Hall Book Ch 3

Question 1

What is cell survival curve?

Answer 1

Describes the relationship between the radiation dose and the proportion of cells that survive.

Question 2

For proliferating cells such as stem cells, hematopoietic system or the interstitial epithelium loss of the capacity for sustained proliferation is called loss of reproductive integrity which is also called

Answer 2

reproductive death

Question 3

Define “clonogenic.”

Answer 3

A survivor that has retained its reproductive integrity and is able to proliferate indefinitely to produce a large clone or colony.

Question 4

In general, a dose of ( ) Gy is necessary to destroy cell function in
nonproliferating systems. By contrast, the mean lethal dose for loss of
proliferative capacity is usually less than ( ) Gy.

Answer 4

100

2

Question 5

Define plating efficiency. Write down the equation for the PE.

Answer 5

The term plating efficiency indicates the percentage of cells seeded that grow into colonies.

PE = number of colonies counted / number of cells seeded x 100

Question 6

Answer 6

A: The linear-quadratic model.
The experimental data are fitted to a linear-quadratic function. There are two
components of cell killing: One is proportional to dose (αD); the other is
proportional to the square of the dose (βD2). The dose at which the linear and
quadratic components are equal is the ratio α/β. The linear-quadratic curve bends
continuously but is a good fit to experimental data for the first few decades of
survival.

Question 7

In the linear-quadratic model, the assumption is that there are two components to cell killing by radiation. What are they?

Answer 7

One that is proportional to dose and one that is proportional to the square of the dose.

Question 8

The notion of a component of cell inactivation that varies with the square of the dose introduces the concept of ( ) action.

Answer 8

dual radiation

Question 9

Cells are killed by ( ) incorporated into the DNA. The radiation dose results from short-range ( ) and is therefore very localized.

Answer 9

radioactive tritiated thymidine

β-particles

Question 10

Certain structural analogues of thymidine, particularly the ( ), are incorporated selectively into DNA in place of thymidine if substituted in cell culture growth medium.

This substitution dramatically increases the ( ) of the mammalian cells to a degree that increases as a function of the amount of the incorporation.

( ), which are not incorporated into DNA, have no such effect on
cellular radiosensitivity.

Answer 10

halogenated pyrimidines

radiosensitivity

Substituted deoxyuridines

Question 11

Factors that modify cell lethality, such as ( ), ( ), and ( ), also affect the production of chromosome damage in a fashion qualitatively and quantitatively similar.

This is at least prima facie evidence to indicate that damage to the
chromosomes is implicated in cell lethality.

Answer 11

variation in the type of radiation

oxygen concentration

dose rate

Question 12

Early work showed a relationship between virus size and radiosensitivity;
later work showed a better correlation with ( ). The
radiosensitivity of a wide range of plants has been correlated with the ( ), which is defined as the ratio of nuclear volume to chromosome number.

The larger the ( ), the ( ) the radiosensitivity.

Answer 12

nucleic acid volume

mean interphase chromosome volume

mean chromosome volume

greater

Question 13

However, although chromosomal DNA is the principal target for radiation induced lethality, sophisticated experiments with microbeams have shown
clearly that low ( ) can be induced by ( ) which pass
through the cytoplasm and never touch the nucleus.

Answer 13

levels of mutations

α-particles

Question 14

Generations of students in radiation biology have been taught that heritable
biologic effects require direct damage to DNA; however, experiments in the last
decade have demonstrated the existence of a ( ), defined as the
( ) traversed by a charged particle but are in ( ) to cells that are.

Answer 14

bystander effect

induction of biologic effects in cells that are not directly

proximity

Question 15

Most microbeam studies have used α-particles because it is easier to focus them accurately, but a bystander effect has also been shown for ( ).

Using single-particle microbeams, a bystander effect has been demonstrated for chromosomal ( ).

Answer 15

protons and soft x-rays

aberrations, cell killing, mutation, oncogenic transformation, and alteration of gene expression

Question 16

The effect is most pronounced when the bystander cells are in ( ) with the irradiated cells.

For example, up to ( )% of bystander cells can be killed in this situation. The bystander effect is much smaller when cell monolayers are sparsely seeded so that cells are separated by several hundred micrometers. In this situation, 5% to 10% of bystander cells are killed, the effect being due, presumably, to cytotoxic molecules released into the
medium.

