Presentation is loading. Please wait.

Presentation is loading. Please wait.

The Oxygen Effect and Reoxygenation

Published byWilfred Wilkerson Modified over 5 years ago

Similar presentations

Presentation on theme: "The Oxygen Effect and Reoxygenation"— Presentation transcript:

1 The Oxygen Effect and Reoxygenation
Radiobiology for the Radiologist, chapter 6, pg The Oxygen Effect and Reoxygenation

2 The Nature of the Oxygen Effect

3 The Nature of the Oxygen Effect
Survival curves for mammalian cells exposed to x-rays in the presence and absence of oxygen Sensitivity to x-rays Aerated → S↑ Hypoxia → S↓ Oxygen enhancement ratio (OER) The ratio of hypoxic to aerated doses needed to achieve the same biological effect High dose (dose > 2Gy) OER = 2.5 – 3

4 The Nature of the Oxygen Effect
Low dose (dose < 2 Gy) OER = 2 Reasons: Variation of OER with the phase of the cell cycle OER (G1 phase) < OER (S phase) G1 more radiosensitive Dominate the survival at low dose region

5 The Nature of the Oxygen Effect
The oxygen enhancement ratio (OER) for various types of radiation Large & important Intermediate Absent

6 The Time at which Oxygen Acts

7 The Time at which Oxygen Acts
Experiment for the time at O2 acts O2 at high pressure chamber “explode” onto single layer bacteria At various time before or after irradiation Result: Oxygen need not be present during the irradiation to sensitize Could be added afterward

8 Mechanism of the Oxygen Effect

9 Mechanism of the Oxygen Effect
Chain of events from the absorption of radiation Absorption of radiation Production of fast charged particles Passing through biologic material Production of a number of ion pairs (10–10 sec) Free radicals (10–5 sec) Break chemical bond Biological damage

10 Mechanism of the Oxygen Effect
O2 acts at the level of the free radicals Reacts with the free radical R‧+ O2 → RO2‧ Form organic peroxide Oxygen fixation hypothesis The damage produced by free radicals in DNA can be repaired under hypoxia May be “fixed” if molecular oxygen is available

11 The Concentration of Oxygen Required

12 The Concentration of Oxygen Required
Survival curve for Chinese hamster cells exposed to x-rays in the presence of various oxygen concentrations Result 100 ppm, noticeable in change 2200 ppm, halfway toward the fully aerated condition ○ Air ● ppm, 1.7 mmHg □ 355 ppm, 0.25 mmHg ■ 100 ppm, mmHg △ 10 ppm, mmHg

13 The Concentration of Oxygen Required
The dependence of radiosensitivity on oxygen concentration Most of this change of sensitivity Increase from 0 – 30 mmHg Further increase little further effect Sensitivity halfway pO2 : 3mm Hg

14 The Concentration of Oxygen Required
Conclusion Very small amounts of oxygen are necessary to produce the dramatic and important oxygen effect observed with x-rays Oxygen tension of the body tissues Venous blood or lymph → 20 – 40 mmHg Different tissues may vary over a wide range from 1 – 100 mmHg Borderline hypoxic tissue, e.g. liver, skeletal muscle

15 Chronic Hypoxia

16 Chronic Hypoxia Definition First described by Thromlison and Gray
Result from the limited diffusion distance of oxygen through tissue that is respiring First described by Thromlison and Gray Specimen : bronchial carcinoma Cell of the stratified squamous cell carcinoma

17 Transverse section of tumor cord.
Stroma Surrounded by intact tumor cells Central necrosis A typical tumor area in which necrosis is not far advanced.

18 Large areas of necrosis
Bands of tumor cells Stroma Large areas of necrosis Large areas of necrosis separated from the stroma by bands of tumor cells about 100 mm wide

19 Chronic Hypoxia The conclusion Small tumor cord Radius < 160 μm
No necrosis Tumor cord > 200 μm Present of necrotic center Tumor cord enlarged further Thickness of the sheath of viable tumor cells remained essentially constant (100 – 180 μm)

20 The diffusion of oxygen from a capillary through tumor tissue
★ ★ O2 is high enough for the cells to be viable O2 is low enough for them to be relative protected from the effects of x-rays These cells may limit the radiocurability of the tumor Proposed solution High pressure oxygen chamber Neutrons Negative π-mesons Heavy charged ions

21 Acute Hypoxia

22 Acute Hypoxia Definition First postulated by Brown in 1980s
Develop in tumors as a result of the temporary closing or blockage of a particular blood vessel Tumor blood vessels open and close in a random fashion Different regions of the tumor become hypoxic intermittently First postulated by Brown in 1980s

23 Diagram illustrating the difference between chronic and acute hypoxia
Result from temporary closing of tumor blood vessels The cells are intermittently hypoxic Normoxia is restored each time the blood vessel opens up again Acute hypoxia Chronic Hypoxia Diagram illustrating the difference between chronic and acute hypoxia

24 The First Experimental Demonstration of Hypoxic cells in a tumor

25 The First Experimental Demonstration of Hypoxic cells in a tumor
By Powers and Tolmach Technique: dilution assay technique Aim: investigate the radiation response of a solid subcutaneous lymphosarcoma in the mouse Survival estimates: between 2 – 20 Gy

