What Is Radiobiology?

Radiobiology (radiation biology) is a science that studies the effects of ionizing radiation on organisms at various levels such as collectives, individuals, tissues, cells, and molecules. The main research objects are: the role of electromagnetic rays, such as ultraviolet, X-ray, and gamma rays; the role of particle rays, such as electron rays, proton rays, deuterium rays, and alpha rays; and the effects of high-speed charged particle rays; Role, etc.

Chinese name: Radiobiology
Foreign name: radiation biology

Main research object: Electromagnetic radiation
Radiobiology: Is a marginal subject

Introduction to Radiobiology

Radiation (or radiation) biology is a marginal subject that mainly studies radiology

Radiobiology related books The effects of radiation on living organisms. Observe the biological effects of different kinds of radiation and the effects of different internal and external factors on biological effects. The scope involves the original response of radiation to living organisms and a series of subsequent physical, chemical and biological changes. Clinical radiobiology or tumor radiobiology is a branch of radiobiology and it is also radiation oncology ( One of the four pillars of oncology (oncology, radiophysics, radiobiology, and radiotherapy). Therefore, the vast majority of countries in the world require clinical radiobiology for training, qualification or promotion of radiation therapists.

Clinical radiobiology is based on the basic theory of radiation biology, combined with the study of the radiobiological characteristics of tumors and normal tissues during clinical radiotherapy and changes in factors during and after treatment, and based on the above understanding, the use of Combining the unique characteristics of radiobiological behavior from molecular, cell, and tissue to the overall level of experimental research, to explore ways or means to improve the efficacy of radiotherapy, in order to continuously improve the effect of tumor treatment and patient quality of life.

With the rapid development of life sciences, the research content and technology of clinical radiobiology have also been continuously developed, enriched and updated. There is no doubt that an in-depth understanding of the basic knowledge and concepts of clinical radiobiology, and grasping the dynamics of clinical radiobiology research, and applying them are of great significance to the improvement of tumor radiotherapy and the improvement of tumor treatment effects.

Radiation biology

Why rays kill cells is related to the ionization properties of rays. Ionizing radiation

Radiobiology related books Lines act on organisms through direct and indirect effects, causing cell damage or death. At present, the target cells of radiation damage are mostly considered to be DNA, which is because the radiation damages the DNA and prevents cell division, resulting in cell division failure or cell damage.

Outcomes of Cell Damage Caused by Radiation

Apoptosis: Apoptosis causes cells to be exposed to a smaller dose

Radiobiology related books Yes, such as lymphocytes and spermatogonia.

Abortion division: Abortion division causes cells not to die immediately after being exposed to lethal dose, but enters the next division cycle, but due to DNA damage, DNA double-strand breaks, so that cell division fails, and finally cell death.

Progeny cell distortion

No change in morphology: After being exposed to radiation, there is a type of cells whose DNA is damaged, but because of this type of cells, the resting cells do not enter the division cycle or have lost their ability to proliferate, such as in the central nervous system Neuron cells and mature liver cells, their radiation damage cannot be shown, they are still normal in morphology, and have original functions, such as neuron cells still have conduction functions, liver cells can still synthesize proteins and various The function of enzymes is not to say that radiation cannot kill these cells. When the irradiation dose reaches a certain level, functional damage and apoptosis will also occur.

Limited division and death: Most cells show limited division and death when exposed to lethal doses. Although their DNA double-strand breaks, they can still barely divide successfully, but the broken DNA replicates multiple times during the division process, and the damage gradually accumulates in the progeny cells, eventually leading to cell death.

Survival: After a few cells were irradiated at a non-lethal dose, the cells were able to repair damaged DNA and divide, leaving no or only minor changes in the progeny cells.

Radiobiological cell survival curve

Most of the cells died after irradiation, and a small number of cells remained.

Radiobiology related books Live, what do you use to reflect the survival of cells after irradiation?

Definition: The curve drawn according to different doses and corresponding different survival rates is the cell survival curve. This curve can be obtained both in vitro and in vivo.

Drawing of cell survival curve: Since the damage of the radiation to the organism is random and the sensitivity of the cell to the radiation is different, we can see that the cell survival curve can appear in two cases. The cell's survival curve is a straight line, indicating that the cell is sensitive to radiation, that is, the cell's DNA is killed by a single hit. However, this is not the case for most cells. In the low-dose area, the survival curve has a shoulder area. When the dose is large, it is a straight line. So the survival curve is a quadratic curve, and we usually use linear quadratic equations to describe it. The shoulder area of the survival curve is due to the fact that cells can not cause cell death after being irradiated with radiation. This cell must also be irradiated with radiation to die. Therefore, there is a cumulative process of radiation damage in low dose areas.

