放射医学专业英语翻译

Unit 4 Section A

DNA Strand Breaks and Chromosomal Abberations Induced

by Ionizing Radiation（1）

is the principal target for the biologic effects of radiation on the basis of strong

circumstantial evidence?

基于详细的证据，辐射生物效应的主要靶点是什么？

2. What is the structure of a deoxyribonucleic acid molecule?

脱氧核糖核酸分子的结构是什么?

DNA Strand Breaks

DNA链断裂

There is strong circumstantial evidence to indicate that deoxyribonucleic acid (DNA) is the

principal target for the biologic effects of radiation, including cell killing mutation, and

carcinogenesis. A consideration of the biologic effects of radiation therefore must begin logically

with a description of the breaks in DNA caused by charged-particle tracks and by the chemical

species produced.

有足够多且详细的证据表明脱氧核糖核酸是辐射生物效应的主要的靶，包括细胞杀伤性

突变和致癌作用。因此，从带电粒子和化学产物导致的DNA链断裂来考虑辐射生物效应是

较合乎逻辑的。

此处是sentense analysis 1.

DNA is a large molecule with a well-known double helix structure. It consists of two strands,

held together by hydrogen bonds between the bases. The “backbone” of each strand consists of

alternating sugar and phosphate groups. The sugar involved is deoxyribose. Attached to this

backbone are four bases, the sequence of which specifies the genetic code. Two of the bases are

single-ring groups (pyrimidines); these are thymine and cytosine. Two of the bases are double-ring

groups (purines); these are adenine and guanine. The bases on opposite strands must be

complementary; adenine pairs with thymine, guanine pairs with cytosine.

众所周知，DNA是双螺旋结构的大分子。包含2条链，碱基间由氢键连接。每条链的

骨架由糖和磷酸基团交替组成。糖是脱氧核糖。四种碱基连接到骨架上，其顺序决定遗传密

码。其中2个碱基是单环结构（嘧啶），分别是胸腺嘧啶和胞嘧啶。两个碱基是双环结构（嘌

呤），分别是腺嘌呤和鸟嘌呤。这些碱基在相反的链上必须是互补的，腺嘌呤与胸腺嘧啶配

对，鸟嘌呤与胞嘧啶配对。

If cells are irradiated with X-rays, many breaks of a single strand occur. These can be

observed and scored as a function of dose if the DNA is denatured and the supporting structure

stripped away. In intact DNA, however, single-strand breaks are of little biologic consequence as

far as a cell killing is concerned because they are repaired readily using the opposite strand as a

template. If the repair is incorrect (misrepair), it may result in a mutation. If both strands of the

DNA are broken, and the breaks are well separated, repair again occurs readily, because the two

breaks are handled separately.

如果细胞受到X射线辐射，单条链可以发生的断裂。如果DNA变性，支持结构脱落的

话，这些断裂能够被观察到，还可以作为剂量的函数分级。然而，在完整的DNA中，就细

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胞杀伤而言，单链断裂具有较少的生物学结果，因为，他们可以利用互补链作为模板立刻得

到修复。如果修复是不正确的（错误修复），可能导致突变。如果DNA的两条链都断裂了，

而且断裂分开的很好，则修复非常方便地再次发生，因为2个断裂是被独立地处理的。

By contrast, if the breaks in the two strands are opposite one another, or separated by only a

few base pairs, this may lead to a double-strand break; that is, the piece of chromatin snaps into

two pieces. A double-strand break is believed to be the most important lesion produced in

chromosomes by radiation; as described in the next section, the interaction of two double-strand

breaks may result in cell killing, mutation, or carcinogenesis.

与之相对，如果两条链的断裂互相互补的，或者仅被几个碱基对分开，这样的话， 将

导致双链断裂，也就是说，这段染色质断成两段。人们认为，双链断裂是辐射在染色体引起

的最重要的损伤，正如下一部分描述的那样，两个双链断裂间的相互作用将导致细胞杀伤，

突变，或者癌症发生。

There are many kinds of double-strand breaks, varying in the distance between the breaks on

the two DNA strands and the kinds of end groups formed. Their yield in irradiated cells is about

0.04 times that of single-strand breaks, and they are induced linearly with dose, indicating that

they are formed by single tracks of ionizing radiation. Double-strand breaks can be repaired by

two basic processes: homologous recombination, requiring an undamaged DNA strand as a

participant in the repair, and end-to-end rejoining via nonhomologous recombination. Homologous

recombination, an error-free process, is relatively rare in mammalian cells, and is carried out by

proteins similar to the rad51 gene product of the yeast S. cerevisiae. Nonhomologous (illegitimate)

recombination is error-prone and probably accounts for many of the premutagenic lesions induced

in the DNA of human cells by ionizing radiation. DNA-dependent protein kinase and the Ku

proteins participate in this repair process. Recently it has been shown that a protein complex that

includes hMre11 and Hrad50 and p95 is also involved in the repair of double-strand breaks in

human cells.

有何多种双链断裂，依DNA双链上断裂之间的距离及形成末端基团的种类而变化。在

受照射细胞，双链断裂的产率是单链断裂的0.04倍，并且，它们同剂量形成线形关系诱导，

表明它们是由电离辐射的单径迹所形成的。双链断裂可能通过两个基本的过程被修复，同源

重组，在这一修复过程中，需要一个未受损伤的DNA作为参与者，以及通过非同源重组末

端间重结合。同源重组是一个无错的过程，在哺乳动物细胞中相对较少发生，并且通过与啤

酒酵母rad51基因产物相似的蛋白实现。非同源（不合逻辑的）重组是易错修复，并且很可

能解释电离辐射引起的人类细胞DNA的许多突变前损伤。DNA依赖蛋白激酶和Ku蛋白参

与了这一修复过程。最近，有证据表明，由hMre11、 d Hrad50 和d p95所组成的蛋白也参

与了人类细胞双链断裂的修复。

In practice, the situation is probably much more complicated because both free radicals and

direct ionizations may be involved. The energy from ionizing radiations is not deposited uniformly

in the absorbing medium but is located along the tracks of the charged particles set in motion 

electrons in the case of X- or -rays, protons and α-particles in the case of neutrons. Radiation

chemists speak in terms of “spurs”, “blobs”, and “short tracks”. There is, of course, a full spectrum

of energy-event sizes, and it is quite arbitrary to divide them into just three categories, but it turns

out to be instructive. A spur contains up to 100 eV of energy and involves, on average, three ion

pairs. In the case of X- or -rays, 95% of the energy deposition events are spurs, which have a

diameter of about 4 nm, which is about twice the diameter of the DNA double helix. Blobs are

much less frequent for X- or -rays; they have a diameter of about 7 nm and contain on average

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about 12 ion pairs. Because spurs and blobs have dimensions similar to the DNA double helix,

multiple radical attack occurs if they overlap the DNA helix. There is likely to be a wide variety of

complex lesions, including base damage as well as double-strand breaks. The term locally

multiply damaged site has been coined by John Ward to describe this phenomenon. Given the size

of a spur and the diffusion distance of hydroxyl free radicals, the multiple damage could be spread

out up to 20 base pairs.

实际上，情况可能是更复杂的，因为可能涉及了自由粒子和直接电离作用。电离辐射所

产生的能量并不是均匀地沉积在吸收介质中，而是沿着运动中的带电粒子分布——例如X

或者射线中的电子，热中子的质子和α离子。辐射化学家称之为“刺迹”、“团迹”和“短

径迹 ”，当然，具有能量事件大小的完整谱，并且相当随意的将它们分成3类，但是，它证

明为是具有指导意义的。一个“刺迹”含有100 eV的能量，并且平均涉及3个离子对。在

X- 或者-射线中，95%的能量沉积事件是“刺迹”，它具有4 nm的直径，大约是DNA双螺

旋直径的2倍。对于X- 或者-射线而言，“团迹”的发生是很少见的，它们的直径大约7nm，

平均含有12个离子对，由于，“刺迹”和“径迹”的尺寸与DNA双螺旋接近，如果它们与

DNA双螺旋重叠，将有多个自由攻击发生。可能一系列广泛的复杂损伤将发生，包括碱基

损伤和双链断裂。John Ward为了描述这一现象，创造了术语局部多位点损伤。已知了“刺

迹”的大小及氢自由基的扩散距离，很多损伤能够扩散至20个碱基对。

In the case of densely ionizing radiations, such as neutrons or α-particles, a greater proportion

of blobs is produced. The damage produced, therefore, is qualitatively different to that produced

by X- or -rays and much more difficult for the cell to repair.

在致密的电离辐射中，例如中子和α-粒子，更多比例的团迹产生。因此，所产生的损

伤与那些X或者 射线产生的损伤性质上不同，而且诶对于细胞来说修复更困难。

Measuring DNA Strand Breaks

DNA链断裂的检测

Both single-strand and double-strand DNA breaks can be measured readily by isolating the

DNA from irradiated cells and causing the pieces to pass through a porous substrate, such as a gel

or a filter. The DNA pieces move under the influence of either flow through the filter or electric

field in the gel (using the fact that DNA is positively charged). Smaller pieces move faster and

farther than larger pieces of DNA and thus can be separated and counted. The larger the dose of

radiation, the more the DNA is broken up. DNA is denatured and lysed by a strong alkaline

preparation so that single-strand breaks are measured. Double-strand breaks are measured in a

neutral preparation.

单链和双链DNA断裂都可以便利地检测，方法是从受照射细胞中分离DNA，使DNA

片段通过多孔基质，如凝胶或滤器。DNA片段在过滤器的流率或者凝胶电场作用的影响下

移动（利用DNA是阳性粒子的事实）。DNA的小片段比大片段移动的快且远，这样的话，

DNA片段就被分开且能够被计数。照射剂量越大，DNA断裂越多。在碱性制剂中，DNA

变性且溶解，所以，单链断裂可以被检测。双链断裂可以在中性制剂中被检测。

DNA in cells is much more resistant to damage by radiation than would be expected from

studies on free DNA. There are two reasons for this: the presence in cells of low molecular weight

scavengers that mop up some of the free radicals produced, and the physical protection afforded

the DNA by packaging. Certain regions of DNA, particularly actively translating genes, appear to

be more sensitive to radiation, and there is some evidence also of sequence-specific sensitivity.

细胞中的DNA 比理想的用来研究的游离DNA对辐射损伤更耐受。就这一点来说，有

两种原因，在细胞中存在低分子量的清除剂，它们清除了电离辐射所产生的自由粒子，并且

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通过折叠赋予DNA物理防护。DNA的特定区域，特别是活跃地翻译基因，显现出对辐射

更为敏感，而且，也有一些序列特异敏感性的证据。

Radiation induces a large number of lesions in DNA, most of which are repaired successfully

by the cell. For mammalian cells, D

0

usually lies between 1 and 2 Gy. The number of DNA lesions

per cell detected immediately after such a dose is approximately: base damage > 1000,

single-strand breaks about 1000, and double-strand breaks about 40.

辐射引起大量的DNA损伤，大多数损伤被细胞成功修复。对于哺乳动物细胞而言，D

0

通常介于1和2 Gy之间。在那样的一个剂量照射后，立即检测到的DNA损伤数目大约是：

碱基损伤> 1000，单链断裂大约是1000，双链断裂大约是40。

Cell killing does not correlate at all with single-strand breaks but relates better to

double-strand breaks. Agents such as hydrogen peroxide, which produce single-strand breaks

efficiently, but very few double-strand breaks, also kill very few cells. On the basis of evidence

such as this, it is concluded that double-strand breaks are the most relevant lesions leading to most

biologic insults from radiation, including cell killing. The reason for this is that double-strand

breaks can lead to chromosomal aberrations, which are discussed in the next section.

细胞杀伤与单链断裂无关，与双链断裂关系密切，试剂，如过氧化氢，有效的产生单链

断裂，但是，几乎很少产生双链断裂，也很少杀伤细胞。在类似这样的证据基础上，可以得

出结论，即双链断裂是导致多数辐射生物损伤的最相关的伤害，包括细胞杀伤。原因是双链

断裂能导致染色体畸变，下一部分将讨论这一内容。

Chromosomes and Cell Division

染色体和细胞分裂

The backbone of DNA is made of molecules of sugar and phosphates, which serve as a

framework to hold the bases that carry the genetic code. Attached to each sugar molecule is a base:

thymine, adenine, guanine, or cytosine. This whole configuration is coiled tightly in a double

helix.

DNA骨架由糖和磷酸盐分子组成，这个框架上的碱基携带遗传密码。附着在糖分子上

的是一个碱基：胸腺嘧啶，腺嘌呤，鸟嘌呤和胞嘧啶。这些结构形成致敏的双螺旋。

Figure 2.13 is a highly schematized illustration of the way

An organized folding of the long DNA helix might be achieved as a closely packed series of

looped domains would in a tight helix. The degree of packing also is illustrated by the relative

dimensions of the DNA helix and the condensed metaphase chromosome.

长的DNA螺旋有序地折叠可以在紧密的双螺旋形成一系列紧密包裹的环行结构域。包

裹的程度表示DNA螺旋和分裂中期浓缩的染色体的相对大小。

图简要地示例了长链DNA螺旋的折叠方式。DNA紧密缠绕和包裹环状结构域，形成

致密的双螺旋结构。包裹的程度表示DNA螺旋和分裂中期浓缩的染色体的相对大小。

The largest part of the life of any somatic cell is spent in interphase, during which the nucleus,

in a stained preparation, appears as a lacework of fine, lightly stained material in a translucent,

colorless material surrounded by a membrane. In the interphase nucleus in most cells, one or more

bodies of various sizes and shapes, called nucleoli are seen. In most cells, little more than this can

be identified with a conventional light microscope. In fact, a great deal is happening during this

time: The quantity of DNA in the nucleus doubles as each chromosome lays down an exact replica

of itself next to itself. When the chromosomes become visible at mitosis, they are each present in

duplicate. Even during interphase, there is good evidence that the chromosomes are not free to

move about within the nucleus but are restricted to “domains.”

