionated radiotherapy
  10. 10. METHODS TO SENSITIZE OR ELIMINATE HYPOXIC CELLS 1. Physical  Overcoming hypoxia by eliminating it with treatment that increases delivery of oxygen to tumor i.e. increases the oxygen carrying capacity of blood and increasing the tumor blood flow a) Hyperbaric oxygen b) Carbogen with or without nicotinamide c) ARCON d) Hyperthermia
  11. 11. METHODS TO SENSITIZE OR ELIMINATE HYPOXIC CELLS 2. Chemical a) Modifiers of Hb b) Hypoxic cell sensitizers c) Hypoxic cytotoxins or bioreductive dugs - Pharmacological targeting of hypoxic cells – cytotoxic to hypoxic tumor cells d) Biologic modifiers e) Chemotherapeutic drugs
  12. 12. HYPERBARIC OXYGEN  An increase in barometric pressure of the gas breathed by the patient during radiotherapy is termed ‘hyperbaric oxygen (HBO) therapy’.  Pioneered by Churchill-Davidson in 1968 at St. Thomas' Hospital in London.  Patients were sealed in chambers filled with pure oxygen raised to a pressure of 3 atm.
  14. 14.  Problems  Feeling of claustrophobia  Unconventional hypofractionated 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
  15. 15. Clinical trial of HBO  largest of the multicentre clinical trials of HBO is performed by the British Medical Research Council. Results:- Benefit observed in (both LRC & OS)  Advanced head and neck cancer  Uterine cervix cancer Benefit was not observed in  bladder cancer; Improvement in LRC (6.6%) & survival
  16. 16. 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 (Horsman et al., 2007).
  17. 17. Diffusion limited chronic hypoxia Hypoxia Perfusion limited acute hypoxia
  18. 18. 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 (Horsman,1995).
  19. 19. ARCON  Accelerated – to overcome proliferation  Hyperfractionated – to spare late responding normal tissues  Carbogen breathing – to overcome chronic hypoxia  Nicotinamide – to overcome acute hypoxia
  20. 20. PHASE III TRIAL  Laryngeal carcinoma(Netherland)  Increase in regional control rate  93% v/s 86%(p=.04)  With equal toxicity
  21. 21. BLOOD TRANSFUSION  Anemia – powerful adverse prognostic factor in pts of Ca Cervix, H& N cancers & lung cancer  Investigated in no. of studies  1st clinical investigation – in advanced cervical cancer  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
  22. 22. ERYTHROPOETIN  Low Hb concentration ↓es radiation response of tumors  Two studies conducted in H & N cancers failed to show any benefit  In one of the studies – pts who received erythropoetin showed significantly poor outcome than those who did not  ? Erythropoietin may stimulate tumor growth  Schedules –  Thrice weekly – 150 U/kg s.c  Weekly - 40000 U s.c.
  23. 23. PERFLUOROCARBONS  Artificial blood substances  Small particles capable of carrying more oxygen or manipulating the oxygen unloading capacity of blood  Potential usefulness uncertain
  24. 24. HYPOXIC CELL SENSITISERS  Nine different drugs have reached clinical evaluation  Misonidazole,  Metronidazole,  Benznidazole,  Desmethyl-misonidazole  Etanidazole,  Pimonidazole  Nimorazole,  Ornidazole  Rsu1069
  25. 25. Hypoxic Cell Radiosensitizers The first candidate to satisfy these criteria was Misonidazole
  26. 26. Hypoxic Cell Radiosensitizers
  27. 27. METRONIDAZOLE  1st generation 5-nitroimidazole  Sensitizer Enhancement ratio - 1.2  Formulations - 500 mg tablets or 500mg /100 ml solution  Half life – 9.8 hrs  Total cumulative dose not to exceed 54 gm/m2  Multiple doses 6gm/m2 3 times/wk for 3- 4week  Optimal time for administration - 4 hour before radiation  Dose limiting toxicity –  Gastrointestinal  Sensory peripheral neuropathy
  28. 28. MISONIDAZOLE  2nd generation 2- nitroimidazole  Higher electron affinity  Sensitizer Enhancement ratio –  1.4 with multiple dose of 2 gm/m2  1.15 with 0.5mg/m2  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
  29. 29. DAHANCA 2 DAHANCA 2, showed a highly significant improvement in the stratification subgroup of pharynx tumors, but not in the prognostically better glottic carcinomas
  30. 30. ETANIDAZOLE (SR2508)  3rd generation, analog of Misonidazole  SER- 2.5-3 with dose of 12 g/m2  Arthralgia seen more often with 48 hr continuous infusion  1000mg/19.4 ml saline solution  Total dose - 40.8 g/m2 at 1.7-2g/m2 3 times/wk for 6 wks  30 min before radiation Lesser neurotoxic due to Shorter half life Lower lipid solubility(less rapidly taken by the neural tissue) No significant benefit was observed in two large head and neck cancer trials, one in the USAand the other in Europe.