The average lethal dose of D0 represents the radiosensitivity of this cell population. The steeper the line, the smaller the D0 value, the smaller the dose required to kill 63% of the cells.

The N value refers to the number of domains of the radiosensitive region contained in the cell, that is, the number of targets.

Dq represents the width of the shoulder width that survives. Within this dose range, cells appear to be non-lethal repairs. The greater the Dq value, the greater the dose required to cause cell index death.

S2 is the survival rate of the cells after 2Gy irradiation.

It should be noted that the cell survival curve only represents the cell level, and there is still a certain distance from the radiation biological effect of the tissue level. Cells cultured in vitro and the complex human body are also significantly different.

(3) The significance of cell survival curve: it is the basis of all radiobiological research.

Radiobiology related books Study the quantitative relationship between various cell biological effects and radiation dose

Compare the effects of various factors on radiosensitivity.

Observe the changes of cell radiosensitivity under aerobic and hypoxic conditions

Compare the radiobiological effects of different radiation segmentation schemes.

Investigate the effectiveness of various radiosensitizers

Comparing the effects of radiotherapy alone and radiotherapy

Compare the biological effects of different LET rays

Study various radiation damage of cells

Models of radiation and other effects in radiation biology

Due to different segmentation methods, the same total dose can produce different radiation effects. Ellis proposed a mathematical model of effects such as radiation in 1971, but clinical practice has confirmed that this mathematical model is only suitable for skin and not applicable to all tissues, especially late-response tissues. Thames and Bentze proposed in the 1980s The LQ model works well to evaluate the clinical radiation effects of different divided doses, not only for tumors, but also for early and late response tissues. The model believes that ionizing radiation acts on target cells and causes cell damage is composed of two damage probabilities, and . When an ionized particle breaks through DNA double-strand breaks, the probability of target cell damage is , which is linear with the dose. relationship. DNA double-strand breaks are generated by two ionized particles through DNA. The probability of occurrence of target cells is , which is a square function with dose. The extended formula is: BED = D (1 + d / ( / )).

Limits of the LQ formula: The LQ equation is based on the complete repair of SLD after each irradiation.

Radiobiology related books There is no assumption of cell proliferation, so incomplete repair factors (Hm) and practical factors (T / Tpot) must also be considered. A large number of animal experiments show that within the range of 1-10Gy split dose, the LQ equation can better reflect the equivalent relationship of the splitting scheme. When the split dose is less than 2Gy, it is estimated that the biological effect is in danger of being overdose. Caution must be exercised when planning radiotherapy.

Clinical significance:

Predict the biological effects of dose splitting.

Equivalent conversion of different dose division methods.

Biological equivalent dose (BED-Biological Equralent Dose) In order to make the difference between the physical dose of the tumor center and other points (that is, dose heterogeneity) and the difference between the physical dose and the biological effect (also known as the biological effect difference) dual differences The results can be finally expressed, and this double difference effect is unified in radiobiology, which is called biological equal dose (BED). In the past, clinicians guessed based on experience and clinical effects only. To achieve a curative dose to the tumor area and protect the surrounding normal tissues, in order to approximate the actual tumor, a tumor controllable probability TCP (Tumor Contral Probability) was proposed. And NTCP (Non Tumor Control Probability), the TCP / NTCP value is used to measure the probability of BED and tumor treatment.

4R Radiobiology 4R

The cell cycle, that is, the relationship between the proliferative phase (G1-S-G2-M) and the stationary phase (G0) was studied in depth. To this end, four Rs were proposed: Repair, Reoxygenation, and redistribution (Redistribution), Regeneration (Regeneration) is used as a guideline for guiding the research of radiobiology to overcome the problems of hypoxia and so on. Radiobiology has been advanced into effective research with clear purpose and strong pertinence.

Radiobiology Repair of Radiation Damage

When cells are irradiated with a non-lethal radiation dose, the cells repair the radiation damage through their own repair mechanisms. Such non-lethal radiation damage includes: potentially lethal radiation damage; sublethal radiation damage. In the 1960s, Elkind discovered that cells damaged by PLD, if in an environment that inhibits cell division, help the cell repair. In vitro culture tests also confirmed that most of the SLD cells have been repaired within 2-4 hours after radiotherapy. However, the repair kinetics of different cells are not the same. Studies on tissue repair kinetics have shown that the repair of SLD and the time after irradiation are different. Exponential relationship, usually 1 / 2T for half repair time. The relationship between the split dose and cell repair kinetics is not very clear at present, but some data show that the large split dose and weak cell repair ability.

Cell radiation damage repair and apoptosis are a contradiction. If the tumor cells have a strong ability to repair PLD, the apoptotic response is lost. Some studies have found that after the cell's DNA is damaged, some genes and oncogenes can affect the apoptosis process of cells. These genes include bcl-1, bcl-x, p53 and so on.