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绝大部分体细胞的整个生命处在分裂间期，在染色标本中，间期的细胞核是透明的，无

颜色的物质中，被一个膜包绕着的淡染物质，看上去象晴天的花边。在多数细胞的间期细胞

核中，可以看见一个或更多的各种大小和形状的小体，叫做核仁。在多数细胞中，用传统的

光学显微镜，很少有比核仁更小的结构能够被区分。事实上，在这一时期，发生大量事件：

当每一个染色体紧挨着它自己放出一个它本身的精确的复制品时，细胞核中的DNA的量倍

增。当染色体在有丝分裂过程中变得可见，它们每一个都正处在复制过程中。有证据表明，

甚至在有丝分裂间期，染色体在细胞核内不是自由移动的，而是被限定与某些区域。

The various events that occur during mitosis are reviewed first. The first phase of division is

called prophase. The beginning of this phase is marked by a thickening of the chromatin and an

increase in its stainability as the chromosomes condense into light coils. By the end of prophase

each chromosome has a lightly staining constriction known as a centromere; extending from the

centromere are the arms of the chromosome. Prophase ends when the chromosomes reach

maximal condensation and the nuclear membrane disappears, as do any nucleoli.

首先，回顾一下在有丝分裂过程中发生的各个事件。分裂的第一个时期被称为分裂前期。

当染色体浓缩成细的螺线管时，染色质增粗，可染性增加，标志着这一时期的开始。在前期

结束时，每一个染色体具有一个淡染的缢痕，即着丝粒；从着丝粒延伸出染色体的臂。当染

色体达到最大的浓缩程度，核膜和核仁消失时，前期结束。

With the disappearance of the nuclear membrane, the nuclear plasm and the cytoplasm mix.

Metaphase then follows, in which two events occur simultaneously. The chromosomes move to

the center of the cell (i.e., to the cell‟s equator), and the spindle forms. The spindle is composed of

fibers that cross the cell, linking its poles. Once the chromosomes are stabilized at the equator of

the cell, their centromeres divide, and metaphase is complete.

随着核膜的消失，核质与细胞质混合。分裂中期开始，在这一期中，两事件同时发生。

染色体移动到细胞的中心（如细胞的赤道部），并且纺锤体形成。纺锤体由穿过细胞的纤维

组成，连接细胞的两极。一旦，染色体固定于细胞的赤道部位，着丝粒分开，分裂中期结束。

The phase that follows, anaphase, is characterized by a movement of the chromosomes on the

spindle to the poles. Chromosomes appear to be pulled toward the poles of the cell by fibers

attached to the centromeres. The arms, particularly the long arms, tend to trail behind.

接下来是分裂后期，此期的特征是纺锤体上的染色体向细胞两极移动。染色体象是被附

属于着丝粒的纺锤丝拉向细胞的两极。染色体臂，特别是长臂，稍稍滞后。

Anaphase is followed by the last step of the process of mitosis, telophase. In this phase the

chromosomes, congregated at the poles of the cell, begin to uncoil. The nuclear membrane

reappears, as do the nucleoli; and as the phase progresses, the chromosome coils unwind until the

nucleus regains the appearance characteristic of interphase.

后期紧接着是有丝分裂的最后一期，分裂末期。在这一期中，聚集在细胞的两极的染色

体的缠绕开始松解。核膜、核仁重新出现；并且随着这一时期的进展，染色体的缠绕持续展

开，直到细胞核恢复到与分裂间期一样的特征。

Unit 4 Section B

The Role of Telomers

端粒的作用

Telomeres cap and protect the terminal ends of chromosomes. The name telomere literally

means “end part.” Mammalian telomeres consist of long arrays of TTAGGG repeats that range in

total length anywhere from 1.5 to 150 kilobases. Each time a normal somatic cell divides,

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telomeric DNA is lost from the lagging strand, because DNA polymerase cannot synthesize new

DNA in the absence of an RNA primer. Successive divisions lead to progressive shortening, and

after 40 to 60 divisions the telomeres in human cells are shortened dramatically so that vital DNA

sequences begin to be lost. At this point the cell cannot divide further and undergoes senescence.

Telomere length has been describes as the “moleculer clock” or generational clock, because it

shortens with age in somatic tissue cells during adult life. Stem cells in self-renewing tissues, and

cancer cells in particular, avoid this problem of aging by activating the enzyme telomerase.

Telomerase is a reverse transcriptase that includes the complementary sequence to the TTAGGG

repeats and so continually rebuilds the chromosome ends to offset the degradation that occurs with

each division. In this way the cells becomes immortal.

端粒加帽于并保护染色体的末端。端粒的名称字面上意思是“末端部分”。哺乳动物的

着丝粒由TTAGGG重复序列的长排列组成，它的总长度在1.5到150千碱基间任意变化。

体细胞的每一次正常分裂，端粒DNA便从延迟链脱落。因为，在缺乏RNA引物的情况下，

DNA聚合酶不能合成新的DNA。连续分裂导致着丝粒逐渐变短，在40-60代分裂后，人类

细胞中的DNA剧烈的变短，以至于重要的DNA 序列开始丢失。此时，细胞不能进一步分

裂，开始老化。人们描述着丝粒长度为分子钟或生育钟，因为在成人生命过程的体细胞组织

细胞中，它随着年龄增长而变短。自我更新组织的干细胞，特别是癌细胞，通过激活端粒酶

而避免了老化问题。端粒酶是逆转录酶，含有TTAGGG重复序列的互补序列，所以，不断

的重建染色体末端，以抵消每次分裂它的降解。以此方式，细胞变成永生的。

In tissue culture, immortalization of cells, that is, cells that pass through a “crisis” and

continue to be able to divide beyond the normal limit, is associated with telomere stabilization and

activity of telomerase. Virtually all human tumor-cell lines and approximately 90% of human

cancer biopsy specimens exhibit telomerase activity. By contrast, normal human somatic tissues,

other than stem cells, do not possess detectable levels of this enzyme. It is an attractive hypothesis

that both immortalization and carcinogenesis are associated with telomerase expression.

在组织培养中，细胞的无限增殖特性，也就是，细胞通过了一个危机，能够超过正常限

制而持续分裂，这于端粒的稳定性及端粒酶的激活有关。事实上，所有的人类肿瘤细胞系及

大约90%的人类癌组织活检标本显示出端粒酶活性。对比之下，正常的人类体细胞组织与

干细胞不同，检测不到这种酶。人们提出了一个有吸引力的假说，即永生性及癌症发生均与

端粒酶表达有关。

Radiation-Induced Chromosome Aberrations

辐射诱导染色体畸变

In the traditional study of chromosome aberration, the effects of ionizing radiations are

described in terms of their appearance when a preparation is made at the first metaphase after

exposure to radiation. This is the time at which the structure of the chromosomes can be discerned.

在传统的染色体畸变的研究中，电离辐射的作用是以受照后第一次分裂中期的染色体标

本来描述的。这一时期是染色体结构能被容易分辨的时期。

The study of radiation damage in mammalian cell chromosomes is hampered by the large

number of mammalian chromosomes per cell and by their small size. Most mammalian cells

currently available for experimental purposes have a diploid complement of 40 or more

chromosomes. There are exception, such as the Chinese hamster, with 22 chromosomes, and

various marsupials, such as the rat kangaroo and woolly opossum, which have chromosome

complements of 12 and 14, respectively. Many plant cells, however, contain fewer and generally

much larger chromosomes; consequently, until recently, information on chromosomes radiation

- 6 -

damage accrued principally from studies with plant cells.

哺乳动物细胞染色体的辐射损伤研究被每个细胞中染色体的庞大的数目及小的尺寸所

妨碍（针对哺乳动物细胞染色体辐射损伤的研究，主要受限于哺乳动物细胞染色体数目多且

尺寸小）。目前，能够得到的用于实验目的的哺乳动物细胞的染色体，多数具有40对或更多

的双倍染色体。但亦有些例外，如中国仓鼠有22条染色体，以及各种有袋类动物，如袋鼠

和绵毛负鼠，分别有12和14条染色体。然而，大多数植物细胞，染色体数目更少及通常更

大；因此，至今关于染色体辐射损伤的信息主要从植物细胞研究中获得。

If cells are irradiated with X-rays, breaks are produced in the chromosomes. The broken ends

appear to be “sticky” and can rejoin with any other sticky end. It would appear, however, that a

broken end cannot join with a normal, unbroken chromosome, although this is controversial.

如果细胞经X射线照射，染色体产生断裂。断裂的末端看上去是粘性的，可能和任何

粘性末端重新连接。然而，将可能出现，断裂末端不能与正常的、未断裂的染色体连接，这

一点是有争议的。

Once breaks are produced, different fragments may behave in a variety of ways: (1) The

breaks may restitute, that is, rejoin in their original configuration. In this case, of course, nothing

amiss is visible at the next mitosis. (2) The breaks may fail to rejoin and give rise to an aberration,

which is scored as a deletion at the next mitosis. (3) Broken ends may reassort and rejoin other

broken ends to give rise to chromosomes that appear to be grossly distorted if viewed at the

following mitosis. This is an oversimplified account; whether actual breaks occur in the

chromosomes at the time of irradiation is not know, nor is the biologic significance of “stickiness”

understood.

一旦断裂发生，不同的片段以不同方式表现（1）断裂可以修复，即以它们最开始的结

构重新连接。当然，在这种情况下，在下一个有丝分裂过程中，不会出现任何差错。（2）断

裂重接失败，开始引起畸变，在下一次有丝分裂中以缺失的形式留下痕迹。（3）断裂末端可

以重配、重连其他的断端，在下个有丝分裂中可见染色体严重的变形。这种解释过于简单，

在实际情况下，染色体受照是是否发生断裂仍不清楚，粘性的生物学意义也仍不为人们所理

解。

The aberrations seen at metaphase are of two classes: chromosome aberrations and chromatid

aberrations. Chromosome aberrations result if a cell is irradiated early in interphase, before the

chromosome material has been duplicated. In this case the radiation-induced break is in a single

strand of chromatin; during the DNA synthetic phase that follows, this strand of chromatin lays

down an identical strand next to itself and replicates the break that has been produced by the

radiation. This leads to a chromosome aberration visible at the next mitosis, because there is an

identical break in the corresponding points of a pair of chromatin strands. If, on the other hand, the

dose of radiation is given later in interphase, after the DNA material has doubled and the

chromosomes consist of two strands of chromatin, then the aberration produced are called

chromatid aberrations. In regions removed from the centromere, chromatid arms may be fairly

well separated, and it is reasonable to suppose that the radiation might break one chromatid

without breaking its sister chromatid, or at least not in the same place. A break that occurs in a

single chromatid arm after chromosome replication and leaves the opposite arm of the same

chromosome undamaged leads to chromatid aberration.

在有丝分裂中期可见两种染色体畸变：染色体畸变和染色单体畸变。一方面，如果细胞

在分裂间期的早期，染色体物质复制之前受照射，将引起染色体畸变。在这种情况下，辐射

引起的断裂是染色质单链的损伤。在接下来的DNA合成期，该染色质单链放弃了与其本身

- 7 -

完全一致的链进行复制产生下一条链，而是复制辐射所致断裂的链。这将导致在下一次有丝

分裂中出现畸变，因为在对应的染色单体的链的相应位置上，具有完全相同的断裂。在另一

方面，如果在间期的后期给予照射，在DNA已经复制，且染色体含有染色质的两条链，那

样的话，产生的畸变叫染色单体畸变。随着着丝粒的分离，染色单体的臂相对较好的分开，

因此，假定辐射没有断裂姐妹染色体的一个染色单体，或者至少不在同一位置的猜想是合理

的。断裂发生在染色体复制后的单个染色单体臂上，而同一染色体的互补的臂未受损伤，这

样的断裂将导致染色单体畸变。

Examples of Radiation-Induced Aberrations

辐射诱导染色体畸变的实例

Many types of chromosomal aberrations and rearrangements are possible. Three types of

aberrations that are lethal to the cell are described, followed by two common rearrangements that

are consistent with cell viability but are involved in carcinogenesis. The three lethal aberrations

are the ring and the dicentric, which are chromosome aberrations, and the anaphase bridge, which

is a chromatid aberration. All three represent gross distortions and are clearly visible. Many other

aberrations are possible but are not described here.

很多种类型的染色体畸变和重排是可能发生的。在此，我们描述对细胞致命的3种类型

畸变，接着是两种普通的重组，这两种重组会伴随着细胞生存，且通常涉及癌变。这三种致

死性畸变是环、双着丝粒体，二者是染色体畸变，及分裂后期桥，它是染色单体畸变。所有

的这三种畸变表现为严重的变形，并且是显而易见。当然还有很多其他的畸变，但在这里并

未涉及。

The formation of a dicentric aberration involves an interchange between two separate

chromosomes. If a break is produced in each one early in interphase and the sticky ends are close

to one another, they may rejoin as shown. This bizarre interchange is replicated during the DNA

synthetic phase, and the result is a grossly distorted chromosome with two centromeres (hence,

dicentric). There also is a fragment that has no centromere (acentric fragment).

