Hall Book Ch 6 (Oxygen Effect and Reoxygenation)

Question 1

Several chemical and pharmacologic agents that modify the biologic effect of
ionizing radiations have been discovered. None is simpler than oxygen, none
produces such a dramatic effect, and, as it turns out, no other agent has
such obvious practical implications.

The oxygen effect was observed as early as 1912 in Germany by Swartz, who noted that the skin reaction produced on his forearm by a radium applicator was ( ) if the applicator was pressed hard onto the skin.

He attributed this to the interruption in ( ). By 1921, it had been noted by Holthusen that Ascaris eggs were relatively resistant to radiation in the absence of (
), a result wrongly attributed to the absence of cell division under these conditions.

Answer 1

reduced, blood flow, oxygen

Question 2

The correlation between ( ) and the presence of ( ) was made by Petry in 1923 from a study of the effects of radiation on vegetable seeds. All of these results were published in the German literature but were apparently little known in the English-speaking world.

Answer 2

radiosensitivity, oxygen

Question 3

In England in the 1930s, Mottram explored the question of oxygen in detail,
basing his investigations on work of Crabtree and Cramer on the survival of
tumor slices irradiated in the ( ) of oxygen.

He also discussed the importance of these findings to radiotherapy. Mottram began a series of experiments that culminated in a quantitative measurement of the ( ) effect by his colleagues Gray and Read, using as a biologic test system the growth inhibition of the primary root of the broad bean Vicia faba.

Answer 3

presence or absence, oxygen

Question 4

Survival curves for mammalian cells exposed to x-rays in the presence and
absence of oxygen are illustrated in Figure 6.1.

The ratio of ( ) is called the oxygen enhancement ratio (OER).

Answer 4

doses administered under hypoxic to aerated conditions needed to achieve the same biologic effect

Question 5

For sparsely ionizing radiations, such as x- and γ-rays, the OER at high doses has a value of between ( ).

The OER has been determined for various chemical and biologic systems with
different end points, and its value for x- and γ-rays always tends to fall in this
range.

There is some evidence that for ( ) growing cells cultured in vitro, the
OER has a smaller value of about ( ) at lower doses, on the order of the daily
dose per fraction generally used in radiotherapy.

Answer 5

2.5 and 3.5, rapidly, 2.5

Question 6

This is believed to result from the variation of OER with the phase of the cell cycle: Cells in G1 phase have a ( ) OER than those in S, and because G1 cells are more ( ), they dominate the low-dose region of the survival curve.

For this reason, the OER of an asynchronous population is slightly ( ) at low doses than at high doses. This result has been demonstrated for fast-growing cells cultured in vitro, for which precise survival measurements are possible, but would be difficult to show in a tissue.

Answer 6

lower, radiosensitive, smaller

Question 7

There is some evidence also that for cells in culture, the survival curve has a complex shape for doses less than ( ) Gy. What effect, if any, this has on the ( ) is not yet clear.

Answer 7

1, OER

Question 8

FIGURE 6.1 Cells are much more ( ) to x-rays in the presence of molecular oxygen than in its absence (i.e., under hypoxia).

The ratio of doses under hypoxic to aerated conditions necessary to produce the same level of cell killing is called the oxygen enhancement ratio (OER).

It has a value close to ( ) at ( ) doses (A) but may have a lower value of about 2.5 at x-ray doses less than about 2 to 3 Gy (B). (Adapted from Palcic B, Skarsgard LD. Reduced oxygen enhancement ratio at low doses of ionizing radiation. Radiat Res.
1984;100:328–339, with permission.)

Answer 8

sensitive, 3.5, high

Question 9

Figure 6.2 illustrates the oxygen effect for other types of ionizing radiations.
For a (     ) ionizing radiation, such as (           ), the survival curve does not have an (        ) 

In this case, survival estimates made in the presence or absence of oxygen fall along a common line; the OER is unity— in other words, there is ( ).

Answer 9

densely, low-energy α-particles, initial shoulder, no oxygen effect

Question 10

For radiations of ( ) ionizing density, such as ( ), the survival curves have a much ( ) shoulder. In this case, the oxygen effect is apparent, but it is much ( ) than is the case for x-rays. In the example shown in Figure 6.2, the OER for neutrons is about ( ).

Answer 10

intermediate, neutrons, reduced, smaller, 1.6

Question 11

FIGURE 6.2 The oxygen enhancement ratio (OER) for various types of radiation. A: X-rays exhibit a ( ) OER of ( ).