Reoxidation of tumor cells after radiation therapy

After receiving radiotherapy, the proportion of hypoxic cells in tumor tissue increased significantly. After 24 hours, the cells developed from hypoxic state to oxygenated state. Mechanism of Hypoxic Cell Reoxygenation:

The total amount of tumor cells decreased, blood vessels were not lost, and blood vessel density was relatively increased.

Selective killing of radiation-sensitive oxygen-rich cells, shortening the distance between hypoxic cells and blood vessels far from blood vessels.

Cell death reduces total oxygen consumption.

The shunting of blood vessels leads to changes in blood circulation.

Migration of tumor cells.

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Cell redistribution during radiation

An interesting phenomenon in segmented radiation is that the cell population will be synchronized during the division phase. The reason may be that the radioactivity is G2 / M cell block. When the radiation damage is repaired, the blocked cells are synchronized in the same division cycle. The timing of the second radiation dose is critical to the survival of the cell population. If the synchronized cells are in the anti-radiation phase, the radiation effect is not strong. If they are in the radiation-sensitive phase, a larger killing effect can be obtained. However, the phenomenon of synchronization is short-lived, and cell populations are quickly redistributed in their inherent proportions. Radiosensitivity of cells in different phases of the division cycle: Cells of different phases in the division cycle have different sensitivity to radiation killing, and the order of radiosensitivity is M> G2> G1> S. S-phase cells are resistant to radiation, and cells with a longer G1 phase also show resistance in the early stages of G1.

Cell proliferation during radiation biology

In clinical work, we can observe such a phenomenon. For example, about 2 weeks during lung cancer radiotherapy, the patient developed symptoms of eating and swallowing pain. After a period of time, about 4 weeks, although the radiation dose continued to accumulate, the patient's Swallowing is also significantly reduced, and the reason is that the accelerated re-proliferation of the esophageal mucosa epithelium causes the radiation damage of the esophagus mucosa to recover to varying degrees. During the radiotherapy process, the cell proliferation rate varies, and the phenomenon of accelerated proliferation occurs in a certain stage, which is called accelerated re-proliferation. There are two types of cells that proliferate in the radiation treatment area. One is to walk from outside the radiation area into the radiation treatment area for cloning. For example, skin, oral mucosa, and digestive tract mucosa are repaired in this way after radiation damage. The other is to irradiate cells in the volume for cloning. Tumor cells generate more tumor cells in this way. Therefore, additional doses are needed to kill cells that accelerate proliferation.

For normal tissues, the factors that promote cell proliferation are: 1 cells that are damaged by radiation can secrete stimulating residual cell division factors; 2 cell death, contact inhibition between residual cells disappears, and division accelerates. Accelerated re-proliferation of normal cells is conducive to the recovery of acute radiation injury. However, the accelerated re-proliferation of tumor cells is not conducive to tumor control. The basic condition for accelerated proliferation is the improvement of blood supply. The cause of tumor re-proliferation is similar to that of normal tissues. Although the inhibition of contact between tumors is weaker than normal tissues, this phenomenon still exists in most tissues. Tumors re-proliferate through the following three pathways: 1 increase the proportion of proliferating cells; 2 shorten the cell cycle time; 3 reduce the proportion of cell loss; 4 change from asymmetric division to symmetric division. In segmented radiotherapy, it is currently unknown exactly how the dynamics of cell proliferation are determined. From the clinical data, the time for tumors to start accelerating and re-proliferating is before the tumor volume begins to shrink in clinical settings. For most head and neck epithelial tumors, accelerated tumor proliferation begins 2-4 weeks after radiotherapy. Clinical and experimental studies have shown that normal tissues have a stronger ability to reproduce than tumor tissues. Radiation damages the surrounding normal tissues while killing the tumor tissues, but because the surrounding normal tissues have a strong ability to recover, the tumors are more easily controlled. Different degrees of damage to normal tissue can leave some sequelae.

Research progress in radiobiology

Principles of Radiation Biology

From the perspective of molecular biology, it is currently believed that radiation mainly affects nuclear DNA (such as MAR region), cell membrane (such as sphingomyelinase-ceramide), and some proteins in the cytoplasm (such as Apaf-1 / IAP, etc.). DNA damage is mainly manifested as strand breaks (single and double stranded), and its repair has two pathways: homologous recombination and non-homologous end joining.

The radiation impedance obtained by some cells in the tumor after radiation is also related to some changes in cell repair ability caused by activation. After irradiation, the plasma membrane and cytoplasm can initiate different conduction pathways and regulate the expression of cytokines, growth factors and cell cycle-related genes by inducing some transcription factors. In addition, radiation can change the tyrosine kinase pathway.