双着丝粒畸变的形成与两个独立的染色体间的互换有关。如果两个染色体中的每一条都

在间期早期产生一个断裂，并且粘性末端互相接近，它们可以重新连接，正如所展现的那样

（图）。这个奇特的互换在DNA合成期会被复制，结果是产生具有两个着丝粒的严重变形

的染色体。（即双着丝粒体）。同时，也产生一个没有着丝粒的片段（无着丝粒片段）。

The formation of a ring is induced by radiation in each arm of a single chromatid early in the

cell cycle. The sticky ends may rejoin to form a ring and a fragment. Later in the cycle, during the

DNA synthetic phase, the chromosome replicates. The fragment has no centromere and probably

will be lost at mitosis because it will not be pulled to either pole of the cell.

在细胞周期的早期，辐射导致染色单体的每个臂形成环畸变。粘性末端重接形成环和一

个片段。在细胞周期的后期，DNA合成期期间，染色体复制。片段没有着丝粒，且很可能

在有丝分裂中丢失，因为它不能被拉向细胞的任何一极。

An anaphase bridge may be produced in a variety of ways. It results from breaks that occur

late in the cell cycle (in G

2

), after the chromosomes have replicated. Breaks may occur in both

chromatids of the same chromosome, and the sticky ends may rejoin incorrectly to form a sister

union. At anaphase, when the two sets of chromosomes move to opposite poles, the section of

chromatin between the two centromers is strectched across the cell between the poles, hindering

the separation into two new daughter cells. The two fragments may join but because there is no

centromere the joined fragments will probably be lost at the first mitosis. This type of aberration

occurs in human cells and is essentially always lethal. It is hard to demonstrate, because

- 8 -

preparations of human chromosomes usually are made by accumulating cells at metaphase but the

bridge is only evident at anaphase. The anaphase bridge is seen clearly as the replicate sets of

chromosomes move to opposite poles of the cell.

分裂后期桥可能以多种方式产生。它由发生在细胞周期的晚期（G

2

期）染色体已复制

后的断裂导致。断裂可能发生在同一染色体的两个染色单体，并且，染色单体可能错误重接

形成姐妹染色单体环。在分裂后期，当两套染色体移动到相反的两极时，在两个着丝粒着丝

点之间的部分染色单体片段横跨细胞的两极，妨碍了两个子细胞的分离。这两个片段可能重

接，但是，由于没有着丝粒重接的片段将在第一次有丝分裂时丢失。此类畸变在人类细胞中

发生，并且基本上总是致命的。由于，人类染色体标本通常由中期的细胞收集制成，而分裂

后期桥仅在后期明显，所以，它很难被阐明。在染色体复制组移向细胞相反的两极时，后期

桥清晰可见。

Two important types of chromosomal changes that are not lethal to the cell are symmetric

translocations and small deletions. The formation of a symmetric translocation involved a break in

two prereplication (i.e., G

1

-phase) chromosomes, with the broken ends being exchanged between

the two chromosomes as illustrated. An aberration of this type is difficult to see in a conventional

preparation but is easy to observe with the technique of fluorescent in situ hybridization, or

chromosome painting, as it commonly is called. Probes are available for every human

chromosome that make them florescent in a bright color. Exchange of material between two

different chromosomes then is readily observable. A translocation is associated with several

human malignancies caused by the activation of an oncogene; Burkitts lymphoma is an example.

另外两种重要的对细胞非致死性的染色体改变是对称性易位和小缺失。如图所示，对称

性易位的形成涉及两个复制前（例如在G1期）染色体的断裂，在这两个染色体间，断裂末

端交换便形成对称易位。在传统的标本中，很难看到这种类型的畸变，但是如果应用荧光原

位杂交或常被称为染色体涂染技术，则很容易观察到。对于人类染色体来说制备明亮的彩色

荧光探针是非常方便的。不同染色体间的物质交换可以被便利地观察到。易位与由癌基因激

活导致的多种人恶性肿瘤相关，Burkitt淋巴瘤就是这样的一个例子。

The other type of nonlethal chromosomal change is a small interstitial deletion. This may

result from two breaks in the same arm of the same chromosome, leading to the loss of the genetic

information between the two breaks. The actual sequence of events in the formation of a deletion

shows an interphase chromosome. It is a simple matter to imagine how to breaks may isolate a

loop of DNA — an acentric ring — which is lost at a subsequent mitosis. A deletion may be

associated with carcinogenesis if the lost genetic material includes a suppressor gene.

另一种非致死性染色体改变的类型是小中间缺失。这可能是由相同染色体的相同臂上的

两个断裂引起，导致两个断裂间的遗传信息丢失。在缺失形成时事件的实际顺序表明了一个

间期染色体。想象出怎样断裂隔离出一个环行DNA，即无着丝粒染色体环是如此简单的事，

它在后来的有丝分裂中丢失。如果丢失的遗传物质包括抑癌基因，则缺失可能与癌症发生有

关。

The interaction between breaks in different chromosomes is by no means random. There is

great heterogeneity in the sites at which deletions and exchanges between different chromosomes

occur; for example, chromosome 8 is particularly sensitive to exchanges. As mentioned previously,

each chromosome is restricted to a domain, and most interactions occur at the edges of domains,

which probably involves the nuclear matrix. Active chromosomes are therefore those with the

biggest surface area to their domains.

不同染色体断裂间的相互作用并不是随机的。不同染色体间的缺失和交换的发生具有位

‟

- 9 -

点异质性，例如，8号染色体对于交换特别敏感。正如之前提到的那样，每一个染色体限定

于一个区域，并且多数相互作用发生在这些区域的边缘，它们可能涉及核基质。因此，活跃

的染色体是那些具有与他们的区域相比最大表面积的染色体。

Chromosome Aberrations in Human Lymphocytes

人类淋巴细胞染色体畸变

Chromosomal aberrations in peripheral lymphocytes have been used widely as biomarkers of

radiation exposure. In blood samples obtained for cytogenetic evaluation within a few days to a

few weeks after total-body irradiation, the frequency of asymmetric aberrations in the

lymphocytes (dicentrics and rings) reflects the dose received. Lymphocytes in the blood sample

are stimulated to divide with a mitogen such as phytohemgglutinin and are arrested at metaphase,

and the incidence of rings and dicentrics is scored. The dose can be estimated by comparison with

in vitro cultures exposed to known doses. A dose-response curve for aberration in human

lymphocytes is produced by γ-rays. The data are fitted by a linear-quadratic relations, as would be

expected, because rings and dicentrics result from the interaction of two chromosome breaks. The

linear component is a consequence of the two breaks resulting from a single charged particle. If

the two breaks result from different charged particles, the probability of an interaction is a

quadratic function of dose.

外周淋巴细胞的染色体畸变已被广泛用于射线照射的生物标志物被广泛使用。在全身照

射后几天到几周时间内而采集血液标本，观察淋巴细胞非对称畸变（双着丝粒体和环），可

反映照射受照射剂量。在丝裂源如植物血凝素的作用下，血样中的淋巴细胞受刺激而分裂，

并阻滞于分裂中期，并且环和双着丝粒的发生率可以被计算。可以通过体外已知照射剂量培

养细胞的比较来评估受照射剂量。γ-射线照射的人淋巴细胞的染色体畸变的剂量效应曲线已

经获得。正如所期望的那样，该数据适合线性平方关系，因为环和双着丝粒是由两个染色体

断裂的相互作用所产生。线性部分是由单个带电粒子引起两个断裂所导致的。 如果两个断

裂由不同的带电粒子引起，相互作用的可能性是剂量函数的平方关系。

During in vivo exposures to ionizing radiation, chromosome aberrations are induced not only

by in mature lymphocytes but also in lymphocyte progenitors in marrow, nodes, or other organs.

The stem cells that sustain asymmetric aberrations (such as dicentrics) die in attempting a

subsequent mitosis, but those that sustain a symmetric nonlethal aberration (such as a translocation)

survive and pass on the aberration to their progeny. Consequently, dicentrics are referred to as

“unstable” aberrations, because their number declines with time after irradiation. Symmetric

translocations, by contrast, are referred to as “stable” aberrations, because they persist for many

years. Either type of aberration can be used to estimate dose soon after irradiation, but if many

years have elapsed, scoring dicentrics underestimates the dose, and only stable aberrations such as

translocations give accurate pictures. Until recently, translocations were much more difficult to

observe than dicentrics, but now the technique of fluorescent in situ hybridization makes the

scoring of such symmetric aberrations a relatively simple matter. The frequency of translocation

assessed in this way correlates with total-body dose in exposed persons even after more than 50

years, as was shown in a recent study of the survivors of the atomic-bomb attacks on Hiroshima

and Nagasaki.

体内受电离辐射照射时，不仅成熟的淋巴细胞，而且在骨髓、淋巴结及其他器官的淋巴

祖细胞也发生染色体畸变。出现不对称性畸变（如双着丝粒）的干细胞在随后的有丝分裂中

死掉，而那些经历对称性非致死性畸变（如易位）的干细胞将存活，并将畸变传递给它们的

子代。因此，双着丝粒指的是非稳定畸变，因为他们的数目在照射后随时间延长而下降。与

- 10 -

之相反，对称易位指的是稳定畸变，因为它们可以存在很多年。不管哪种畸变可以在照射后

很快用于剂量估算，但是，如果许多年过去了，评分双着丝粒体则会低估剂量大小，只有稳

定畸变如易位才能做出正确的剂量估算。最近，易位较双着丝粒更难观察，但是现在原位荧

光杂交技术使这样的对称性畸变的评价相对简单。以这种方式估计的转位频率依然与受照人

的总剂量相关，甚至在受照后50年，正如近来在广岛、长崎原子弹袭击的幸存者中的研究

所表明的一样。

Unit 5 Section A

1. Please conceive the possible shape of cell-survival curves caused by irradiation.

想象一下辐射导致细胞存活曲线的可能形状。

2. How do you understand the definition of cell survival?

如何理解细胞存活的定义？

Reproductive Integrity

增殖完整性

A cell-survival curve describes the relationship between the radiation dose and the proportion

of cells that survive. What is meant by “survival?” Cell survival, or its converse, cell death, may

mean different things in different contexts; therefore, a precise definition is essential. For

differentiated cells that do not proliferate, such as nerve, muscle, or secretory cells, death can be

defined as the loss of a specific function. For proliferating cells, such as stem cells in the

hematopoietic system or the intestinal epithelium, loss of the capacity for sustained proliferation

— that is, loss of reproductive integrity — is an appropriate definition. This is sometimes called

reproductive death. This is certainly the endpoint measured with cells cultured in vitro.

细胞存活曲线描述了辐射剂量和存活比例之间的关系。Survival是什么意思呢？细胞存

活或者其反义词，细胞死亡，在不同的情况下可能有不同的含义；因此，给出一个明确的定

义是必要的。对于分化而不增殖的细胞，例如神经、肌肉或者分泌细胞，死亡被定义为特定

功能的丧失。对于增殖细胞，例如造血系统或者肠上皮的干细胞，失去持续增殖的能力，也

就是说，增殖完整性的丧失，就是一个合适的定义。有些时候叫做增殖死亡。这当然是体外

培养细胞研究的终点。

This definition reflects a narrow view of radiobiology. A cell still may be physically present

and apparently intact, may be able to make proteins or synthesize DNA, and may even be able to

struggle through one or two mitoses; but if it has lost the capacity to divide indefinitely and

produce a large number of progeny, it is by definition dead; it has not survived. A survivor that has

retained its reproductive integrity and is able to proliferate indefinitely to produce a large clone or

colony is said to be clonogenic.

这个定义反应了放射生物学的一个比较狭隘的观点。细胞仍旧可以生理性存在并且表面

上完整，能够合成蛋白质和DNA，甚至能够勉强地完成1或者2次有丝分裂；但是如果它

已经失去了无限分裂和产生大量子代细胞的能力，则被定义为死亡；它已经不处在存活状态

了。一个存活下表保留增殖的完整性，并且能够无限增殖产生大量的克隆或者集落则称其为

具有克隆源性。

This definition is generally relevant to the radiobiology of whole animals and plants and their

tissues. It has particular relevance to the radiotherapy of tumors. For a tumor to be eradicated, it is

only necessary that cells be “killed” in the sense that they are rendered unable to divide and cause

further growth and spread of the malignancy. Cells may die by different mechanisms, as is

described here subsequently. For most cells, death while attempting to divide, that is, mitotic death,

- 11 -

is the dominant mechanism following irradiation. For some cells, programmed cell death or

apoptosis is important. Whatever the mechanism, the outcome is the same: The cell loses its

ability to proliferate indefinitely, that is, its reproductive integrity.

这个定义普遍适用于放射生物学领域所有动物、植物和它们的组织。尤其是肿瘤的放射

治疗。要想根治肿瘤，在某种程度上杀伤细胞，而所谓的杀死就是使肿瘤细胞失去分裂的能

力并且无法继续生长及恶性扩散。细胞可以通过不同的机制死亡，这将在此逐渐描述。对大

多数细胞来说，在其试图进入有丝分裂时出现死亡，这种死亡被称为有丝分裂死亡，它是辐

射后主要的死亡机制。对某些细胞来说，程序性死亡或者凋亡是重要的死亡机制。无论机制

如何，最终的结果都是一样的：细胞丧失了无限增殖的能力，也就是失去它的增殖完整性。

In general, a dose of 100 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 2 Gy.