26 First component Dose : < 9 Gy Slope (D0) : 1.1 Gy Second component Dose > 9 Gy Slope (D0) : 2.6 Gy 2.5 time shallower Fraction of surviving cells as a function of dose for a solid subcutaneous lymphosarcoma in the mouse irradiated in vivo

27 The First Experimental Demonstration of Hypoxic cells in a tumor
The survival curve consists of two separate component Strongly suggests that the tumor consist of two separate groups of cells Oxygenated cells Hypoxic cells The shallow component of the curve cut the surviving fraction axis Survival level : 1% Means: 1% of the clonogenic cells in the tumor were deficient in O2

28 The First Experimental Demonstration of Hypoxic cells in a tumor
At lower doses dominated by the killing of the well-oxygenated cells At higher doses Oxygenated cells are depopulated severely The response of the tumor is characteristic of the response of hypoxic cells Conclusion A solid tumor could contain cells sufficiently hypoxic to be protected from cell killing by x-rays Still clonogenic and capable for tumor regrowth

29 Proportion of Hypoxic cells in Various Animal Tumors

30 Proportion of Hypoxic cells in Various Animal Tumors
Moulder and Rockwell Published a survey of all published data in hypoxic fractions 42 tumor types studies 37 tumor types contain hypoxic cells Hypoxic fraction: range from 0 – 50% Average: about 15% Dische and Denekamp Proportion of hypoxic cells in human Consistence with the 10 – 15 % characteristic of many animal tumors

31 Evidence for Hypoxia in Human Tumors
Analogy can be made with mouse tumors, in which hypoxia can be demonstrated unequivocally. Histologic appearance suggests the possibility of hypoxia Blinding of radioactive-labeled nitroimidazoles occurs Oxygen-probe measurements are predictive Pretreatment hemoglobin levels are powerful prognostic factor in SCC of the cervix, carcinoma of the bronchus, and TCC of the bladder

32 Reoxygenation

33 Reoxygenation Van Putten and Kallman Result:
Determined the proportion of hypoxic cell in mouse sarcoma without irradiation and after various fractionated radiation treatment. Result: Proportion of hypoxic cells Untreated : 14% 1.9 Gy/Fx/Day × 5 days : 18% (test in 3 days later) 1.9 Gy/ Fx/Day × 4 days : 14% (test in 1 day later) The proportion of hypoxic cells is about the same.

34 Significant of fractionation
Reasons: A dose of x-rays kills a greater proportion of aerated than hypoxic cells More radiosensitive After oxygenation, preirradiation pattern tends to return Significant of fractionation Allow sufficient time for oxygenation The presence of hypoxic cells does not greatly influence the response of tumor

35 Time Sequence of Reoxygenation

36 Time Sequence of Reoxygenation
Percentage of hypoxic cells in a transplantable mouse sarcoma as a function of time after a dose of 10 Gy of x-rays By Kallman & Bleehen Immediately after irradiation 100% of viable cells are hypoxic By 6 hours, percentage of hypoxic cells has fallen to a close value to the preirradiation level

37 The extent and rapidity of reoxygenation is extremely variable and impossible to predict
△ Mouse osteosarcoma ● mouse fibrosarcoma Cell type Reoxygenation Mammary carcinoma Rapid & well Rat sarcoma Two waves Osteosarcoma Not all cells & slow Fibrosarcoma Rapid but not complete ▲ Rat sarcoma ○ Mouse mammary carcinoma The proportion of hypoxic cells as a function of time after irradiation with a large dose for 5 transplanted tumors in experimental animals

38 Mechanism of Reoxygenation
In chronic hypoxia Cell killed by radiation are broken down and removed from tumor population Restructuring or a revascularization of tumor Tumor shrinks in size Closer to blood supply Taking place over period of days as the tumor shrinks In acute hypoxia Blood vessel is temporarily closed during irradiation Quickly reoxygenate when that vessel reopens

39 The Important of Reoxygenation in Radiotherapy

40 The Important of Reoxygenation in Radiotherapy
The reoxygenation studies with C3H mouse mammary carcinoma Reoxygenation 2 – 3 days after irradiation The proportion of hypoxic cells is lower than in untreated tumors Prediction Several large dose of x-rays given at 48 hours intervals would virtually eliminate the problem of hypoxic cells in this tumor

41 The Important of Reoxygenation in Radiotherapy
Fowler and his colleagues The x-ray schedule for cure of this tumor Five large doses in 9 days Suggestion X-irradiation can be an extremely effective form of therapy But ideally required optimal choice of fractionation pattern

42 The Important of Reoxygenation in Radiotherapy
Demands a detailed knowledge of the time course of reoxygenation in the particular tumor to be irradiated Available for only a few animal tumors Impossible to obtain for human Evidence from radiotherapy clinic Eradication doses for many tumors 60 Gy in 30 fractions Hypothesis Human tumors do not respond to conventional R/T Do not reoxygenate quickly and efficiently