B: Neutrons (15-MeV d+ → T) are between these extremes, with an OER of ( ).

C: The OER for low-energy α-particles is unity. (Adapted from Barendsen GW, Koot CJ, van Kersen GR, et al.

The effect of oxygen on impairment of the proliferative capacity of human cells
in culture by ionizing radiations of different ( ). Int J Radiat Biol Relat Stud
Phys Chem Med. 1966;10:317–327; and Broerse JJ, Barendsen GW, van Kersen
GR. Survival of cultured human cells after irradiation with fast neutrons of
different energies in hypoxic and oxygenated conditions. Int J Radiat Biol Relat
Stud Phys Chem Med. 1968;13:559–572, with permission.)

Answer 11

larger, 2.5, 1.6, LET

Question 12

In summary, the oxygen effect is large and important in the case of ( ) ionizing radiations, such as ( ); is absent for ( ) ionizing radiations, such as ( ); and has an intermediate value for ( ).

Answer 12

sparsely, x-rays, densely, α-particles, fast neutrons

Question 13

For the oxygen effect to be observed, oxygen must be present during the
radiation exposure or, to be precise, during or within ( ) after the radiation exposure.

Sophisticated experiments have been performed in which oxygen, contained in a chamber at high pressure, was allowed to “explode” onto a single layer of bacteria (and later mammalian cells) at various times before or after irradiation with a 2-μ electron pulse from a linear accelerator.

It was found that oxygen need not be present during the irradiation to sensitize but could be ( ), provided the delay was not too long. Some sensitization occurred with oxygen added as late as ( ) after irradiation.

Answer 13

microseconds, added afterward, 5 milliseconds

Question 14

Experiments such as these shed some light on the mechanism of the oxygen effect. There is general agreement that oxygen acts at the level of the ( ).

Answer 14

free radicals

Question 15

The chain of events from the absorption of radiation to the final expression of biologic damage has been summarized as follows:

1. The absorption of radiation leads to the production of ( ) particles.
2. The charged particles, in passing through the biologic material, produce several (
   ).
3. These ion pairs have very short life spans (about 10^−10 second) and produce free
   radicals, which are highly reactive molecules because they have an ( ) electron.

Answer 15

fast-charged, ion pairs, unpaired valence

Question 16

The free radicals are important because although their life spans are only about ( ) second, that is appreciably longer than that of the ion pairs. To a large extent, it is these free radicals that ( ) that result in the final expression of biologic damage; however, it has been observed that the extent of the damage depends on the presence or absence of ( ).

Answer 16

10^−5, break chemical bonds, produce chemical changes, and initiate the chain of events

oxygen

Question 17

If molecular ( ) is present, DNA reacts with the free radicals (R·). The DNA radical can be chemically restored to its reduced form through reaction with a ( ) group.

Answer 17

oxygen, sulfhydryl (SH)

Question 18

However, the formation of RO2·, an ( ), represents a ( ) form of the target material; that is, the reaction results in a change in the chemical composition of the material exposed to the radiation.

This reaction cannot take place in the absence of ( ); since then, many of the ionized target molecules are able to repair themselves and recover the ability to function normally. In a sense, then, oxygen may be said to “fix” or make permanent the radiation lesion. This is known as the ( ). The process is illustrated in Figure 6.3.

Answer 18

organic peroxide, nonrestorable

oxygen, oxygen fixation hypothesis

Question 19

FIGURE 6.3 ( ). About ( ) of the biologic damage produced by x-rays is by indirect action mediated by ( ). The damage produced by free radicals in DNA can be repaired under ( ) but may be “fixed” (made permanent and irreparable) if molecular oxygen is available.

Answer 19

The oxygen fixation hypothesis, two-thirds, free radicals, hypoxia

Question 20

A question of obvious importance is the concentration of oxygen required to
potentiate the effect of radiation. Is the amount required small or large?

Many investigations have been performed using bacteria, plants, yeast, and mammalian cells, and the similarities between them are ( ).

The simple way to visualize the effect of oxygen is by considering the change of slope of the mammalian cell survival curve.

Figure 6.4 is a dramatic representation of what happens to the survival curve in the (
) of oxygen.

Curve A is characteristic of the response under conditions of equilibration with ( ).