Answer 16

gap-junction communication

30

Question 17

The existence of the bystander effect indicates that the target for radiation damage is larger than the ( ) and, indeed, larger than the cell itself. Its importance is primarily at ( ) doses, where not all cells are “hit,” and it may have important implications in risk estimation.

Answer 17

nucleus

low

Question 18

In addition to the experiments described previously involving sophisticated
single-particle microbeams, there is a body of data involving the transfer of
medium from irradiated cells that results in a biologic effect (cell killing) when
added to unirradiated cells. These studies, which also evoke the term bystander
effect, suggest that irradiated cells ( ) into the medium that is
capable of killing cells when that medium is transferred onto ( ) cells.

Answer 18

secrete a molecule

unirradiated

Question 19

Most bystander experiments involving medium transfer have used ( ) x- or
γ-rays.

Answer 19

low-LET

Question 20

Apoptosis was first described by Kerr and colleagues as a particular set of
changes at the microscopic level associated with cell death. The word apoptosis
is derived from the Greek word meaning “falling off,” as in petals from flowers
or leaves from trees. Apoptosis, or ( ), is common in
embryonic development in which some tissues become obsolete.

It is the mechanism, for example, by which tadpoles lose their tails.

Answer 20

programmed cell death

Question 21

This form of cell death is characterized by a stereotyped sequence of
morphologic events.

One of the earliest steps a cell takes if it is committed to die
in a tissue is to ( ) with its neighbors. This is evident as the
dying cell rounds up and detaches from its neighbors.

( ) at the nuclear membrane and fragmentation of the nucleus are then evident. The cell shrinks because of cytoplasmic condensation, resulting from ( ).

Eventually, the cell separates into several membrane-bound fragments of differing sizes termed apoptotic bodies, which may contain cytoplasm only or nuclear fragments.

Answer 21

cease communicating

Condensation of the chromatin

crosslinking of proteins and loss of water

Question 22

The morphologic hallmark of apoptosis is the ( ) in either crescents around the periphery of the nucleus or a group of spheric fragments.

Answer 22

condensation of the nuclear chromatin

Question 23

Double-strand breaks (DSBs) occur in the linker regions between ( ), producing DNA fragments that are multiples of approximately ( ) base pairs. These fragments result in the characteristic ladders seen in gels.

In contrast, necrosis causes a ( ) of DNA in gels.

Apoptosis occurs in normal tissues, as described previously, and also can be induced in some normal tissues and in some tumors by radiation.

Answer 23

nucleosomes

185

diffuse “smear”

Question 24

As a mode of radiation-induced cell death, apoptosis is highly cell-type
dependent. ( ) cells are particularly prone to rapid radiation-induced cell death by the apoptotic pathway.

In most tumor cells, ( ) is at least as important as apoptosis, and in some cases, it is the only mode of cell death.

Answer 24

Hemopoietic and lymphoid

mitotic cell death

Question 25

Several genes appear to be involved in apoptosis what are they?

First, apoptosis after radiation seems commonly to be a ( )-dependent process; ( ) is a suppressor of apoptosis.

Answer 25

p53

Bcl-2

Question 26

The most common form of cell death from radiation is ( ): Cells
die attempting to divide because of damaged chromosomes. Death may occur in
the first or a subsequent division following irradiation. Many authors have
reported a close quantitative relationship between ( ) and the induction
of ( ).

Answer 26

mitotic death

cell killing

specific chromosomal aberrations

Question 27

The results of one of the most elegant studies by Cornforth and Bedford are shown in Figure 3.4. showing relationship between the average number of “lethal” aberrations
per cell (i.e., asymmetric exchange-type aberrations such as dicentrics and rings)
and the log of the surviving fraction in AC 1522 normal human fibroblasts
exposed to x-rays.

It should be noted that these experiments were carried out in a cell line where apoptosis is not observed. The log of the ( ) is plotted against the average number of ( ) per cell, that is, asymmetric exchange-type aberrations such as ( ).

There is virtually a one-to-one correlation. In addition, there is an excellent correlation between the fraction of cells surviving and the fraction of cells without visible aberrations.

Answer 27

surviving fraction

putative “lethal” aberrations

rings and dicentrics

Question 28

Data such as these provide strong circumstantial evidence to support the
notion that (             ) aberrations represent the principle
mechanism for radiation-induced mitotic death in mammalian cells.