43 Hypoxia and Tumor Progression

44 Hypoxia and Tumor Progression
Clinical study in Germany Correlation between local control in advance carcinoma of the cervix, treated by R/T Using O2 probe measurement Result pO2s > 10 mmHg → local control↑ pO2s < 10 mmHg → local control↓ Suggestion Hypoxia is a general indicator of tumor aggression

45 Hypoxia and Tumor Progression
Another study in United State Soft-tissue sarcoma for R/T Correlation between tumor oxygenation and the frequency of distant metastases Result pO2s > 10 mmHg → distant metastasis 35 % pO2s < 10 mmHg → distant metastasis 70 % Conclusion Level of tumor oxygenation influences the aggressiveness of the tumor

46 Hypoxia and Tumor Progression
Inactivation → p53 tumor suppression gene Overexpression → bcl-2 antiapoptotic gene Illustration how hypoxia is linked with malignant progression

47 Thanks for your attention !
The End Thanks for your attention !

Download ppt "The Oxygen Effect and Reoxygenation"

Similar presentations

Radiation Safety Course: Biological Effects

Radiation Safety Course: Biological Effects
 Since the cell cycle is known, now we must ask what controls it  Noted that healthy cells in contact will not divide ◦ Essentially, this is how our.

 Since the cell cycle is known, now we must ask what controls it  Noted that healthy cells in contact will not divide ◦ Essentially, this is how our.
Modifiers of cell survival: Linear Energy Transfer Lecture Ahmed Group

Modifiers of cell survival: Linear Energy Transfer Lecture Ahmed Group
Modifiers of Cell Survival: Repair

Modifiers of Cell Survival: Repair
Tumor Markers Lecture one By Dr. Reem Sallam. Objectives  To briefly introduce cancers, their incidence, some common terms, and staging system.  To.

Tumor Markers Lecture one By Dr. Reem Sallam. Objectives  To briefly introduce cancers, their incidence, some common terms, and staging system.  To.
Ahmed Group Lecture 6 Cell and Tissue Survival Assays Lecture 6.

Ahmed Group Lecture 6 Cell and Tissue Survival Assays Lecture 6.
Modifiers of Cell Survival: Oxygen Effect

Modifiers of Cell Survival: Oxygen Effect
Radiation Exposure, Dose and Relative Biological Effectiveness in Medicine Background Image: http://www.upmccancercenters.com/radonc/images/3D-dose-cropped.jpg.

Radiation Exposure, Dose and Relative Biological Effectiveness in Medicine Background Image:
Some remaining questions in particle therapy radiation biology Bleddyn Jones University of Oxford 1. Gray Institute for Radiation Oncology & Biology 2.

Some remaining questions in particle therapy radiation biology Bleddyn Jones University of Oxford 1. Gray Institute for Radiation Oncology & Biology 2.
Radiation Therapy (RT). What is cancer? Failure of the mechanisms that control growth and proliferation of the cells Uncontrolled (often rapid) growth.

Radiation Therapy (RT). What is cancer? Failure of the mechanisms that control growth and proliferation of the cells Uncontrolled (often rapid) growth.
Tumor Markers Lecture one By Dr. Waheed Al-Harizi.

Tumor Markers Lecture one By Dr. Waheed Al-Harizi.
At the position d max of maximum energy loss of radiation, the number of secondary ionizations products peaks which in turn maximizes the dose at that.

At the position d max of maximum energy loss of radiation, the number of secondary ionizations products peaks which in turn maximizes the dose at that.
TRAINING COURSE ON RADIATION DOSIMETRY: Radiobiology Basics – RBE, OER, LET Anthony WAKER University of Ontario Institute of Technology Thu. 22/11/2012,

TRAINING COURSE ON RADIATION DOSIMETRY: Radiobiology Basics – RBE, OER, LET Anthony WAKER University of Ontario Institute of Technology Thu. 22/11/2012,
Radiation therapy is based on the exposure of malign tumor cells to significant but well localized doses of radiation to destroy the tumor cells. The.

Radiation therapy is based on the exposure of malign tumor cells to significant but well localized doses of radiation to destroy the tumor cells. The.
Time, Dose, and Fractionation

Time, Dose, and Fractionation
Ahmed GroupLecture 11 SOLID TUMOR ASSAY SYSTEMS LECTURE 11.

Ahmed GroupLecture 11 SOLID TUMOR ASSAY SYSTEMS LECTURE 11.
Lecture 25 Hyperthermia.

Lecture 25 Hyperthermia.
A phase I study on the combination of neoadjuvant radiotherapy plus pazopanib in patients with locally advanced soft tissue sarcoma of the extremities.

A phase I study on the combination of neoadjuvant radiotherapy plus pazopanib in patients with locally advanced soft tissue sarcoma of the extremities.
Tumors Models, and Response of Tumors Martin Brown April 23, 2012

Tumors Models, and Response of Tumors Martin Brown April 23, 2012
 Cell cycle is known, so now we ask what controls it  We have observed many factors that influence a cell’s ability to move forward in the cycle ◦ Kinetochores.

 Cell cycle is known, so now we ask what controls it  We have observed many factors that influence a cell’s ability to move forward in the cycle ◦ Kinetochores.

Similar presentations

Ads by Google