Curve B is a survival curve for irradiation in as low a level of ( ) as usually can be obtained under experimental conditions (10 ppm of oxygen in the gas phase). The introduction of a very small quantity of oxygen, 100 ppm, is readily noticeable in a change in the slope of the survival curve.

A concentration of 2,200 ppm, which is about 0.22% oxygen, moves the survival curve about halfway toward the fully aerated condition.

Answer 20

striking, presence of various concentrations, air, hypoxia

Question 21

FIGURE 6.4 Survival curves for Chinese hamster cells exposed to x-rays in the
presence of various oxygen concentrations.

Answer 21

Open circles, air (A); closed circles, 2,200 ppm of oxygen or pO2 of 1.7 mm Hg; open squares, 355 ppm of oxygen or pO2 of 0.25 mm Hg; closed squares, 100 ppm of oxygen or pO2 of 0.075 mmHg; open triangles, 10 ppm of oxygen or pO2 of 0.0075 mm Hg (B), which corresponded to the lowest level of hypoxia that could usually be obtained under
experimental conditions. (Adapted from Elkind MM, Swain RW, Alescio T, et
al. Oxygen, nitrogen, recovery and radiation therapy. In: Shalek R, ed. Cellular
Radiation Biology. Baltimore, MD: Williams & Wilkins; 1965:442–466, with
permission.)

Question 22

Other experiments have shown that, generally, by the time a concentration of
oxygen corresponding to ( )% has been reached, the survival curve is virtually
indistinguishable from that obtained under conditions of ( ).

Answer 22

2, normal aeration

Question 23

Furthermore, increasing the amount of oxygen present from that characteristic of
air to (      )% oxygen (            ) the slope of the curve. This has led to the more usual “textbook representation” of the variation of radiosensitivity with oxygen concentration as shown in Figure 6.5.

Answer 23

100, does not further affect

Question 24

The term used here to represent ( ) is proportional to the reciprocal of the ( ) of the survival curve. It is arbitrarily assigned a value of unity for ( ) conditions.

Answer 24

radiosensitivity, D0, anoxic

Question 25

As the oxygen concentration increases, the biologic material becomes progressively more ( ) to radiation, until, in the presence of 100% oxygen, it is about ( ) times
as sensitive as under complete anoxia.

Note that the rapid change of radiosensitivity occurs as the partial pressure of oxygen (pO2) is increased from 0 to about ( ).

A further increase in oxygen tension to an atmosphere of pure oxygen has little, if any, further effect.

Answer 25

sensitive, 3, 30 mm Hg (5% oxygen)

Question 26

An oxygen concentration of ( )% (or about 3 mm Hg) results in a radiosensitivity ( ) between the characteristic of hypoxia and that of fully oxygenated conditions.

Answer 26

0.5, halfway

Question 27

FIGURE 6.5 An idealized representation of the dependence of radiosensitivity
on oxygen concentration. If the radiosensitivity under extremely anoxic
conditions is arbitrarily assigned a value of unity, the relative radiosensitivity is
about ( ) under ( ) conditions.

Most of this change of sensitivity occurs as the oxygen tension increases from ( ) mm Hg. A further increase of oxygen content to that characteristic of air or even pure oxygen at high pressure has ( ) further effect.

Answer 27

3, well-oxygenated, 0 to 30, little

Question 28

A relative radiosensitivity halfway between ( ) and ( ) occurs for a pO2 of about 3 mm Hg, which corresponds to a concentration of about 0.5% oxygen. This illustration is idealized and does not represent any specific experimental data. Experiments have been performed with yeast, bacteria, and mammalian cells in culture; the results conform to the general conclusions summarized here.

It is evident, then, that ( ) amounts of oxygen are necessary to produce the dramatic and important oxygen effect observed with x-rays.

Answer 28

anoxia, full oxygenation, very small

Question 29

Although it is usually assumed that the oxygen tension of most normal tissues is similar to that of venous blood or lymph (20 to 40 mm Hg), in fact, oxygen probe measurements indicate that the oxygen tension may vary between different tissues over a wide range from ( ) mm Hg.

Many tissues are therefore ( ) and contain a small proportion of cells that are radiobiologically ( ). This is particularly true of, for example, the liver and skeletal muscles. Even mouse skin has a small proportion of hypoxic cells that show up as a change of slope if the survival curve is pushed to low survival levels.

Answer 29

1 to 100, borderline hypoxic, hypoxic

Question 30

It is important to recognize that hypoxia in tumors can result from two quite
different mechanisms. Chronic hypoxia results from the ( ) distance of oxygen through tissue that is respiring.