Figure 3.5 illustrates, in a much oversimplified way, the relationship between
chromosome aberrations and cell killing.

Answer 28

asymmetric exchange-type

Question 29

As explained in Chapter 2, cells, in which there is an asymmetric exchange-type aberration such as ( ), lose their reproductive integrity. Exchange-type aberrations require ( ) chromosome breaks. At low doses, the two breaks may result from the passage of ( ) set in motion by the absorption of a photon of x- or γ-rays.

Answer 29

a dicentric or a ring

two

a single electron

Question 30

The probability of an interaction between the two breaks to form a lethal
exchange-type aberration is ( ) to dose.

Consequently, the survival curve is ( ) at low doses.

At higher doses, the ( ) chromosome breaks may result from ( ) electrons.
The probability of an interaction between the two breaks is then proportional to the (
) of the dose.

If this ( ) component dominates, the survival curve bends over and becomes curved. Thus, the linear-quadratic relationship characteristic of the induction of chromosome aberrations is carried over to the cell survival curve.

Answer 30

proportional

linear

two

two separate

square

quadratic

Question 31

Autophagy is literally defined as a ( ) process that uses ( ) of long-lived proteins and organelles to restore or maintain cellular homeostasis.

Autophagy is evolutionarily conserved and is considered a dynamic
process that involves a unique series of steps, of which the sequestration of
portions of the cytoplasm and organelles in a double-membrane vesicle, called
an ( ), is a hallmark characteristic.

Answer 31

self-digestive

lysosomal degradation

autophagosome

Question 32

These autophagosomes ultimately fuse with ( ), where protein and organelles are degraded and reprocessed. Autophagosomes then fuse with lysosomes, which acidify as they 100 mature to become autolysosomes in a step called autophagic flux.

Answer 32

lysosomes

Question 33

Autophagy is a multistep process that is genetically regulated by a unique set of genes termed ( ). These Atgs were first discovered in yeast, and approximately 30 Atg orthologs have been identified in mammals that include two ubiquitin-like conjugation systems: ( ).

Answer 33

autophagy-related genes (Atgs)

the Atg12-Atg5 and the Atg8 (LC-3)-phosphatidylethanolamine

Question 34

These systems (the Atg12-Atg5 and the Atg8 (LC-3)-phosphatidylethanolamine) are required for the elongation of the ( ). However, the proteins and trafficking mechanisms involved in the autophagosomal maturation step are not completely understood.

Although autophagy was initially described as a ( ) mechanism for
cells to survive and generate nutrients and energy, studies have been published to
demonstrate that continuous exposure to ( ) can also
promote autophagic, or what has been termed programmed ( ).

Answer 34

autophagosomal membrane

protective

a stress-inducing condition

type II, cell death

Question 35

Defective autophagy has been characterized in different diseases including
( ).

Although autophagy can be found in cells dying from stress, it is unclear whether
it represents a drastic means for the cell to survive by digesting part of itself or
whether it actually promotes cell death.

Evidence for both possibilities exist in different cell types and will require further studies to clarify its role in irradiated cells.

Answer 35

infections, neurodegeneration, aging, Crohn disease, heart disease, and cancer

Question 36

The induction of apoptosis by anticancer agents, as described previously,
including ionizing radiation, is directed at specifically eliminating cancer cells.

However, defects in apoptosis observed in many solid tumor cells possess
( ) because of mutations in key regulatory proteins and develop resistance to killing by apoptosis when exposed to chemotherapy and radiotherapy.

Previous studies have reported that the ( ) observed in human tumors leads cancer cells to acquire resistance to apoptosis and to stimulate ( ) to maintain energy demand and prevent necrosis.

Answer 36

diminished apoptotic programs

metabolic stress

autophagy

Question 37

Furthermore, chemotherapeutic agents and radiotherapy have been reported to
induce ( ).

Although the mechanism underlying this form of cell death is unclear, accumulation of (
) in response to chemotherapy or radiotherapy suggests that this type of cell death is associated with an ( ).

Answer 37

autophagy and autophagic cell death

autophagosomes

inhibition of the maturation and degradation process

Question 38

The signals for the induction of autophagy by radiotherapy are still under
investigation but may involve signaling from the ( ),
particularly, the ( ), which is described in more detail in Chapter 26.