  31. 31. ETANIDAZOLE  RTOG phase III study with Etanidazole in head and neck tumors n- 521 patients Conventionally fractionated RT RT with Etanidazole 2mg/m2 with out Etanidazole three times wk  No grade III or IV central nervous system or peripheral neuropathy was observed.  The 2-year actuarial local tumor control was 40% in each arm, and the survival was 41% and 43%, respectively, in the irradiation alone and the irradiation plus etanidazole arms No overall benefit when Etanidazole added to conventional radiotherapy
  32. 32. PIMONIDAZOLE  4- nitroimidazole  More potent than Misonidazole  Uncharged at acid pH, thus promoting its accumulation in ischaemic regions of tumours.  Several – fold ↑ in tumor concentration  Maximum tolerated dose – 750 mg/m2  Dose limiting toxicity – CNS manifesting as disorientation & malaise  A pimonidazole trial was started in uterine cervix, but was stopped when it became evident that those patients who received pimonidazole showed a poorer response.
  33. 33. 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  dose-limiting toxicity is nausea and vomiting
  34. 34. NIMORAZOLE
  35. 35. NIMORAZOLE – DAHANCA 5 Significant improvement in terms of LRC & OS Nimorazole significantly improves the effect of radiotherapeutic management of supraglottic and pharynx tumors and can be given without major side-effects
  36. 36. As a consequence, nimorazole has now become part of the standard treatment schedule for head and neck tumours in Denmark.
  37. 37. DEVELOPMENT OF NITROIMIDAZOLES Metronidazole Misonidazole more active, toxic, benefit in subgroup Etanidazole less toxic, not active Nimorazole less active, much less toxic, benefit in H& N cancer
  38. 38. Summary of nitroimidazoles trials
  39. 39. NEWER NITROIMIDAZOLES Doranidazole  promising preliminary results were obtained in a phase III study with intraoperative radiotherapy in advanced pancreatic cancer Sanazol  which in an International Atomic Energy Agency multicentre randomized trial (Dobrowsky et al., 2007) in cervical cancer was found to significantly increase local control and survival following radical radiotherapy
  40. 40. OVERGAARD META-ANALYSIS  10,779 patients  83 RCT  Hyperbaric oxygen (HBO) (28 trials),  Hypoxic radiosensitizers (52 trials),  Oxygen or carbogen breathing (3 trials),  Blood transfusion (1 trial). The tumor sites were  Bladder (16 trials),  Uterine cervix (15 trials),  Central nervous system (13 trials),  Head and neck (24 trials),  Lung" (11 trials),  Esophagus (2 trials),  Mixed (2trials).
  41. 41. RESULTS OF META-ANALYSIS Statistically significant benefit in LRC(4.7%) & OS (2.7%)
  42. 42. Locoregional tumor control was stastically significant in H&N (p=0.0002)
  43. 43. HYPOXIC CYTOTOXINS BIOREDUCTIVE DRUGS  Elimination of radioresistant hypoxic cells by selectively killing them.  These compounds undergo intracellular reduction to form active cytotoxic species, primarily under low oxygen tensions.  Maximum cytotoxicity to cells at maximum distance from tumor blood vessels  Overcome major cause of resistance of solid tumors – inadequate oxygenation & drug delivery to tumor cells distant to blood vessel
  44. 44. Quinone antibiotics • MMC • EO9 • porfiromycin Nitroaromatic compounds • Misonidazole • (Rb-6145) • Nlcq-1, Cb1954, Sn23862 • Pr-104 Benzotriazine di-N-oxides • Tirapazamine • chlorambucil N- oxide • AQ4N (banoxantrone),
  45. 45. QUINONE ANTIBIOTIC - MITOMYCIN C  Prototype bioreductive drug  Used as chemotherapy agent for many years  Cytotoxic to relative radio resistant hypoxic cells  But the differential cytotoxicity between hypoxic and oxygenated cells , however is small  Acts as an alkylating agent after intracellular activation & inhibits DNA – DNA cross linking, DNA depolymerization  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
  46. 46. PORFIROMYCIN  A mitomycin C derivative  Provides greater differential cytotoxicity between hypoxic and oxygenated cells in vitro Phase III study  Compared patients treated with conventionally fractionated radiation plus mitomycin C versus radiation plus porfiromycin  The median follow-up - >6 years. Hematologic and non- hematologic toxicity was equivalent in the two treatment arms  Mitomycin C was superior to porfiromycin with respect to 5-year local relapse-free survival (91.6% vs. 72.7%; p = 0.01)