The distance to which oxygen can diffuse is largely limited by the ( ). Many tumor cells may remain hypoxic for long periods.

Answer 30

limited diffusion, rapid rate at which it is metabolized by respiring tumor cells

Question 31

In contrast to chronic hypoxia, acute hypoxia is the result of the ( ), which
lacks smooth muscle and often has an incomplete ( ).

Answer 31

temporary closing of a tumor blood vessel owing to the malformed vasculature of the tumor

endothelial lining and basement membrane

Question 32

Tumor cells are exposed to a ( ), ranging from the highest in cells surrounding the capillaries to almost anoxic conditions in cells more distant from the capillaries.

This is significant because both ( ) have been shown to drive malignant progression.

Answer 32

continuum of oxygen concentrations, chronic and acute hypoxia

Question 33

Chronic Hypoxia: As already mentioned, radiotherapists began to suspect that oxygen influences the radiosensitivity of tumors in the 1930s. It was, however, a paper by
Thomlinson and Gray in 1955 that triggered the tremendous interest in ( ) as
a factor in radiotherapy; they described the phenomenon of chronic hypoxia that
they observed in their histologic study of fresh specimens of ( ).

Cells of the stratified squamous epithelium, normal or malignant, generally remain in contact with one another; the vascular stroma on which their nutrition depends lies in contact with the epithelium, but capillaries do not penetrate between the cells. Tumors that arise in this type of tissue often grow in solid cords that, seen in section, appear to be circular areas surrounded by stroma.

The centers of large tumor areas are necrotic and are surrounded by intact tumor cells, which consequently appear as rings. Figure 6.6A, reproduced from Thomlinson and Gray, shows a transverse section of a tumor cord and is typical of areas of a tumor in which necrosis is not far advanced. Figure 6.6B shows large areas of necrosis separated from stroma by a narrow band of tumor cells about 100 μm wide.

Answer 33

oxygen, bronchial carcinoma

Question 34

By viewing a large number of these samples of human bronchial carcinomas,
Thomlinson and Gray recognized that as the tumor cord grows larger, the
necrotic center also ( ), so that the thickness of the sheath of viable tumor
cells remains essentially ( ). This is illustrated in Figure 6.7.

Answer 34

enlarges, constant

Question 35

The obvious conclusion was that tumor cells could proliferate and grow
actively only if they were close to a supply of ( ) from the
stroma. Thomlinson and Gray then went on to calculate the distance to which
oxygen could diffuse in respiring tissue and came up with a distance of about
( ) μm.

This was close enough to the thickness of viable tumor cords on their histologic sections for them to conclude that oxygen depletion was the principal factor leading to the development of necrotic areas in tumors. Using more appropriate values of oxygen diffusion coefficients and consumption values, a better estimate of the distance that the oxygen can diffuse in respiring tissue is about 70 μm. This, of course, varies from the (
), as illustrated in Figure 6.8.

Answer 35

oxygen or nutrients, 150, arterial to the venous end of a capillary

Question 36

FIGURE 6.8 The diffusion of oxygen from a capillary through tumor tissue.
The distance to which oxygen can diffuse is limited largely by the rapid rate at
which it is metabolized by respiring tumor cells. For some distance from a
capillary, tumor cells are well oxygenated. At greater distances, oxygen is
depleted, and tumor cells become necrotic.

Hypoxic tumor cells form a layer, perhaps one or two cells thick, in between. In this region, the oxygen concentration is high enough for the cells to be viable but low enough for them to be relatively ( ) from the effects of x-rays.

These cells may limit the radiocurability of the tumor. The distance to which oxygen can diffuse is about ( ) μm at the arterial end of a capillary and less at the venous end.

Answer 36

protected, 70

Question 37

By histologic examination of sections, it is possible to distinguish only two
classes of cells: (1) those that appear to be proliferating well and (2) those that
are dead or dying.

Between these two extremes, and assuming a steadily decreasing oxygen concentration, one would expect a region in which cells would be at an oxygen tension high enough for cells to be ( ) but low enough to render the cells ( ) from the effect of ionizing radiation.

Answer 37

clonogenic, protected

Question 38

Cells in this region would be relatively protected from a treatment with x-rays because of their low oxygen tension and could provide a focus for the subsequent regrowth
of the tumor (Fig. 6.8).