通常，在非增殖系统中，100 Gy的剂量足以摧毁细胞的增殖功能。与之相比，对于失

去了增殖能力的细胞来说平均致死剂量通常不到2 Gy。

The in vitro Survival Curve

体外培养细胞的存活曲线

The capability of a single cell to grow into a large colony, which can be seen easily with the

naked eye, is a convenient proof that it has retained its reproductive integrity. The loss of this

ability as a function of radiation dose is described by the dose-survival curve.

可简单证明单个细胞仍保有其增殖完整性的证据就是该细胞具有能长成一个大的、肉眼

可见克隆的能力。通常用剂量-存活曲线来描述这种能力的丧失与照射剂量之间的关系。

Survival curves are so basic to an understanding of much of radiobiology that it is worthwhile

to go through the steps involved in a typical experiment using an established cell line culture.

存活曲线是理解许多放射生物学知识的基础，因此仔细探讨用培养细胞株所进行的典型

的存活实验是值得的。

If a parallel dish is seeded with cells, exposed to a dose of 8 Gy of X-rays, and incubated for

1 to 2 weeks before being fixed and stained, then the following may be observed: (1) Some of the

seeded single cells are still single and have not divided, and in some instances the cells show

evidence of nuclear deterioration as they die an apoptotic death; (2) some cells have managed to

complete one or two divisions to form a tiny abortive colony; and (3) some cells have grown into

large colonies that differ little from the unirradiated controls, although they may vary more in size.

These cells are said to have survived, because they retained their reproductive integrity.

如果平行的培养皿接种细胞后，受到8 Gy X射线照射后，并且培养1到2周后被固定

和染色，那么可以观察到如下现象：(1) 一些接种的单细胞仍旧是单细胞没有分裂，在一些

情况下，细胞表现出细胞核退化的证据，就像以凋亡性死亡一样；(2) 一些细胞完成1或者

2个分裂，形成一个小的发育不全的集落；(3) 一些细胞长成大的与未照射组差别不大的集

落，尽管它们在尺寸上可以变化更大。这些细胞被称为存活细胞，因为它们保持增殖完整性。

Two thousand cells had been seeded into the dish exposed to 8 Gy. Because the plating

efficiency is 70%, 1400 of the 2000 cells plated would have grown into colonies if the dish had

not been irradiated. In fact, there are only 32 colonies on the dish; the fraction of cells surviving

the dose of X-rays is thus: 32/1400 = 0.023.

2000个细胞接种到培养皿中，接受8 Gy照射。因为接种效率（platting efficiency，PE）

是70%，也就是如果培养皿没有被照射，2000个细胞中有1400个细胞长成集落。实际上，

在培养皿中有32个集落，这个剂量下X射线的细胞存活分数是32/1400=0.023.

In general, the surviving fraction is given by

- 12 -

surviving fraction = colonies counted/cells seeded × (PE/100)

通常，存活分数以下列公式表示

存活分数=计数的集落数/接种的细胞数×（PE/100）

This process is repeated so that estimates of survival are obtained for a range of doses. The

number of cells seeded per dish is adjusted so that a countable number of colonies results:too few

reduces statistical significance; too many cannot be counted accurately because they tend to merge

into one another）. This technique, and the survival curve that results, does not distinguish the

mode of cell death, that is, whether the cells died mitotic or apoptotic deaths.

不断重复这个过程就可以得到一定剂量范围的存活估算结果。要对每个培养皿接种的细

胞数进行调整以便得到一个可以计数的克隆数：(太少会降低统计学意义，克隆数太多克隆

之间容易融合到一起，不能准确地计数克隆数）该技术以及以及由该技术得到的存活曲线不

能区分细胞死亡的方式，也就是说不能区分有丝分裂死亡还是凋亡。

The Shape of the Survival Curve

存活曲线的形状

Survival curves for mammalian cells usually are presented in the form shown in Figure 3.3,

with dose plotted on a linear scale and surviving fraction on a logarithmic 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) radiations, such as X-rays, the survival curve starts

out straight on the log-linear plot with a finite initial slope; that is, the surviving fraction is an

exponential function of dose. At higher doses, the curve bends. This bending or curving region

extends over a dose range of a few grays. At very high doses the survival curve often tends to

straighten 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.

哺乳动物的存活曲线通常用线性刻度表示剂量，而存活分数用对数刻度表示。可以用相

对简单的术语定性地描述存活曲线。对于稀疏的辐射（低传能线密度例如X射线）来说，

存活曲线在半对数坐标系中，在低剂量范围内，开始是直线分布的，并具有有限初始斜率，

也就是说存活分数与剂量呈指数函数关系。在较高的剂量时，存活曲线变弯曲，这个弯曲或

者曲线形状的区域覆盖了超过了几戈瑞的剂量范围。在非常高的剂量时，存活曲线再次趋向

于一条直线，存活分数恢复到剂量的指数函数。一般来说，不会出现这样的曲线形状，除非

是照射剂量超过了放疗所用的日常分割剂量。

By contrast, for densely ionizing (high linear energy transfer) radiations, such as α-particles

or low-energy neutrons, the cell-survival curve is a straight line from the origin; that is, survival

approximates to an exponential function of dose.

与之相反，对于致密电离辐射（高传能线密度），例如α-粒子或者低能中子，细胞存活

曲线从初始就是直线，存活分数与剂量近似于指数函数关系。

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 on

the basis of（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.

尽管定性地描述存活曲线的形状是个简单的事情，但从生物物理学事件的角度对观察到

- 13 -

的生物学结果做出解释则不然。为了解释哺乳动物细胞存活曲线的形状，人们提出了许多生

物物理模型和理论。尽管根据其中任何一个可用的模型或者理论都可以推导出一条与实验数

据相符的曲线，但是这些从不同的模型或者理论中选出的与实验数据真正吻合的理论或者模

型是永远不可能的。生物学数据精确度不够，或者不同理论预测的曲线之间缺乏本质差异倒

是有可能的。

Two descriptions of the shape of survival curves are discussed briefly, with a minimum of

mathematics. First, the multitarget model that was widely used for many years still has some merit.

In this model, the survival curve is described in terms of an initial slope, D

1

, resulting from

single-event killing; a final slope, D

0

, resulting from multiple-event killing; and some quantity

(either n or D

q

) to represent the size or width of the shoulder of the curve. The quantities D

1

and D

0

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 37% of its previous value. D1,the initial slope, is the dose required to

reduce the fraction of surviving cells to 0.37 on the initial straight portion of the survival curve.

The final slope, D0, is the dose required to reduce the fraction of survival from 0.1 to 0.037 or

froom 0.01 to 0.0037, and so on.. Because the surviving fraction is on a logarithmic scale and the

survival curve becomes straight at higher doses, the dose required to reduce the cell population by

a given factor (to 0.37) is the same at all survival levels. It is, on average, the dose required to

deliver one inactivating event per cell.

在此简要讨论一下解释哺乳动物细胞存活曲线的两种理论。首先，已经广泛应用很多年

的多靶模型仍旧有有价值。在这个模型中，可以用以下几个参数来描述存活曲线，由单次死

亡事件导致的初始斜率， D

1

，多次死亡事件导致的最终斜率，D

0

；以及一些代表曲线肩部

大小或者宽度的量（n或者Dq）。D

1

和D

0

的数值是初始斜率以及最终斜率的倒数，也是存

活分数降低到37%时所需的剂量。由于存活分数为对数刻度，且在高剂量时存活曲线是直

线，所以在高剂量区域对应的存活水平下，将细胞存活降低一定系数（0.37）所需的剂量都

是相同的。该剂量就是使每个细胞产生一个使其死亡事件时所需的平均剂量。

The extrapolation number, n, is a measure of the width of the shoulder. If n is large (e.g., 10

or 12), the survival curve has a broad shoulder. If n is small (e.g., 1.5 to 2), the shoulder of the

curve is narrow. Another measure of shoulder width is the quasithreshold dose, shown as D

q

.

Similarly, the quasithreshold dose is almost a threshold 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 no effect. There is no

dose below which radiation produces no effect, so there can be no true threshold dose; D

q

, the

quasithreshold dose, is the closest thing.

外推值n代表存活曲线肩区的宽度。如果n很大（比如10或者12），存活曲线具有一

个比较宽的肩区。如果n较小(如1.5或者2)，则曲线具有狭窄的的肩区。另一个检测肩区

宽度的是准阈剂量，以Dq表示。同样的，准阈剂量也是一个阈剂量。它是指存活曲线的直

线部分，反向延长，切割通过曲线y轴原点平行线所代表的剂量。阈剂量是指在此剂量以下

的照射没有效应。但是只要有辐射就会有效应，因此不存在真实的阈剂量。准阈剂量就是十

分接近阈剂量的参数。

The three parameters, n, D

0

, and D

q

are related by the expression

log

e

n = D

q

/D

0

这3个参数，n，D

0

和Dq之间的关系表示如下：log

e

n = D

q

/D

0

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 exchange-type chromosome aberrations

- 14 -

that are clearly the result of an interaction between separate breaks.

线性平方模型也已经作为描述存活曲线可以选择的模型。它是在明确由两个断裂之间产

生的交互式染色体畸变的相互关系描述的基础上直接发展而来。

The linear-quadratic model assumes that there are two components to cell killing by radiation,

one that is proportional to dose and one that is proportional to the square of the dose. The notion

of a component of cell inactivation that varies with the square of the dose introduces the concept

of dual-radiation action. This idea goes back to the early work with chromosomes in which many

chromosome aberrations are clearly the result of two separate breaks.

线性平方模型认为辐射造成细胞死亡分成两部分，一部分与剂量成正比，另一部分与剂

量的平方成正比。随着剂量平方变化的细胞失活概念引入了双重辐射作用的观点，改观的追

溯了早期对染色体畸变的研究，认为许多染色体畸变明确来源于两个独立的断裂事件。（例

如双着丝粒，环和后期桥，对细胞都是致命的）。

By this model, the expression for the cell-survival curve is

S



e





D





D

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 equal if

αD = βD

2

or D = α/β

根据此模型，细胞存活曲线表示为

S



e





D





D

，其中S是细胞在剂量D下的存活分

数，α和β是常数。如果细胞死亡的构成成分中，阈剂量成正比和与剂量平方成正比恰好相

等，则αD = βD

或者 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.

这点是非常重要的，具有可重复性：在等于α与β之比的剂量下，线性和平方对死亡的

贡献是相等的。

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.

线性平方公式的特征是所产生的细胞存活曲线是连续弯曲的，没有最后的直线部分。这

与实验观察到的不一致，如果存活曲线下降到10-7或者以下的细胞存活率，那么其剂量-效

应关系在对数性坐标系中大约接近于直线，也就是细胞死亡是剂量的指数函数。然而，在细

胞杀伤的初始10或者更多直到到达任何一个临床放疗日分割剂量时，线性平方模型来表示

这些数据是合适的。它最大的优点是具有两个可调性参数：α和β。

2

2

2

Unit 5 Section B

1. What is the sensitive site for radiation-induced cell lethality, the nucleus or the cytoplasm?

辐射诱导细胞致死的敏感位点是什么，是细胞核还是细胞浆

2. What is the main characteristic of apoptosis?

- 15 -

细胞凋亡的主要特征是什么？

Mechanisms of Cell Killing

细胞杀伤的机制

1. DNA as the target

DNA靶点

Abundant evidence shows that the sensitive sites for radiation-induced cell lethality are

located in the nucleus as opposed to the cytoplasm. Early experiments with nonmammlian systems,

such as frog‟s eggs, amoebae, and algae, were designed so that either the cell nucleus or the

cytoplasm could be irradiated selectively with a microbeam. The results indicated that the nucleus

was very much more radiosensitive than the cytoplasm.

大量的证据表明辐射诱导的细胞致死敏感靶点定位于细胞核而不是细胞质。早期用非哺

乳动物系统进行实验，例如以青蛙卵、阿米巴原虫和藻类等，都被设计成用微束装置选择性

地辐射细胞核或者细胞质。结果表明，细胞核的敏感性高于细胞质。

In later experiments, Munro irradiated mammalian cells with short-range α-particles from

polonium. Individual cells attached to a glass coverslip were studied. A large proportion of the

cytoplasm could be irradiated by locating a polonium microneedle at a known distance from the

cell; the α-particles from the polonium have definite well-defined range, and it is possible to

ensure that the α-particles irradiate the cytoplasm without reaching the nucleus. By the same token,

it is possible to position the α-source above the cell and to irradiate the nucleus with α-particles

but irradiate a minimal amount of cytoplasm. It was found that large numbers of α-particles,

corresponding to a dose in excess of 250 Gy, if delivered to the cytoplasm, had no effect on cell

proliferation. By contrast, the penetration of a few α-particles a distance of 1 or 2 μm into the

nucleus could prove to be lethal.

在后续的实验中，Munro用源于钋的短程α-粒子照射哺乳动物细胞。采用将单个细胞贴

附于玻璃盖玻片上进行研究的方式。大部分的细胞质能够被离细胞已知距离的钋微探针照射

到；来源于钋的α-粒子具有明确的照射距离，能够确保其照射细胞质而照不到细胞核。依

据相同的记号，在细胞上定位α源是可能的，且用α-粒子照射细胞核时照射少量的细胞质。

研究发现，超过250 Gy的大剂量α-粒子如果被传送到细胞质，对细胞增殖没有效应。与之

相反，距离细胞核1到2 μm较少的α-粒子穿透能够证明是致死的。

Evidence for chromosomal DNA as the principal target for cell killing is circumstantial but

overwhelming. There is evidence that the nuclear membrane may be involved, also; indeed, the

one does not exclude the other, because some portion of the DNA may be intimately involved with

the membrane during some portions of the cell cycle. This accumulated evidence strongly

indicates that chromosomal DNA is the principal target for radiation-induced lethality.