  47. 47.  Local-regional relapse-free survival (82% vs. 65.3%; p = 0.05)  Disease-free survival (72.8% vs. 52.9%; p = 0.03)  There were no significant differences between the two arms with respect to overall survival (49% vs. 54%) or distant metastasis-free rate (80% vs. 76%)  Their data supported the continuing use of mitomycin C as an adjunct to radiation therapy in advanced head and neck cancer and will become the control arm for future studies PORFIROMYCIN…
  48. 48. 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  Analysis of DNA and chromosomal breaks after hypoxic exposure to Tirapazemine suggests that DNA double-strand breaks are the primary lesion causing cell death  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
  49. 49. TIRAPAZEMINE  Hypoxic/cytotoxicity ratio – ratio of drug concentration under aerated and hypoxic condition required to produce same cell survival  Unlike the oxygen-mimetic sensitizers, tirapazamine-mediated therapeutic enhancement occurs both when the drug is given before or after irradiation.  Tirapazamine can also enhance the cytotoxicity of cisplatin
  50. 50. N= 121 STAGE III/IV SCC OF THE HEAD AND NECK RANDOMIZED TO RECEIVE DEFINITIVE RADIOTHERAPY (70 GY IN 7 WEEKS) Tirapazamine On day 2 of weeks 1, 4, and 7, 290 mg/m2 was administered for 2 hours, followed 1 hour later by cisplatin 75 mg/m2 for 1 hr followed immediately by radiotherapy In addition, tirapazamine 160 mg/m2 was given before radiation three times/week in weeks 2 and 3 Cisplatin 50 mg/m2 was given before radiotherapy on day 1 of weeks 6 and 7 of radiotherapy and Fluorouracil 360 mg/m2/d was given by continuous infusion from day 1 - 5 (120-hour infusion) of weeks 6 and 7 of radiotherapy Arm 2. n-58Arm 1,n-62
  51. 51.  Three-year failure-free survival rates were 55% with TPZ/CIS and 44% with chemo RT( p .16)  Three-year locoregional failure-free rates were 84% in the TPZ/CIS arm and 66% in the chemo RT arm (p .069)  Toxicity  More febrile neutropenia and grade 3 or 4 late mucous membrane toxicity were observed with TPZ/CIS  Compliance with protocol treatment was satisfactory on both arms
  52. 52. Markers of hypoxic cells
  53. 53. MARKERS OF HYPOXIC CELLS Radioactive labeled nitroimidazoles Bioreduction Deposition of radionuclide Quickly excreted Without breaking down Hypoxia Aerobic tissue
  54. 54. RADIOACTIVE LABELED NITROIMIDAZOLES  Nitroimidazole can be labeled with I 123  Hypoxic region of tumour can be visualized with single photon emission computed tomography  Now, tumor Hypoxia can be detected by [18F]-Misonidazole Positron Emission( FMISO-PET) in Patients With Advanced Head and Neck Cancer imaging  Noninvasive procedure that can be used as predictive assay in individual patients  The availability of methods to detect significant areas of hypoxia can allow selection of patients who may benefit from method of overcoming hypoxia
  55. 55. CONCLUSION  1896 -First radiotherapy treatment.  1909 -First clinical observation by Gollwald Schwarz showing Reduced blood flow caused radioresistance.  1953- First experimental observation of potential importance of hypoxia in radiotherapy.  1955 -First observation of hypoxia in human tumors.  1955 -First hyperbaric treatment.  1968- Results from first randomized trial.  1976 -First randomized study with hypoxie radiosensitizer.  19,95- More than 10000 patients in 83 randomized trials. Metaanalysis shows highly significant survival and local control benefit.  2013- Still no impact on general dinical practice.
  56. 56. NOVEL DRUGS  5 promising redox modulators are in development.  Tirapazamine  AQ4N  RSR13 facilitates delivery of oxygen to tumor cells, thereby rendering them more sensitive to radiation.  Motexafin gadolinium, with a porphyrin-like structure, selectively accumulates in tumor cells and thereby enhances radiation-induced DNA damage.  HIF-1 inhibitors target a transcription factor that regulates hypoxia related events and cell survival.
  57. 57. HIF-1 TARGETING AGENTS  Soluble guanylyl cycle activators (e.g., YC-1) (84, 85),  HSP90 inhibitors (e.g., geldanamycin radicicola) (80, 81, 86),  PI3K inhibitors (e.g., wortmannin, LY294002)  mTOR inhibitors(e.g., Rapamycin, CCI-779)  Microtubule modifiers (e.g., 2-methyloxyestradiol, vincristine,Taxol)  topoisomerase I inhibitors