Based on these ideas, it was postulated that the presence of a relatively small proportion of hypoxic cells in tumors could limit the success of radiotherapy in some clinical situations.

These ideas about the role of oxygen in cell killing dominated the thinking of
radiobiologists and radiotherapists in the late 1950s and early 1960s. A great
deal of thought and effort was directed toward solving this problem. The
solutions proposed included the use of ( ), the development of novel radiation modalities such as neutrons, negative π-mesons, and heavy-charged ions, and the development of ( ).

Answer 38

high-pressure oxygen chambers, hypoxic cell sensitizers

Question 39

Acute Hypoxia

Regions of acute hypoxia develop in tumors as a result of the ( ). If this blockage were permanent, the cells downstream, of course, would eventually die and be of no further consequence.

There is, however, good evidence that tumor blood vessels open and close in a random fashion, so that different regions of the tumor become hypoxic ( ).

In fact, acute hypoxia results from ( ) because of the malformed vasculature.

Answer 39

temporary closing or blockage of a particular blood vessel, intermittently, transient fluctuations in blood flow

Question 40

At the moment when a dose of radiation is delivered, a proportion of tumor cells may be hypoxic, but if the radiation is ( ) until a later time, a ( ) group of cells may be hypoxic.

The occurrence of acute hypoxia was postulated in the early 1980s by Martin Brown and was later demonstrated unequivocally in rodent tumors by Chaplin and his colleagues.

Figure 6.9, which illustrates how acute hypoxia is caused by ( ), also depicts the difference between acute and chronic hypoxia. In contrast to acutely hypoxic cells, chronically hypoxic cells are less likely to become reoxygenated and will die unless they are able to access a blood supply.

Answer 40

delayed, different, fluctuating blood flow

Question 41

FIGURE 6.9 Diagram illustrating the difference between chronic and acute hypoxia. Chronic hypoxia results from the limited diffusion distance of oxygen in respiring tissue that is actively metabolizing oxygen. Cells that become hypoxic in this way remain hypoxic for long periods until they die and become necrotic. Acute hypoxia results from the ( ).

The cells are intermittently hypoxic because ( ) is restored each time the blood vessel opens up again. (Adapted from Brown JM. Tumor hypoxia, drug resistance, and metastases. J Natl Cancer Inst. 1990;82:338–339, with permission.)

Answer 41

temporary closing of tumor blood vessels, normoxia

Question 42

The ( ), described in Chapter 21, was used by Powers and
Tolmach to investigate the radiation response of a solid subcutaneous
lymphosarcoma in the mouse.

Survival estimates were made for doses from 2 to 25 Gy. The results are shown in Figure 6.10, in which the dose on a linear scale is plotted against the fraction of surviving cells on a logarithmic scale.

Answer 42

dilution assay technique

Question 43

FIGURE 6.10 Fraction of surviving cells as a function of dose for a solid
subcutaneous lymphosarcoma in the mouse irradiated in vivo. The first part of
the curve has a slope ( ) of 1.1 Gy; the second component of the curve has a
shallower slope D0 of 2.6 Gy, indicating that these cells are ( ). (Adapted
from Powers WE, Tolmach LJ. A multicomponent x-ray survival curve for
mouse lymphosarcoma cells irradiated in vivo. Nature. 1963;197:710–711, with
permission.)

Answer 43

D0, hypoxic

Question 44

The survival curve for this solid tumor clearly consists of two separate
components. The first, up to a dose of about 9 Gy, has a D0 of 1.1 Gy. The
second has a shallower D0 of 2.6 Gy. This biphasic survival curve has a final
slope about 2.5 times shallower than the initial portion, which strongly suggests
that the tumor consists of two separate groups of cells: one ( ) and the
other ( ). If the shallow component of the curve is extrapolated backward to
cut the surviving fraction axis, it does so at a survival level of about 1%. From
this, it may be inferred that about 1% of the clonogenic cells in the tumor were
deficient in oxygen.

Answer 44

oxygenated, hypoxic

Question 45

The response of this tumor to single doses of radiation of various sizes is explained readily on this basis. If 99% of the cells are well oxygenated and 1% are hypoxic, the response to lower doses is dominated by the killing of the well-oxygenated cells.

For these doses, the hypoxic cells are depopulated to a negligibly small extent. Once a dose of about 9 Gy is exceeded, however, the oxygenated compartment of the tumor is depopulated severely, and the response of the tumor is characteristic of the response of hypoxic cells.