染色体DNA作为细胞杀伤的主要靶点的证据是详尽的且是无可争辩的。有证据表明，

实际上核膜也参与其中。实际上，二者并不排斥，因为在细胞周期的某个时段，DNA同核

膜是紧密联系的。大量证据足够证明染色体DNA是辐射诱导致死的主要靶。

2. Apoptotic and mitotic death

凋亡性死亡和有丝分裂死亡

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 programmed

cell death, is common in embryonic development in which some tissues become obsolete. It is the

mechanism, for example, by which tadpoles lose their tails.

- 16 -

Kerr和他的同事在显微镜水平将细胞凋亡描述为与细胞死亡有关的一系列特殊变化。

Apoptosis这个词来源于希腊语，意为“凋落”，就像花瓣从花上凋谢，或者叶子从树上脱落。

细胞凋亡、或者程序性细胞死亡，在胚胎发育时某些组织的退化中常见。例如，它是蝌蚪尾

巴的消失就是细胞凋亡。

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 cease communicating

with its neighbors. Condensation of the chromatin at the nuclear membrane and fragmentation of

the nucleus are then evident. The cell shrinks because of cytoplasmic condensation, resulting from

cross-linking of proteins and loss of water. Eventually the cell separates into a number of

membrane-bound fragments of differing sizes termed apoptotic bodies, which may contain

cytoplasm only, or nuclear fragments. The morphologic hallmark of apoptosis is the condensation

of the nuclear chromatin in either crescents around the periphery of the nucleus, or a group of

spheric fragments.

此种形式的细胞死亡是以模式化发生的形态学事件为特征。当组织中细胞将要死亡的时

候，最早期的步骤之一是停止同它的邻近细胞的通讯。然后有明显的核膜内染色质固缩、细

胞核断裂形成碎片。由于蛋白质交联剂水分流失，细胞质凝固进而引起细胞皱缩。最终，细

胞被分割成若干个大小相等的膜包裹的碎片，即凋亡小体，其中可能只含有细胞质或细胞核

碎片。细胞凋亡的形态学特征是核染色体的固缩，形成新月体围绕在细胞核外围，或者形成

球状片段。

Double-strand breaks occur in the linker regions between nuclosomes, to produce DNA

fragments that are multiples of approximately 185 base pairs. These fragments result in the

characteristic ladders seen in gels. In contrast, necrosis causes a diffuse “smear” 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.

双链断裂发生在核小体之间的连接区域，进而产生大约185碱基对整数倍的DNA片段。

这些片段在凝胶电泳中看呈特征性的阶梯状。相反，坏死细胞的DNA凝胶电泳则呈弥散状

（Smear）。正如前面描述的，细胞凋亡存在于正常组织中，也可以由电离辐射诱导一些正常

组织和肿瘤产生。

As a mode of radiation-induced cell death, apoptosis is highly cell-type dependent.

Hemopoietic and lymphoid cells are particularly prone to rapid radiation-induced cell death by the

apoptotic pathway. In most tumor cells, mitotic cell death is at least as important as apoptosis, and

in some cases it is the only mode of cell death. A number of genes appear to be involved. First,

apoptosis after radiation seems commonly to be a p53-dependent process; bcl-2 is a suppressor of

apoptosis.

作为辐射诱导的细胞死亡方式，细胞凋亡高度依赖于细胞种类。造血细胞和淋巴细胞在

收到照射后易通过细胞凋亡途径快速发生辐射诱导的细胞死亡。在大多数的肿瘤细胞中，细

胞有丝分裂死亡至少是同细胞凋亡同等重要的，并且在某些情况下，它也是唯一的细胞死亡

模式。很多基因参与了细胞凋亡。辐射后细胞凋亡通常是一个p53依赖的过程，bcl-2是凋

亡的抑制因子。

The most common form of cell death from radiation is mitotic death: Cells die in attempting

to divide because of damaged chromosomes. Death may occur in the first or a late division

following irradiation. Many authors have reported a close quantitative relationship between cell

killing and the induction of specific chromosomal aberrations. It should be noted that these

experiments were carried out in a cell line where apoptosis is not observed. The log of the

- 17 -

surviving fraction is plotted against the average number of putative “lethal” aberrations per cell,

that is, asymmetric exchange-type aberrations such as rings and dicentrics. There is virtually a

one-to-one correlation. In addition, there is an excellent correlation between the fraction of cell

surviving and the fraction of cells without visible aberrations.

由辐射诱导的细胞死亡形式中最普遍的是有丝分裂死亡：由于染色体损伤，细胞在试图

进行分裂时而死亡。死亡可以发生在辐射后第一次或之后的细胞分裂时。很多的学者已经报

道了在细胞死亡和特异性染色体畸变诱导之间存在紧密的定量关系。应当强调的是，这些实

验是一株细胞为模型进行的，在该细胞株中没有观察到细胞凋亡。绘出存活分数的对数值与

每个细胞内假定的致死畸变（环和双着丝粒）平均数之间的关系曲线。实际上，二者之间存

在着一一对应的关系。另外，在细胞存活分数与无可见畸变的细胞分数之间存在极佳的相关

关系。

Data such as these provide strong circumstantial evidence to support the notion that

asymmetrical exchange-type aberrations represent the principle mechanism for radiation-induced

mitotic death in mammalian cells.

这些数据都强有力地提供了间接证据来支持非对称互换类型的畸变是哺乳动物细胞中

辐射诱导有丝分裂死亡的主要机制。

Exchange type aberrations require two chromosome breaks. At low doses, the two breaks

may result from the passage of a single electron set in motion by the absorption of a photon of X-

or γ-rays. The probability of an interaction between the two breaks to form a lethal exchange-type

aberration is proportional to dose. Consequently, the survival curve is linear at low doses. At

higher doses the two chromosome breaks may result from two separate electrons. The probability

of an interaction between the two breaks is then proportional to the square of the dose. If this

quadratic 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.

交互型畸变需要2个染色体断裂。在低剂量区，这两个断裂可能是由吸收的X- 或者γ-

射线光子所激发的单个电子穿过而导致的。两个断裂之间的相互作用形成致死交互型畸变的

可能性同剂量成正比。因此，低剂量下的存活曲线是线性的。在高剂量下，两个染色体畸变

由两个不同的电子造成的。两个断裂间发生相互作用的可能性与剂量的平方成正比。如果二

次方部分占优，存活曲线就会变得弯曲。因此，染色体畸变的诱导和剂量间的线性平方关系

特征推广到细胞的存活曲线。

Survival Curve for Various Mammalian Cells in Culture

体外培养的各种哺乳动物细胞的存活曲线

Survival curves have been measured for many established cell lines grown in culture. These

cell lines have been derived from the tissues of humans or other mammals, such as small rodents.

In some cases the parent tissue has been neoplastic, and in other cases it has been normal. All

mammalian cells studied to date, normal or malignant, regardless of their species of origin exhibit

X-ray survival curves; there is an initial shoulder followed by a portion that tends to become

straight on a log-linear plot. The size of the initial shoulder is extremely variable. For some cell

lines the survival curve appears to bend continuously, so that the linear-quadratic relationship is a

better fit and n has no meaning. The D0 of the X-ray survival curves for most cells cultured in

vitro fall in the range of 1 to 2 Gy. The exceptions are cells from patients with cancer-prone

syndromes, such as ataxia telangiectasia (AT); these cells are much more sensitive to ionizing

radiations, with a D0 for X-rays of about 0.5 Gy. This in vitro sensitivity correlates with a

- 18 -

hypersensitivity to radiotherapy found in these persons.

已经建立了许多体外培养的细胞株的存活曲线。这些细胞株来源于人类组织或者其他哺

乳动物，如小型的啮齿类动物。在某些情况下，供体组织是瘤性的，而在其他情况下，它是

正常的。至今，所有哺乳动物细胞研究，无论是正常的或者恶性的，不管它们来自什么物种，

表现出X射线的存活曲线（在图中展示的那样）；在半对数坐标系中，曲线有一个初始的肩

区，紧接着的部分近似于直线。初始肩区的大小会有很大差异。对于某些细胞株来说，存活

曲线可能持续弯曲，因此更符合线性平方关系，且n无意义。大多数体外培养的细胞的X

射线存活曲线的D

0

值为1到2 Gy。有一个例外，癌症易感综合征例如共济失调性毛细血管

扩张症患者的细胞对电离辐射更敏感，其X射线的存活曲线的D

0

值大约0.5 Gy。这些细胞

的体外敏感性与这些患者对放疗的超敏感性有关。

In more recent years, extensive studies have been made of the radiosensitivity of cells of

human origin, both normal and malignant, grown and irradiated in culture. In general, cells from a

given normal tissue show a narrow range of radiosensitivities if many hundreds of persons are

studied. By contrast, cells from human tumors show a very broad range of D0 values; some cells

such as those from squamous carcinomas tend to be more radioresistant, and sarcomas are

somewhat more radiosensitive. Each tumor type, however, has a broad spectrum of

radiosensitivities that tend to overlap. Tumor cells bracket the radiosensitivity of cells from normal

tissues; that is, some are more sensitive, and others are more resistant.

最近几年，对体外培养并照射的人源细胞（包括正常细胞和癌变细胞）的辐射敏感性做

了大量的研究。通常，如果对数百人的某一正常组织的细胞辐射敏感性进行研究，得到的辐

射敏感性差异很小。相反地，人类肿瘤细胞的D

0

值呈现的范围则较宽。某些细胞，如鳞癌

细胞往往具有辐射抗性，而肉瘤细胞在某种程度上是辐射敏感的。然而，每种类型的肿瘤都

具有范围较宽的辐射敏感性且倾向于重叠。肿瘤细胞的辐射敏感性可以覆盖正常组织细胞的

辐射敏感性，也就是说，一些很敏感，一些抗性很强。

Survival-Curve Shape and Mechanism of Cell Death

存活曲线形状和细胞死亡的机制

Mammalian cells cultured in vitro vary considerably in their sensitivity to killing by radiation.

This includes survival curves for asynchronous cultures of mouse tumor cells (EMT6) as well as

for six cell lines derived from human tumors. Asynchronous EMT6 cells are the most

radioresistant, followed closely by glioblastoma cells of human origin; thereafter radiosensitivity

increases, with two neuroblastoma cell lines being the most sensitive. Although asynchronous

cells show this wide range of sensitivities to radiation, it is a remarkable finding that mitotic cells

from all of these cell lines have essentially the same radiosensitivity. The implication of this is that,

if the chromosomes are condensed during mitosis, all cell lines have the same radiosensitivity

governed simply by DNA content, but in interphase the radiosensitivity differs, because of

different conformations of the DNA.

体外培养哺乳动物细胞对辐射杀伤的敏感性差异很大。（这是一个图，说的是图中包括）

这包括非同步化培养的小鼠肿瘤细胞（EMT6）以及来源于人肿瘤的6种细胞株的存活曲线。

非同步化培养的EMT6细胞是辐射抗性最强的，紧接着的是人源的恶性胶质瘤细胞；此后，

辐射敏感性逐渐增加，对辐射较敏感的2株神经母细胞瘤细胞细胞。虽然非同步化培养的细

胞辐射敏感性差异很大，然而值得注意的是，来源于这些细胞的有丝分裂期细胞基本上具有

相似的辐射敏感性。这意味着如果有丝分裂时染色体是聚集的，那么所有的细胞株具有相同

的辐射敏感性，其敏感性只取决于DNA含量。但是在间期，由于DNA构象不同，因此辐

射敏感性不同。

- 19 -

Characteristic laddering is indicative of programmed cell death, or apoptosis, during which

the DNA breaks up into discrete lengths as previously described. The most radioresistant cell lines,

which have broad shoulders to their survival curves, show no evidence of apoptosis; the most

radiosensitive, for which survival is an exponential function of dose, show clear DNA laddering as

an indication of apoptosis. The increased clarity of the laddering correlates with increasing

radiosensitivity together with a smaller and smaller shoulder to the survival curve. Many of the

established cell lines that have been cultured in vitro for many years, and with which many of the

basic principles of radiation biology were demonstrated, show no apoptotic death and have an

abrogated p53 function. Continued culture in vitro appears often to select for cells with this

characteristic.

如前所述，电泳图上形成的特征性梯状条带，说明DNA断裂成不同长度的片段，发生

细胞程序性死亡或者凋亡。辐射抗性最强的细胞株，其存活曲线有很宽的肩区，没有很明显

的细胞凋亡；辐射敏感性最强的细胞株，存活分数与剂量之间为指数函数，显示出清晰的

DNA梯状条带说明发生了细胞凋亡。辐射敏感性越强，则梯状条带越清晰，同时存活曲线

的肩部越窄。许多在体外培养多年且被用于阐明许多已知放射生物学基本原理的细胞株，都

显示出无凋亡性死亡发生和p53功能的缺失。持续的体外培养经常为了选出这种特征的细

胞。

Mitotic death results (principally) from exchange-type chromosomal aberrations; the

associated cell-survival curve therefore is curved in a log-linear plot, with a broad initial shoulder.

As is shown subsequently here, it also is characterized by a substantial dose-rate effect. Apoptotic

death results from mechanisms that are not understood clearly yet, but the associated cell-survival

curve appears to be a straight line on a log-linear plot ― that is, survival is an exponential function

of dose. In addition, there appears to be little or no dose-rate effect, though data are sparse on this

point.