Many in vivo and in vitro experiments have shown that, before or after radiotherapy, because the tumor cell growth environment is different from the surrounding normal tissues, the cells are often in a genetically unstable state. Most molecular targeted therapies target abnormally expressed genes in tumors. Activity to turn off the gene's conduction pathway.

Radiobiology molecular target

According to the report at the 46th ASTRO conference, molecular targeted therapy can be roughly classified

Cell division Nano is targeted at the following radiation-related pathways: intracellular conduction pathways, cell death pathways, cell cycle and tumor angiogenesis and COX2 blockade. These findings suggest that the combination of radiation and molecular targeted therapy can alter the radiosensitivity of tumor cells.

Studies have confirmed that the proportion of hypoxic cells in tumors is related to tumor aggressiveness and treatment outcome. Tumor cells can activate some genes during the process of hypoxia, HIF-1a is one of them, and its activation can change gene stability and angiogenesis and tumor cell metabolism. On the other hand, tumor cells are genetically unstable under hypoxic conditions.

Radiobiological Possibility Solutions

Therefore, it is necessary to work hard to explore the biomarkers of hypoxic cells. Galectin-1 is considered to be one of the proteins induced by hypoxia. Current studies have shown that this new protein is closely related to the degree of oxidation in vitro and in clinical head and neck squamous cell carcinoma tissues, but it is not detected in patients' plasma.

With the rapid development of imaging technology, it has become possible to determine the spatial distribution of different subpopulation cells in tumors with different clone-derived oxygen saturation, proliferation rate, and radiosensitivity. Combining these data with the reverse treatment planning system and intensity-modulating techniques, the expected treatment gain ratio before treatment has been mentioned on the agenda.

In addition, this conference also reported a large amount of information on radiotherapy combined with drugs selected based on molecular targeting of radiation in an attempt to change the 5R's of segmented radioactive organisms, opening up a new platform for radiomolecular biology research.

Selection and Application of Experimental Animals in Radiobiology Research

I. The role of experimental animals in radiobiology research

Conducting radiobiological research is one of the most complex tasks in experimental medicine. Because in the research of radiobiology experiments, not only workers are required to abide by the corresponding measures to prevent exposure or contamination beyond the allowable dose, but also to obtain stable results that can objectively reflect the real situation of the interaction between radiation and biological objects. This must meet many conditions at the same time, one of the most important conditions is to choose the animal species suitable for the needs of the research project, and establish experimental models.

Exceeding a certain dose of high-energy radiation on the body can cause a series of systemic syndromes, known as radiation sickness, or Acute Radiation Syndrome. This disease is rarely seen in peacetime, and it is only seen in the context of nuclear war and nuclear gangs. Therefore, the study of this disease is based on the selection of various experimental animals in the laboratory. Today, most of our knowledge about radiation damage does not come from Fanghiroshima or Changfang, nor from several reactors that have been involved in accidents. A large amount of knowledge has been accumulated through the use of various experimental animals for animal experiments. The long-term genetic effects of radiation have so far been limited to animal experiments.

Since various experimental animals can be selected at any time in the laboratory and exposed to different doses, they can be copied into different types of radiation diseases or radiation injuries with similar lesions and a large number of cases, which provides extremely convenient conditions for radiobiology research. , Has greatly promoted the development of radiology.

Effects of experimental animals on radiation effects

When the same kind and dose of radiation acts on the body in the same way, the consequences that occur often vary with the type, age, gender, and body condition of the animal, that is, there are different radiation responses. The concept of radiosensitivity is commonly used in radiobiology research to observe the sensitivity of individual tissues and cells. Radiosensitivity refers to the degree and speed of certain changes in the body or its tissues under the action of radiation when all irradiation conditions are completely and consistently consistent. If the changes are large and they occur rapidly, it indicates that the sensitivity is high. Otherwise, the opposite is true. In general literature, the morphological damage of cells or tissues or death of the body is used as the basis for judging radiosensitivity. The radiation sensitivity referred to below is based on this.

Radiation biology nuclear radiation

Nuclear radiation is the flow of microscopic particles or energy released during the transition of an atomic nucleus from one structure or one energy state to another structure or another energy state. There are two types of radiation sources: natural and artificial. Radiation is divided into two categories: electromagnetic radiation and ion radiation. Electromagnetic waves pass through space and transmit energy called electromagnetic radiation. -ray: transformation from the nucleus, energy range 0.1Mev; X-ray: interaction from electrons outside the nucleus, including bremsstrahlung radiation and characteristic X-rays, energy range 1Kev ~ 0.1Mev; UV: energy ratio X-rays and -rays Much lower, energy range 1ev ~ 0.1Kev. Ion radiation is divided into charged particle radiation and uncharged ion radiation.