Answer 45

This biphasic survival curve was the first unequivocal demonstration that a solid tumor could contain cells sufficiently hypoxic to be protected from cell killing by x-rays but still clonogenic and capable of providing a focus for tumor regrowth.

Question 46

The presence or absence of molecular oxygen dramatically influences the
biologic effect of x-rays.

The OER is the ratio of doses ( )

Answer 46

under hypoxic to aerated conditions that produce the same biologic effect.

Question 47

The OER for x-rays is about ( ) at high doses and is possibly lower ( ) at
doses less than about 2 Gy.

Answer 47

3, about 2

Question 48

The OER ( ) as linear energy transfer increases.

Damage from low LET radiation such as x-ray, gamma ray, or beta particles mostly mediated by ( ) action nd has a very (large) oxygen enhancement ratio (OER of ~3)

Answer 48

decreases, indirect

Question 49

High LET radiation such as alpha particles, neutrons, or slow proton causes more damage through ( ) action which is NOT oxygen dependent.

High LET radiation also has ( ) OER of ~1.

Answer 49

direct, lower

Question 50

The OER approaches unity (i.e., no oxygen effect) for ( ).

For ( ), the OER has an ( ) value of about 1.6.

Answer 50

α-particles, neutrons, intermediate

Question 51

To produce its oxygen effect, ( ) must be present during the radiation
exposure or at least during the lifetime of the ( ) generated by the
radiation.

Answer 51

molecular oxygen, free radicals which is about 10^-5 seconds

Question 52

Oxygen “fixes” (i.e., makes permanent) the damage produced by ( ).
In the ( ) of oxygen, damage produced by the ( ) action may be
( ).

Answer 52

free radicals, absence, indirect, repaired

Question 53

Only a ( ) quantity of oxygen is required for radiosensitization; ( )%

oxygen (pO2 of about ( ) mm Hg) results in a radiosensitivity ( ) between
hypoxia and full oxygenation.

Answer 53

small, 0.5, 3, halfway

Question 54

There are two forms of hypoxia that are the consequence of different mechanisms: (
) hypoxia and ( ) hypoxia.

Answer 54

chronic, acute

Question 55

Chronic hypoxia results from the ( ) of oxygen through
respiring tissue.

Acute hypoxia is a result of the ( ) of tumor blood vessels and
is therefore transient.

In either case, there may be cells present during irradiation that are at a
sufficiently ( ) to be intransigent to killing by x-rays but
high enough to be viable.

Answer 55

limited diffusion range, temporary closing, low oxygen tension

Question 56

Most ( ) in animals have been shown to contain hypoxic
cells that limit curability by ( ) doses of x-rays.

Hypoxic fractions vary from 0% to 50%, with a tendency to average about ( )%.

Answer 56

transplantable tumors, single, 15

Question 57

There is strong evidence that human tumors contain ( ) cells. This
evidence includes histologic appearance, oxygen probe measurements, the
binding of ( ), PET and ( ) studies, and pretreatment ( ) levels.

Answer 57

hypoxic, nitroimidazoles, SPECT, hemoglobin

Question 58

Oxygen probes with ( ) times, implanted in a tumor and moving
quickly under computer control, may be used to obtain the oxygen profile of
a tumor.

Answer 58

fast response

Question 59

Hypoxia in tumors can be visualized by the use of hypoxia markers such as
( ) or ( ).

Answer 59

pimonidazole, HIFs

Question 60

( ) is the process by which cells that are hypoxic at the time of irradiation become oxygenated afterward.

Answer 60

Reoxygenation

Question 61

The extent of reoxygenation and the rapidity with which it occurs ( ) for different experimental animal tumors.

If reoxygenation is ( ), hypoxic cells have ( ) influence on the outcome of a fractionated radiation schedule.

Answer 61

vary widely, rapid and complete, little

Question 62

The “slow” component is caused by the reoxygenation of ( ) cells as the tumor shrinks. The “fast” component of reoxygenation is caused by the reoxygenation of ( ) cells as tumor blood vessels open and close.

Answer 62

chronically hypoxic, acutely hypoxic

Question 63

Reoxygenation cannot be measured in ( ), but presumably it occurs, at least in those tumors controlled by ( ) radiotherapy.

There is clinical evidence that in addition to causing radioresistance, ( ) may play an important role in malignant progression and in metastasis.

Answer 63

human tumors, conventional fractionated, hypoxia