有丝分裂死亡主要是由交互式染色体畸变导致的；因此，在半对数坐标系上相关细胞的

存活曲线有着较宽的初始肩区。正如此后在这里展示的一样，明显的剂量率效应也是其特征。

导致细胞凋亡性死亡的机制还不清楚，但是相关细胞的存活曲线在半对数坐标系形中似乎是

直线的，也就是说存活分数是剂量的指数函数。此外，该存活曲线的剂量率效应很小甚至没

有，虽然关于这一点的研究数据不是很多。

Although there are some cell lines in which mitotic death dominates and others in which

apoptosis is the rule, most cell lines fall somewhere in between, with contributions from both

mitotic and apoptotic death following a radiation exposure, in varying proportions. It has been

proposed that the dose-response relationship be described by the following relation:

S



e



(



M





A

)D





M

D

in which S is the fraction of cells surviving a dose D, αM and αA describe the contributions

to cell killing from mitotic and apoptotic death that are linear functions of dose, and βM describes

the contribution to mitotic death that varies with the square of the dose.

尽管在一些细胞株中有丝分裂死亡占主要地位，另一些是细胞凋亡占主导地位，但是大

多数细胞株在受到照射后，有丝分裂死亡和细胞凋亡对细胞的死亡都有贡献（辐射后有丝分

裂死亡和凋亡都存在），虽然各自所占比例可能有所不同。有人提出下面的公式描述其剂量



(



M





A

)D





M

D

效应关系：

S



e

2

2

其中，S表示剂量D下细胞存活分数，α

M

和α

A

描述的是与剂量呈线性关系的有丝分裂

- 20 -

死亡和凋亡性死亡对细胞杀伤的贡献，β

M

描述的是岁剂量平方而变化的有丝分裂死亡对细

胞死亡的贡献。

Effective Survival Curve for a Multifraction Regimen

多次分割的放射治疗的有效存活曲线

Because multifraction regimens are used most often in clinical radiotherapy, it is frequently

useful to think in terms of an effective survival curve. If a radiation dose is delivered in a series of

equal fractions, separated by sufficient time for repair of sublethal damage to occur between doses,

the effective dose survival curve becomes an exponential function of dose. The shoulder of the

survival curve is repeated many times so that the effective survival curve is a straight line from the

origin through a point on the single-dose survival curve corresponding to the daily dose fraction.

The effective survival curve is an exponential function of dose whether the single-dose survival

curve has a constant terminal slope (as shown) or is continuously bending, as implied by the

linear-quadratic relation. The D0 of the effective survival curve (i.e., the reciprocal of the slope),

defined to be the dose required to reduce the fraction of cells surviving to 37%, has a value close

to 300 cGy for cells of human origin. This is an average value and can differ significantly for

different tumor types.

由于临床放疗常常采用对此分割的方法，所以通常要考虑多次分割治疗的有效存活曲

线。如果将辐射剂量等分后多次分割照射，并在两次照射期间间隔足够长的时间来完成亚致

死性损伤的修复，那么有效剂量存活曲线是剂量的指数函数。存活曲线的肩区会多次重复出

现，因此有效存活曲线是起自原点、穿过单一剂量存活曲线上相当于每日分割剂量的一个点

的直线。无论单剂量存活曲线的斜率是常数还是曲线持续弯曲，有效存活曲线都是剂量的指

数函数，表示为线性平方关系。有效存活曲线的D

0

值（斜率的倒数）是将细胞存活分数减

少到原来的37%的剂量，对于人源性细胞来说，其值接近于0.3 Gy。这是平均值，在不同类

型的肿瘤细胞中D

0

值差异很大。

For calculation purposes, it is often useful to use the D10, the dose required to kill 90% of the

population. For example, D10 = 2.3 × D0, in which 2.3 is the natural logarithm of 10.

为了计算的目的，通常使用D

10

值，即杀伤90%的细胞群所需要剂量。例如，D

10

=2.3×

D

0

，2.3是10的自然对数。

Unit 6 Section A

1. Which situation of the cells in the entire cell cycle can we observe with a conventional light

microscope?

用常规的光学显微镜能够观察到整个细胞周期细胞所处的位置吗？

2. What are the advantages using bromodeoxyuridine to label the cells?

用溴脱氧尿苷标记细胞的优点是什么？

3. Do you know how to produce a synchronously dividing cell population?

你知道怎么产生同步分裂的细胞群吗？

The Cell Cycle

细胞周期

Mammalian cells propagate and proliferate by mitosis. When a cell divides, two progeny

cells are produced, each of which carries a chromosome complement identical to that of the parent

cell. After an interval of time has elapsed, each of the progeny may undergo a further division.

The time between successive divisions is known as the mitotic-cycle time, or, as it is commonly

called, the cell-cycle time.

- 21 -

哺乳动物细胞通过有丝分裂进行繁殖和增殖。细胞分裂时会产生2个子代细胞，每一个

子代细胞携含有和亲代细胞相同的互补的染色体。一段时间后，一些子代细胞会进一步分裂。

两次成功有丝分裂的间隔时间称为有丝分裂周期（时间），或者通常所说的细胞周期时间。

If a population of dividing cells is observed with a conventional light microscope, the only

event in the entire cell cycle that can be identified and distinguished is mitosis or division itself.

Just before the cell divides to form two progeny, the chromosomes (which are diffuse and

scattered in the cell in the period between mitoses) condense into clearly distinguishable forms. In

addition, in monolayer cultures of cells, just before mitosis, the cells round up and become loosely

attached to the surface of the culture vessel. This whole process of mitosis ― in preparation for

which the cell rounds up, the chromosome material condenses, and the cell divides into two and

then stretches out again and attaches to the surface of the culture vessel ― lasts only about 1 hour.

The remainder of the cell cycle, the interphase, occupies all of the intermitotic period. No events

of interest can be identified with a conventional microscope during this time.

用普通光学显微镜观察分裂的细胞时，可观察到在整个细胞周期中唯一可鉴别和区分的

是有丝分裂（也称自身分裂）。只有在细胞分裂形成两个自带细胞前，染色体才会浓缩成清

晰可辨的形态（一般在两次有丝分裂间隔期，染色体散在分布于细胞核中）。才外，对于单

层培养的细胞而言，在即将分裂前细胞会变圆且松散地贴在培养皿的表面。整个有丝分裂时

间仅持续1小时左右，包括细胞变圆前的准备、染色体材料浓缩和细胞分裂成两个再伸展开

并贴附在培养皿表面。细胞周期中除了有丝分裂意外的时期称为间期，包括连续两次有丝分

裂之间的所有时间。在此期间有普通光学显微镜无法鉴别出任何特别的改变。

Because cell division is a cyclic phenomenon, repeated in each generation of the cells, it is

usual to represent it as a circle. The circumference of the circle represents the full mitotic cycle

time for the cells (Tc); the period of mitosis is represented by M. The remainder of the cell cycle

can be further subdivided by using some marker of DNA synthesis. The original technique was

autoradiography, introduced by Howard and Pelc in 1953.

细胞分裂是发生在每一代细胞中的周期性的现象，通常用一个圆形来代表细胞周期。

整个圆周代表整个细胞周期（Tc）；有丝分裂期用M表示。而其他的细胞周期可使用一些

DNA合成标记物进一步做亚分割。最初的技术是由Howard和Pelc在1953年发展的放射性自

显影术。

The basis of the technique is to feed the cells thymidine, a basic building block used for

3

making DNA, which has been labeled with radioactive tritiated thymidine （tritium）(H-TdR).

Cells that are actively synthesizing new DNA as part of the process of replicating their

chromosome complements incorporate the radioactive thymidine. The surplus radioactive

thymidine then is flushed from the system, the cells are fixed and stained so that they may be

viewed easily, and the preparation of cells is coated with a very thin layer of nuclear (photographic)

emulsion.

此技术的基础是给予细胞以放射活性的氚（

3

H-TdR）来标记制造DNA的基础材料胸腺

嘧啶。这些细胞合成的新DNA中，染色体组在复制过程中就插入了放射性的胸腺嘧啶。然

后将多余的放射性胸腺嘧啶从系统中洗去，固定和染色细胞以便观察，再将准备好的细胞涂

上一层非常薄的细胞核感光乳剂。

β-Particles from cells that have incorporated radioactive thymidine pass through the nuclear

emulsion and produce a latent image. When the emulsion subsequently is developed and fixed, the

area through which a β-particle has passed appears as a black spot. It is then a comparatively

simple matter to view the preparation of cells and to observe that some of the cells have black

- 22 -

spots or “grains” over them, which indicates that they were actively synthesizing DNA at the time

radioactive thymidine was made available. Other cells do not have any grains over their nuclei;

this is interpreted to mean that the cells were not actively making DNA when the radioactive label

was made available to them. If the cells are allowed to grow for some time after labeling with

tritiated thymidine, so that they move into mitosis before being fixed, stained, and

autoradiographed, then a labeled mitotic cell may be observed.

掺入放射性胸腺嘧啶的细胞放出β-粒子，通过感光乳剂显现出来。随后，当感光乳剂被

显影和固定后便可发现β-粒子通过的区域会形成黑点，这是一种相对简单、可看见细胞过程

的方法。可观察到一些细胞有黑点或颗粒，代表细胞在合成DNA时利用了放射性胸腺嘧啶；

而一些细胞的细胞核没有任何颗粒，表明在此期间细胞并没有进行DNA合成。如果细胞被

氚化胸腺嘧啶标记后再生长一段时间，则细胞在被固定、染色和放射自显影前会进入有丝分

裂期，于是变可观察到被标记的有丝分裂细胞。

In recent years the use of tritiated thymidine to identify cells in the DNA synthetic phase (S)

has been replaced largely with the use of 5-bromodeoxyuridine, which differs from thyrnidine

only by the substitution of a bromine atom for a methyl group. If this halogenated pyrimidine is

fed to the cells, it is incorporated into DNA in place of thymidine and its presence can be detected

by using an appropriate stain. In a black-and-white print, cells incorporating bromodeoxyuridine

appear darkly stained. In practice they are easier to recognize because the stain is brightly colored.

To identify cells that are in S phase and have incorporated bromodeoxyuridine even more readily,

one can use an antibody （a fluorochrome-tagged） against bromodeoxyuridinc-substituted DNA,

which fluoresces brightly under a fluorescence microscope. If time is allowed between labeling

with brornodeoxyuridine and staining, then a cell may move from S to M phase, and a stained

mitotic cell is observed. If the cell is in the first mitosis after bromodeoxyuridine incorporation,

both chromatids of each chromosome are equally stained, but by the second mitosis, one

chromatid is stained darker than the other.

近年来，大多数使用5-溴脱氧尿嘧啶替代氚化胸腺嘧啶来鉴别DNA合成期（S）。5-溴

脱氧尿嘧啶和胸腺嘧啶的不同仅在于以溴原子取代了一个甲基。假如将此卤化嘧啶加到细胞

中，则它会取代胸腺嘧啶掺入DNA，并用适当的染色法便可检测。在黑白影像中，掺入溴

脱氧尿嘧啶呈现深染状态。实际上，因为染色是明亮的，所以更容易辨认。鉴别处于S期并

且掺入溴脱氧尿嘧啶的细胞甚至更容易，可用具有荧光标记的抗体去结合含有溴脱氧尿嘧啶

替代的DNA，在荧光显微镜下会呈现亮荧光。如果在溴脱氧尿嘧啶标记和染色之间的时间

足够，细胞会从S期进入M期，便可以观察到已染色的有丝分裂细胞。假如细胞处于溴脱

氧尿嘧啶掺入后第一次有丝分裂期，每条染色体的染色单体会均匀染色，但对于第二次有丝

分裂而言，其中一条染色单体会较另一条染色略深。

The use of bromodeoxyuridine has two advantages over conventional autoradiography using

tritiated thymidine. First, it does not involve radioactive material. Second, it greatly shortens the

time to produce a result, because if cells are coated with emulsion to produce an autoradiograph,

they must be stored in a refrigerator for about 1 month to allow β-particles from the incorporated

tritium to produce a latent image in the emulsion.

使用溴脱氧尿嘧啶与传统上氚化胸腺嘧啶放射自显影相比较有两个好处。其一，它不是

放射性物质；其二，极大地缩短了出结果的时间，因为若细胞被感光乳剂来产生放射性自显

影的话，它们必须被放在冰箱里月1个月以便让β-粒子从含有氚的细胞中释放出来，才能在

感光乳剂中显影。

By using either of these techniques it can be shown that cells synthesize DNA only during a

- 23 -

discrete well-defined fraction of the cycle, the S phase. There is an interval between mitosis and

DNA synthesis in which no label is incorporated. This first „gap” in activity was named G

1

by

Howard and Pelc, and the nomenclature is used today. After DNA synthesis has been completed,

there is a second gap before mitosis, G

2

.

无论哪种技术，都表明细胞DNA的合成只发生在S期。介于有丝分裂期和DNA合成期之

间有一个无标记掺入的间隔期，Howard和Pelc将第一个间隙命名为G1，而这一术语一直沿

用至今。DNA合成结束后至有丝分裂期发生前，会有第二个间隙称之为G2.

All proliferating mammalian cells, whether in culture or growing normally in a tissue, have a

cycle of mitosis (M), followed by G

1

, S, and G

2

, after which mitosis occurs again. The relative

lengths of these various constituent parts of the cell cycle vary according to the particular cells

studied.