Answer 38

endoplasmic reticulum

protein kinase-like endoplasmic reticulum kinase (PERK)

Question 39

Induction of endoplasmic reticulum stress in cells that have lost their ability to die by (
) when exposed to radiation results in radiosensitization. This data suggests that the combination of ( ) agents and ( ) could
enhance cell killing by inducing ( ) cell death. Thus, in the regulation of
cancer, autophagy should be considered a new target for anticancer therapy.

Answer 39

apoptosis

endoplasmic stress-inducing

ionizing radiation

autophagic

Question 40

Survival curves for mammalian cells usually are presented in the form shown in
Figure 3.3, with dose plotted on a ( ) scale and surviving fraction on a
( ) scale.

Qualitatively, the shape of the survival curve can be described
in relatively simple terms. At “low doses” for sparsely ionizing (low-linear
energy transfer [LET]) radiations, such as x-rays, the survival curve starts out
( ) on the log-linear plot with a ( ) initial slope; that is, the surviving
fraction is an ( ) function of dose.

Answer 40

linear, logarithmic, straight, finite, exponential

Question 41

At higher doses, the survival curve ( ). This bending or curving region extends over a dose range of a few grays.

At very high doses, the survival curve often tends to ( ) again; the surviving fraction returns to being an exponential function of dose. In general, this does not occur until doses in excess of those used as daily fractions in radiotherapy have been reached.

Answer 41

bends, straighten

Question 42

FIGURE 3.3 shows shape of survival curve for mammalian cells exposed to radiation.
The fraction of cells surviving is plotted on a ( ) scale against dose on a
( ) scale.

For ( ) or ( ) neutrons (said to be densely ionizing),
the dose–response curve is a ( ) line from the origin (i.e., survival is an
exponential function of dose).

Answer 42

logarithmic, linear, α-particles, low-energy, straight

Question 43

The survival curve can be described by just one parameter, the ( ). For x- or γ-rays (said to be sparsely ionizing), the dose– response curve has an initial linear slope, followed by a shoulder; at higher doses, the curve tends to become ( ) again. A: The linear-quadratic model.

Answer 43

slope, straight

Question 44

The experimental data are fitted to a linear-quadratic function. There are two
components of cell killing: One is proportional to ( ); the other is
proportional to the ( ).

Answer 44

dose (αD), square of the dose (βD2)

Question 45

The dose at which the ( ) and ( ) components are equal is the ratio α/β.

Answer 45

linear, quadratic

Question 46

The linear-quadratic curve bends ( ) but is a good fit to experimental data for the first few decades of survival.

Answer 46

continuously

Question 47

In the multitarget model, the curve is described by the ( ), the final slope ( ), and a parameter that represents the width of the shoulder, either ( ).

Answer 47

initial slope (D1), D0, n or Dq

Question 48

By contrast, for densely ionizing (high-LET) radiations, such as ( ), the cell survival curve is a ( ) line from the origin; that is, survival approximates to an (
) of dose (see Fig. 3.3).

Answer 48

α-particles or low-energy neutrons, straight, exponential function

Question 49

Although it is a simple matter to qualitatively describe the shape of the cell
survival curve, finding an explanation of the biologic observations in terms of
biophysical events is another matter.

Many biophysical models and theories have been proposed to account for the shape of the mammalian cell survival curve.

Almost all can be used to deduce a curve shape that is consistent with
experimental data, but it is never possible to choose among different models or
theories based on goodness of fit to experimental data. The biologic data are not
sufficiently precise, nor are the predictive theoretic curves sufficiently different,
for this to be possible.

Two descriptions of the shape of survival curves are discussed briefly with a
minimum of mathematics (see Fig. 3.3).

First, the ( ) model that was widely used for many years still has some merit (see Fig. 3.3B). In this model, the survival curve is described in terms of an ( ), D1, resulting from ( ); a final ( ), resulting from ( ) killing; and some quantity (either n or Dq) to represent the size or width of the shoulder of the curve.

Answer 49

multitarget, initial slope = D1, single-event killing, slope, D0, multiple-event

Question 50

In multitarget model, the quantities D1 and D0 are the reciprocals of the initial and final slopes. In each case, it is the dose required to reduce the fraction of surviving cells to (
)% of its previous value (i.e., e−1).