所有增殖的哺乳动物细胞，无论是培养的还是组织中正常生长的，都有有丝分裂期（M），

接着是G

1

、S和G

2

，然后有丝分裂再度发生。这些细胞周期中不同组成部分的相对长短根

据特定的细胞而有所不同。

This is an important point: the difference among mammalian cell-cycle times in different

circumstances, varying from about 10 hours for a hamster cell grown in culture to hundreds of

hours for stem cells in some self-renewal tissues, is the result of a dramatic variation in the length

of the G

1

period. The remaining components of the cell cycle, M, S, and G

2

, vary comparatively

little among different cells in different circumstances.

非常重要的一点是：不同环境下哺乳动物细胞周期时间的差异，从培养的中国仓鼠细胞

的大约10小时到自我再生组织的干细胞的数百小时，主要是G1期时间长度巨大差别的结果。

细胞周期的其余部分M、S和G2在在不同环境中的不同细胞间的差异较小。

The description of the principal phases of the cell cycle (M, G

1

, S, G

2

) dates from Howard

and Pelc in 1953 as previously discussed. During a complete cell cycle, the cell must accurately

replicate the DNA once during S phase and distribute an identical set of chromosomes equally to

two progeny cells during M phase. In recent years we have learned much more about the

mechanisms by which the cycle is regulated in eukaryotic cells. Regulation occurs by the periodic

activation of different members of the cyclin-dependent kinase (CDK) family. In its active form,

each CDK is complexed with a particular cyclin. Different CDK-cyclin complexes are required to

phosphorylate a number of protein substrates, which drive such cell-cycle events as the initiation

of DNA replication or the onset of mitosis. CDK-cyclin complexes are also vital in preventing the

initiation of a cell-cycle event at the wrong time.

正如先前所讨论的，细胞周期重要时期（M, G

1

, S, G

2

)的描述数据来自1953年Howard和

Pelc的报告。在一个完整的细胞周期中，细胞必须在S期正确复制DNA一次，然后在M期将

染色体平均分非两个子代细胞。近年来，我们获得了更多真核细胞细胞周期的调控机制。细

胞周期的调节主要是通过周期素依赖性激酶（CDK）家族不同成员的周期性激活而发生。

不同的Cdk-cyclin复合物需要磷酸化几个不同蛋白质底物来启动DNA复制或有丝分裂。此

外，CDK-cyclin复合物也可防止细胞周期在错误的时间启动。

Extensive regulation of CDK-cyclin activity, by a number of transcriptional and

posttranscriptional mechanisms, ensures perfect timing and coordination of cell-cycle events. The

CDK catalytic subunit by itself is inactive, requiring association with a cyclin subunit and

phosphorylation of a key threonine residue (usually T-160) to become fully active. The

CDK-cyclin complex is reversibly inactivated either by phosphorylation on a tyrosine residue

(usually Y-l5) located in the adenosine triphosphate-binding domain, or by association with

- 24 -

cyclin-kinase inhibitory proteins. After the completion of the cell-cycle transition, the complex is

inactivated irreversibly by ubiquitin-mediated degradation of the cyclin subunit.

CDK-cyclin活性的调节主要通过一些转录和转录后调节机制，以确保细胞周期时间的精

确和协调。CDK激酶的自我催化亚单位是失活的，需要同周期素亚单位的结合并使关键的

苏氨酸残基（通常是T-160）的磷酸化，才能获得完全活性。CDK-cyclin复合物可通过位于

腺苷酸三磷酸（ATP）结合区中酪氨酸的（通常是Y-15）的磷酸化，或者与周期素激酶抑制

蛋白的结合而可逆性失活。当整个细胞周期转位完成后，复合物会经由泛素介导的细胞周期

亚单位降解实现不可逆失活。。

Entry into S phase is controlled by CDKs that are sequentially regulated by cyclins D, E and

A. D-type cyclins act as growth-factor sensors, with their expression depending more on the

extracellular cues than on the cell‟s position in the cycle. Mitogenic stimulation governs both their

synthesis and complex formation with CDK4 and CDK6, and catalytic activity of the assembled

complexes persists through the cycle as long as mitogenic stimulation continues. Cyclin E

expression in proliferating cells is normally periodic and maximal at the G

1

-S transition, and

throughout this interval it enters into active complexes with its catalytic partner, CDK2.

细胞进入S期主要由CDK控制，而CDK需要周期素D、E和A的调节。D型周期素具有生

长因子的感受器的作用，其表达更多地依赖于细胞外因子，而非仅仅由细胞所处周期的位置

决定。有丝分裂调控D型周期素的合成及它与Cdk4和Cdk6结合而形成复合物。当有丝分裂刺

激进行时，结合后的复合物会在整个细胞周期中持续进行催化作用。在增殖细胞中周期素E

通常呈现周期性的表达，并在G1-S转换点表达最高。在整个过程中，周期素E和Cdk2形成活

化的复合物。

Synchronously Dividing Cell Cultures

同步化分裂细胞的培养

In the discussion of survival curves the assumption was implicit that the population of

irradiated cells was asynchronous; that is, it consisted of cells distributed throughout all phases of

the cell cycle. A study of the variation of radiosensitivity with the position or age of the cell in the

cell cycle was made possible only by the development of techniques to produce synchronously

dividing cell cultures ― populations of cells in which all of the cells occupy the same phase of the

cell cycle at a given time.

在存活曲线讨论中，假设受照射细胞群是非同步化的；换句话说，这些细胞处于细胞周

期的不同时期。要研究细胞周期中处于不同位置或不同代数的细胞的辐射敏感性变化，只有

通过技术发展产生同步分裂的培养细胞，即在假定时间，细胞器群体中的所有细胞均处于细

胞周期的相同时相。

There are essentially two techniques that have been used to produce a synchronously dividing

cell population. The first is the mitotic harvest technique, first described by Terasima and Tolmach.

This technique can be used only for cultures that grow in monolayers attached to the surface of the

growth vessel. It exploits the fact that if such cells are close to mitosis, they round up and become

loosely attached to the surface. If at this stage the growth medium over the cells is subjected to

gentle motion (by shaking), the mitotic cells become detached from the surface and float in the

medium. If this medium then is removed from the culture vessel and plated out into new petri

dishes, the population consists almost entirely of mitotic cells. Incubation of these cell cultures at

37°C then causes the cells to move together synchronously in step through their mitotic cycles. By

delivering a dose of radiation at various times after the initial harvesting of mitotic cells, one can

irradiate cells at various phases of the cell cycle.

- 25 -

有两种技术能够产生同步化分裂的细胞群体。第一种方法是由Terasima和Tolmach首先

提出的有丝分裂收获技术。这项方法只适用于贴壁的单层细胞。此技术的依据是假如细胞已

接近于有丝分裂期，细胞会变圆且稀松地黏附在培养皿上。此时如果轻摇培养皿，则有丝分

裂的细胞会从表面脱落而漂浮在培养液中。然后将培养液转移如新的培养皿中，此群细胞几

乎完全处于有丝分裂期。将这群细胞在37°C中培养，则这些细胞会同步通过有丝分裂周期。

因此，在有丝分裂收获起始后不同时间给予辐射照射，可达到对细胞周期中不同时期的细胞

进行照射的目的。

An alternative method for synchronizing cells, which is applicable to cells in a tissue as well

as cells grown in culture, involves the use of a drug. A number of different substances may be

used. One of the most widely applicable is hydroxyurea. If this drug is added to a population of

dividing cells, it has two effects on the cell population. First, all cells that are synthesizing DNA

take up the drug and are killed. Second, the drug imposes a block at the end of the G

1

period; cells

that occupy the G

2

, M, and G

1

compartments when the drug is added progress through the cell

cycle and accumulate at this block.

无论是组织中的细胞或者培养皿中的细胞，另一种获得同步化细胞的方法是使用药物。

有几种不同的药物可供使用。其中一种最常使用的药物是羟基脲。此药物假如正在分裂的细

胞群体后，对细胞群体有两种效应。首先，所有细胞在S期正在合成DNA时会摄入羟基脲而

导致细胞死亡。其次，此药物会强迫细胞静止在G1的末期，即使细胞处于G2、M或G1期，

当加入羟基脲便会造成细胞周期向前行进并最后停在G1的末期。

Hydroxyurea is left in position for a period equal to the combined lengths of G

2

, M, and G

1

for that particular cell line. By the end of the treatment period, all of the viable cells left in the

population are situated in a narrow “window” at the end of G

1

, poised and ready to enter S. If the

drug then is removed from the system, this synchronized cohort of cells proceeds through the cell

cycle. Techniques involving one or another of a wide range of drugs have been used to produce

synchronously dividing cell populations in culture, in organized tissues (in a limited number of

cases), and even in the whole animal.

羟基脲对于特定细胞系的G

2

、M和G

1

整段时期的作用均相等。处理时间结束时，所

有的存留的细胞均处于G

1

末期这个狭窄的“窗口期”，静止不动并等待着进入S期。如果将

药物自系统中移除，则所有细胞同步向前通过细胞周期。对于培养细胞、组织（有限的个案），

甚至在整体动物中，技术上已经可以使用多种药物来产生同步分裂的细胞群体。

Unit 6 Section B

1. Which phase is the most sensitive to radiation in cell cycle? What are the characteristics of the

surviving curve?

细胞周期中那个时相辐射最敏感？存活曲线的特征是什么？

2. What is the main characteristic of radiosensitivity with cell age in the mitotic cycle generally?

有丝分裂期的细胞放射敏感性的主要特征是什么？

3. What are the possible implications of the age-response function in radiotherapy?

放疗中分期-反应的可能意义是什么？

The Effect of X-Rays on Synchronously Dividing Cell Cultures

X射线对同步分裂的培养细胞的影响

In an experiment mammalian cells, harvested at mitosis, were irradiated with a single dose of

6.6 Gy at various times afterward, corresponding to different phases of the cell cycle. The data

were obtained using Chinese hamster cells in culture. One hour after the mitotic cells were seeded

- 26 -

into the petri dishes, when the cells were in G

1

, a dose of 6.6 Gy resulted in a surviving fraction of

about 13%. The proportion of cells that survive the dose increases rapidly with time as the cells

move into S phases; by the time the cells near the end of S phase, 42% of the cells survive this

same dose. When the cells move out of S into G

2

and subsequently to a second mitosis, the

proportion of surviving cells falls again. This pattern of response is characteristic for most lines of

Chinese hamster cells and has been reported by a number of independent investigators.

在哺乳动物细胞实验中，细胞都在有丝分裂期收获，在后续的细胞周期的不同时相，给

予单次6.6 Gy照射，对应的在细胞周期的不同时相。这些数据主要来自培养的中国仓鼠细胞。

将有丝分裂的细胞接种到培养皿1小时后，此时细胞正处于G

1

期，6.6 Gy照射后存活分数是

13%。当随着细胞进入S期时，在相同剂量下，细胞存活的比例快速增加。当接近S末期时，

相同剂量下细胞的存活率约为42%。当细胞结束S期进入G2期并且随后进入第2次有丝分裂

时，细胞的存活比例再次降低。这种反应模式是多数中国仓鼠细胞株的特征，而且被几个不

同的研究者报道。。

Complete survival curves at a number of discrete points during the cell cycle were measured

by Sinclair. Survival curves are shown for mitotic cells, for cells in G

1

and G

2

, and for cells in

early and late S phase. It is at once evident that the most sensitive cells are those in M and G

2

,

which are characterized by a survival curve that is steep and has no shoulder. At the other extreme,

cells in the latter part of S phase exhibit a survival curve that is less steep, but the essential

difference is that the survival curve has a very broad shoulder. The other phases of the cycle, such

as G

1

and early S, are intermediate in sensitivity between the two extremes.

Sinclair利用细胞周期过程中几个不连续的点测量而完成完整的存活曲线。有丝分裂细

胞的存活曲线已经被显示了，对应的细胞处在G

1

和G

2

，或者早S和晚S期。很明显，更敏感

的细胞处在G2和M期，存活曲线特征为陡峭而且没有肩区。相反，在S期晚期的存活曲线较

为平缓，期主要差异是存活曲线具有比较宽的肩区。细胞周期的其他时期，如G1和晚S期的

敏感性则介于二者中间。

The following is a summary of the main characteristics of the variation of radiosensitivity

with cell age in the mitotic cycle: (1) Cells are most sensitive at or close to mitosis. (2) Resistance

is usually greatest in the latter part of S phase. (3) If G

1

phase has an appreciable length, a resistant

period is evident early in G

1

, followed by a sensitive period toward the end of G

1

. (4) G

2

phase is

usually sensitive, perhaps as sensitive as M phase.

下面列出有丝分裂各时相辐射敏感性变化的主要特征：(1) 在接近于有丝分裂期时细胞

更敏感。(2) 在晚S期辐射抗性最大。(3) 如果G1期足够长，则可发现在G1初的细胞对辐射

较不敏感；而在G末期的细胞则较为敏感。(4) G2期通常是对辐射敏感的，有可能具有和M

期细胞一样的辐射敏感性。

A number of cells lines other than HeLa and hamster have been investigated, some of which

tend to agree with these results and some of which are contradictory. The summary points listed

here are widely applicable, but exceptions to every one of these generalizations have been noted

for one cell line or another.

除了Hela细胞和中国仓鼠细胞，研究人员已经研究了许多其他的细胞株。有些结果是相

同的，而有一些则是相反的。这里列举的要点及上述观点被广泛应用，但对于不同的细胞株，

这些通则中的每一点仍可能会有例外。

Molecular Checkpoint Genes

分子检查点基因

Cell-cycle progression is controlled by a family of genes known as molecular checkpoint

- 27 -

genes. It has been known for many years that mammalian cells exposed to a small dose of

radiation tend to experience a block in the G

2

phase of the cell cycle. For example, the inverse

dose-rate effect reported for cells of human origin, whereby over a limited range of dose rates

around 0.30 to 0.40 Gy/h cells become more sensitive to radiation-induced cell killing as the dose

rate is reduced, results from the piling up of cells in G

2

, which is a radiosensitive phase of the cell

cycle. The mechanisms for this observation in human cells are not understood in detail, but the

molecular genetics in yeast have been worked out and the search is on for homology in mam-

malian cells.

细胞周期进程主要由分子检查点基因家族所控制。早在许多年就已知，当哺乳动物细胞

接受小剂量照射后趋向于停留在细胞周期的G2期。例如，在人类细胞的研究中提出的反剂

量率效应，当剂量率在0.30到0.40 Gy/h范围内，导致细胞聚集在G2这个辐射敏感期，因此剂

量率降低时细胞更容易被杀死。在人类细胞中观察到的机制在细节方面并未完全被了解，但

酵母菌的分子遗传已被攻克，而且正在开展在哺乳动物细胞中的同源通路研究。

In several strains of yeast, mutants have been isolated that are more sensitive than the wild

type both to ionizing radiation and ultraviolet light, by a factor between 10 and 100. The mutant

gene has been cloned and sequenced and found to be a “molecular checkpoint gene.” In the most

general terms, the function of checkpoint genes is to ensure the correct order of cell-cycle events,

that is, to ensure that the initiation of later events is dependent on the completion of earlier events.

The particular genes involved in radiation effects halt cells in G

2

, so that an inventory of

chromosome damage can be taken, and repair initiated and completed, before the complex task of

mitosis is attempted. Mutant cells that lose this gene function move directly into mitosis with

damaged chromosomes and are therefore at a higher risk of dying, hence their greater sensitivity

to radiation, or for that matter to any DNA-damaging agent.

在酵母的几个不同品种中，已分离出对辐射和紫外线敏感性比野生株高10 ～100倍的突

变种。已经克隆出突变基因并测序，发现是分子检查点基因。最常见观点认为检查点基因的

功能是确保细胞周期事件顺序的正确，即保证后续事件起始依赖于上一个事件的完成。涉及

到辐射效应的特异性基因使细胞停在G2期，然后在进行复杂的有丝分裂之前，大量的染色

体损害被发现并在分裂开始前启动并完成修复。失去G2检查基因功能的突变细胞会直接带

着损伤的染色体进入分裂期，因而更容易死亡。因此，这些细胞对辐射或者DNA损伤剂更

敏感。

It has been proposed that a checkpoint control monitors spindle function during mitosis. If the

spindle is disrupted by a microtubular poison, progression through mitosis is blocked. The

checkpoint control is involved in this dependency of mitosis on spindle function. It is thought that

the mechanism of action of checkpoint genes involves p34 protein kinase, levels of which control

passage through mitosis. It is likely that mammalian cells that lack checkpoint genes would be

sensitive not only to radiation-induced cell killing but also to carcinogenesis. Cells with damaged

chromosomes that survive mitosis are likely to give rise to errors in chromosome segregation at

mitosis, and this is one of the hallmarks of cancer.

有假说认为在有丝分裂过程中有一个检查点可以控制和监测纺锤体的功能，如果纺锤体

功能被微管毒素破坏，通往有丝分裂的进程便会因此终止。此检查点的控制与有丝分裂对纺

锤体的依赖有关。通常认为G2检查点基因的作用机制与Cdk1（p34蛋白激酶）有关，期水平

高低可控制有丝分裂的进程。缺乏检查点基因的哺乳动物不仅对辐射诱导的细胞杀伤敏感，

而且对癌症形成也敏感。染色体受损的细胞，若在有丝分裂中存活，可能会导致有丝分裂染

色体分离的错误发生概率升高，而此现象就是癌症的指标之一。

- 28 -

The Age-Response Function for a Tissue in vivo

活体组织的分期-反应函数

Most studies of the variation in radiosensitivity with phase of the mitotic cycle have been

done with mammalian cells cultured in vitro because of the ease with which they can be made to

divide synchronously. The rnitotic harvest technique is clearly only applicable to monolayer

cultures, but techniques that involve a drug, such as hydroxyurea, to produce a synchronously

dividing population can be applied to some organized tissues.

多数探讨分裂周期中细胞辐射敏感性变化的研究，主要以体外培养的哺乳动物细胞为

主，因此其比较容易引发同步分裂。有丝分裂收获法只能用于单层培养的细胞；有些涉及药

物作用的技术，如用羟基脲来产生同步分裂细胞等，则可应用于某些组织中。

The crypt cells in the mouse jejunum are a classic self-renewal tissue. The rapidly dividing

crypt cells can be synchronized by giving each mouse five intraperitoneal injections of

hydroxyurea every hour. The rationale for this regimen is that all S cells are killed by the drug, and

cells in other phases of the cycle are accumulated at the G

1

-S boundary for at least 4 hours (the

overall time of the five injections). The response of the jejunal crypt cells to a single dose of 11 Gy

of γ-rays are delivered at

various times after the synchronizing action of the five injections of

hydroxyurea. The number of crypt cells per circumference of the sectioned jejunum varies by a

factor of 100, according to the phase in the cycle at which the radiation is delivered, ranging from

about two survivors per circumference for irradiation 2 hours after the last injection of

hydroxyurea to about 200 survivors per circumference by 6 hours. The DNA synthetic activity of

the synchronized jejunal mucosa was monitored by injecting groups of mice with tritiated

thymidine at hourly intervals after the last injection of hydroxyurea and subsequently removing a

sample of the jejunum and assaying the radioactive content.

小鼠空肠黏膜上皮可作为典型的自我更新组织代表。给予小鼠每小时腹腔内注射一次羟

基脲，连用5次，快速分裂中的隐窝细胞便可同步化。此方法的原理是所有S期的细胞都会被

药物杀死而其他时期的细胞至少4 h后（5次注射的整体时间）都会聚集在G1期和S期的交界

处。空肠隐窝细胞在注射5次羟基脲同步化后，于不同时间点对单次11 Gy

γ-

射线照射的响

应。每圈切断的空肠上隐窝下表数目可能相差100倍，这主要由照射时细胞正处于细胞周期

的哪个时相所决定。这种差距的变化表现为，最后一次注射羟基脲后2 h给予照射，每圈只

有2个细胞存活，而到注射后6 h给予辐射，有200个细胞存活。最后一次注射羟基脲后1 h，

再给小鼠注射氚化胸腺嘧啶，随后每小时将空肠取出并测定其放射活性，采用此方法可检测

同步化的空肠黏膜的DNA合成活性。

These data indicate clearly that the radiosensitivity of crypt cells in the mouse jejunum varies

substantially with the phase of the cell cycle at which the radiation is delivered. Further, the

pattern of response in this organized normal tissue, with a sensitive period between G

1

and S and

maximum radioresistance late in S, is very similar to that characteristic of many cell lines cultured

in vitro.

这些资料证明小鼠空肠隐窝细胞的辐射敏感性与在细胞周期的哪个时期给予辐射有关。

此外，在整体正常组织中的响应模式，在G1期和S期之间的敏感时期及在S末期的最大辐射

抗性，都与体外培养细胞系的特征相似。

Variation of Sensitivity With Cell Age for Neutrons

中子的细胞周期时期敏感性变化

With the introduction of neutrons for use in radiotherapy in place of conventional modalities,

such as X- or γ-rays, all possible radiobiologic parameters of the two types of radiation were

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compared.

随着中子被引入放疗替代常规的模式，比如利用X-或者γ-射线，并与这两种辐射的所有

可能的放射生物学指标进行了比较。

It was found that the variation in radiosensitivity as a function of cell age was qualitatively

similar for neutrons and X-rays; that is, with both types of radiation, maximum sensitivity is noted

at or close to mitosis, and maximum resistance is evident late in S phase. There are, however,

quantitative differences between neutrons and X-rays in this respect, as in every other. The range

of radiosensitivity between the most resistant and the most sensitive phases of the cell cycle is

much less for fast neutrons than for X-rays. Although the variation of sensitivity with cell age is

reduced in neutrons compared with X-rays, it is still very evident and cannot by any means be

ignored. The pattern of response as a function of cell age is similar for γ-rays and neutrons, with

maximum resistance occurring in late S phase for both types of radiation. The magnitude of the

variation is, however, less for neutrons than for γ-rays.

研究发现，对于中子和X射线来说辐射敏感性变化作为细胞分期的函数在本质上是相似

的，最大的敏感性是在或者接近有丝分裂期，最大辐射抗性明显是在S晚期。但是，在中子

和X射线之间，这方面或者其他方面，存在一定量的差异。在最抗性和最敏感的细胞周期时

相放射敏感性的范围是快中子比X射线低。虽然中子较X射线细胞分期的敏感性降低了，它

仍旧非常明显，且不可忽略。作为细胞周期分期的函数的效应模式对γ-射线和中子是相似的，

最大的抵抗是S晚期。变化的范围中子较γ-射线小。

It has been argued that the reduced cycle related fluctuations in radiation response that occur

with neutrons could represent an advantage over conventional therapeutic radiation modalities,

such as X- or γ-rays. There could be an important difference in the response of normal tissues and

of neoplastic tissues to neutrons if the age-density distributions of normal and neoplastic tissues

were dissimilar as a consequence of different rates of proliferation. At all events the reduced

age-response function seen with neutrons represents a difference between this relatively densely

ionizing radiation and X-rays over and above the oxygen effect.

减少应用中子时细胞周期对辐射效应的波动显示出超过X和γ-射线常规放疗的优势已

经争论过了。如果正常和肿瘤组织时相密度分布因为不同的增殖比率导致差异，则正常组织

和肿瘤组织对中子的效应存在差异。在相对致密的电离辐射和X射线之间，除了氧效应外，

在所有的事件中，中子辐射展现的时相效应函数出现明显的差别。

Mechanisms for the Age-Response Function

分期-反应函数的机制

The reasons for the sensitivity changes through the cell cycle are not at all understood.

Several correlations have been proposed, of which two are mentioned here. First, if DNA is the

primary target for radiation-induced cell lethality, as commonly is supposed, then changes in the

amount or form of the DNA might be expected to result in variations in sensitivity. During S

phase the DNA content doubles as the genome is replicated; just before mitosis the chromosome

material appears to condense into discrete entities. These two events coincide with the periods of

minimum and maximum radiosensitivity. The nature of any cause-and-effect relationship is not

clear; all that is observed really is a correlation. Second, there is also a correlation between

changing radiosensitivity through the cell cycle and varying levels of naturally occurring

sulfhydryl compounds in the cell. Either or both of these factors may be at the root of the

important and substantial changes in radiosensitivity that cells exhibit as they progress through

their generation cycle.

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整个细胞周期中辐射敏感性的变化原因仍未完全被了解。几个相互关系已经被提出，这

里重点提及两个。首先，如果DNA是辐射诱导细胞死亡的主要的靶点，正如大家通常认同

的，DNA的数量和形式可能被认为是导致敏感性变化的原因。在S期，因为基因组的复制导

致DNA含量翻倍，有丝分裂前染色体物质呈现出浓缩成独立的个体。这两个事件与最小和

最大的辐射敏感性之间的时间差异匹配。任何因果关系的本质还不清楚，所有的实际观察到

都确定是相关的。第二，在通过细胞周期是放射敏感性变化与细胞中正常出现巯基复合物的

变化水平之间也存在一定的相互关系。这些因素的一或者二个可能是细胞通过细胞周期所展

现的放射敏感性重要和本质变化的基础。

The Possible Implications of the Age-Response Function in Radiotherapy

放疗中分期-反应函数的可能意义

If a single dose of radiation is delivered to a population of cells that are asynchronous ― that

is, distributed throughout the cell cycle ― the effect is different on cells occupying different

phases of the cell cycle at the time of the radiation exposure. A greater proportion of cells is killed

in the sensitive portions of the cell cycle, such as those at or close to mitosis; a smaller proportion

of those in the DNA synthetic phase is killed. The overall effect is that a dose of radiation, to some

extent, tends to synchronize the cell population, leaving the majority of cells in a resistant phase of

the cycle. Between dose fractions, movement of cells through the cycle into more sensitive phases

may be an important factor in “sensitizing” a cycling population of tumor cells to later doses in

fractionated regimen. This is considered sensitization resulting from reassortment. It results in a

therapeutic gain, because sensitization by this mechanism occurs only in rapidly dividing cells and

not in late-responding normal tissues.

如果给予非同步化的细胞群单次照射，也就是说处在不同细胞周期的细胞均受到照射，

其效应不同。大部分细胞会在细胞周期的敏感部分被杀死，如处在或接近有丝分裂期）；而

在DNA合成期被杀死的细胞只有很小一部分。辐射的整体效应是倾向于同步化细胞群体，

使得大部分细胞处于细胞周期的抗性时相。在两次分割剂量之间，细胞通过细胞周期进入辐

射敏感时相，从而导致细胞对下一次照射敏感，这是达到放射治疗目的的一个重要的因素。

这就是辐射敏感性的在分布。由于此机制仅存在于快速分裂的细胞而非晚反应的正常组织，

因此可以获得治疗效果。

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