As illustrated in Figure 3.3B, D1, the initial slope, is the dose required to reduce the fraction of surviving cells to ( ) on the initial straight portion of the survival curve. The final slope, ( ), is the dose required to reduce survival from ( ) or from ( ), and so on.

Because the surviving fraction is on a logarithmic scale and the survival curve becomes (
) at higher doses, the dose required to reduce the cell population by a given factor (to 0.37 or e−1) is the ( ) at all survival levels. It is, on average, the dose required to deliver one inactivating event per cell.

Answer 50

37, 0.37, D0, 0.1 to 0.037, 0.01 to 0.0037, straight, same

Question 51

In the multitarget model, the extrapolation number, n, is a measure of the ( ). If n is large (e.g., 10 or 12), the survival curve has a ( ) shoulder. If n is small
(e.g., 1.5 to 2), the shoulder of the curve is ( ).

Another measure of shoulder width is the ( ) dose, shown as ( ) in Figure 3.3.

This sounds like a term invented by a committee, which in a sense it is. An easy way to remember its meaning is to think of the hunchback of Notre Dame. When the priest was handed the badly deformed infant who was to grow up to be the hunchback, he cradled him in his arms and said, “We will call him Quasimodo—he is almost a person!”

Answer 51

width of the shoulder, broad, narrow

quasithreshold, Dq

Question 52

In the multitarget model, similarly, the quasithreshold dose is almost a ( ) dose. It is
defined as the dose at which the straight portion of the survival curve,
extrapolated backward, cuts the dose axis drawn through a survival fraction of
unity.

A threshold dose is the dose below which there is ( ) effect. There is no dose below which radiation produces no effect, so there can be no true threshold dose; Dq, the quasithreshold dose, is the closest thing.

At first sight, this might appear to be an awkward parameter, but in practice,
it has certain merits that become apparent in subsequent discussion. The three
parameters, n, D0, and Dq, are related by the expression log(en) = Dq / D0

Answer 52

threshold, no

Question 53

The linear-quadratic model has taken over as the model of choice to describe
survival curves. It is a direct development of the relation used to describe
( ) aberrations that are clearly the result of an
interaction between two separate breaks. This is discussed in some detail in
Chapter 2.

Answer 53

exchange-type chromosome

Question 54

The linear-quadratic model, illustrated in Figure 3.3A, assumes that there
are two components to cell killing by radiation: one that is proportional to ( )
and one that is proportional to the ( ).

The notion of a component of cell inactivation that varies with the square of the dose introduces the concept of ( ) radiation action. This idea goes back to the early work with chromosomes in which many chromosome aberrations are clearly the result of ( ) breaks. (Examples discussed in Chapter 2 are dicentrics, rings, and
anaphase bridges, all of which are likely to be lethal to the cell.)

Answer 54

dose, square of the dose

dual, two separate

Question 55

In the linear-quadratic model, the expression for the cell survival curve is
S = e^(−αD −βD^2) in which S is the fraction of cells surviving a dose D, and α and β are constants.

The components of cell killing that are proportional to dose and to the square of
the dose are ( ) if αD = βD2 or D = α/β

This is an important point that bears repeating: The linear and quadratic
contributions to cell killing are equal at a dose that is equal to the ratio of α to β.

A characteristic of the linear-quadratic formulation is that the resultant cell
survival curve is continuously bending; there is no final straight portion. This
does not coincide with what is observed experimentally if survival curves are
determined down to seven or more decades of cell killing in which case the
dose–response relationship closely approximates to a straight line in a log-linear
plot; that is, cell killing is an exponential function of dose. In the first decade or
so of cell killing and up to any doses used as daily fractions in clinical
radiotherapy, however, the linear-quadratic model is an adequate representation
of the data. It has the distinct advantage of having only two adjustable
parameters: α and β.

Answer 55

equal

Question 56

Senescence has been classified as a ( ) mechanism.

Why?

Answer 56

tumor suppressor, b/c it prevents excessive cellular divisions in response to inappropriate growth signals or division of cells that have accumulated DNA damage.

Question 57

What are the two genes involved in regulating senescence?

Answer 57

p53 and Rb

Question 58

Define senescence.

Answer 58

It’s a cellular response to stress that leads to an irreversible cell cycle arrest that is characterized by the activation of the p53 and retinoblastoma (Rb).

And it is associated with chromatin modifications that result in the silencing of genes necessary to promote transition from the G1 to S phase.