X-rays, gamma rays and charged particles are the most types of radiation used for cancer treatment. On the other hand, systemic radiation therapy uses radioactive substances, such as radioactive iodine, that travel in the blood to kill the cancer cells. A better understanding of biological effects of radiation will lead to efficient use and better protection. Biological effectiveness of radiation depends on the linear energy transfer LET , total dose, fractionation rate and radiosensitivity of the targeted cells or tissues Hall, Low LET radiations X-rays, gamma rays and beta particles deposit a relatively small quantity of energy.
On the other hand, radiation particles either negatively charged electrons , positively charged protons, alpha rays, and other heavy ions deposits more energy on the targeted areas called the Bragg peak and causes more biological effects than the low LET radiations. However, tumors have developed multiple strategies to resist radiation damage. However, when using external-beam radiation healthy tissues are unavoidably exposed to radiation, which increases the normal tissue complication probability.
Over the years, technological improvements in radiation therapy delivery have aimed to widen the therapeutic window while reducing the normal tissue impact and increase in target tissue tumor control Durante and Loeffler, ; Loeffler and Durante, , and the benefits will be three-fold: patient cure, organ preservation and cost-efficiency.
The overall outcome of radiation treatment is cell or tissue damage; if it is not repairable eventually kill the cells. Effectiveness of radiation therapy that have been developed over years showed an increase in the number of cancer survivors, but preventing or reducing late effects are a significant public health issue. Furthermore, increase in the number of cancer survivors has stimulated interest in the quality of life of cancer survivors.
The situation is important among non-elderly adults. In particular, children are inherently more radiosensitive and have more remaining years of life during which radiation induced late effect in normal cells could manifest in their hyperproliferation Allan and Travis, However, understanding the tumor biology and considerable technical advancement e. Ionizing radiation has been used for more than a century to treat the cancer based on the rationale that the rapidly proliferating cancer cells are sensitive to the radiation treatment than normal cells Bernier et al.
Under the target-cell damage, the major effect of ionizing radiation on tissues are the direct cell killing mostly by damaging the DNA, resulting in the depopulation of cell populations and subsequent functional deficiency. Radiation induced double strand breaks DSBs represent the most lethal types of DNA damage, leading to cell death, if unrepaired.
However, DNA damage response mechanisms represent a vital line of defense against exogenous and endogenous damage caused by radiation and promote two distinct outcomes: survival and the maintenance of genomic stability. Radiation mainly acts in two ways. Multiple pathways are involved in the genome maintenance of a cell after its exposure to ionizing radiation.
Radiation therapy like the most anticancer treatments achieves its therapeutic effect by inducing DNA damage and thereafter cell death Baskar et al. Several experiments were performed indicating that the DNA of cancer cells repair more slowly and also produce more DNA breaks single strand break and double strand breaks than the normal cells Parshad et al.
Therefore, ionizing radiation as applied in the cancer treatment induces a complex response in the cells. Some processes aim to repair the radiation induced damage of the normal cells, whereas others counteract the damage or induce cancer cell death.
Growing evidence suggests that various signaling pathways including the DNA repair response pathways shows redundancy in normal cells Moding et al. Since cancer cells have various mutations that cause the loss of this redundancy and therefore targeting the DNA damage response pathways in the cancer cells can induce cell death.
Radiation damages the genetic material DNA causing single strand breaks SSB or double strand breaks DSB in the cells, thus blocking their ability to divide and proliferate further.
Mechanisms involved in the decrease of radiosensitivity of the fast doubling cancer cells, while increasing radioresistant of the slow doubling normal cells benefits the cancer patients. However, whether p53 induces apoptosis or cell cycle arrest for the DNA damage repair is a complex process and partly depends on the abundance of the p53 protein low protein levels lead to cell cycle arrest and high protein levels lead to apoptosis Lai et al.
However, various DNA repair mechanisms within the tumor cells interfere with the radiation induced damage and further increase the radioresistance of cancer cells Jorgensen, Besides the DNA repair pathways, ionizing radiation also triggers cancer cells adaptive cellular responses.
Various treatment resistant signal transduction pathways are activated and the resistance can be either intrinsic or an acquired resistance during the fractionated radiation treatment Toulany and Rodemann, Signaling pathways that provide cancer cells with a proliferative advantage or allow them to evade the cell death remains a major clinical problem.
One of the molecular events by which tumors can become radioresistant is through the ligand-independent activation of signal transduction pathways such as those regulated by membrane-bound receptor tyrosine kinases RTKs. These pathways control the most hallmarks of cancer, including cell cycle, survival, metabolism, invasion, angiogenesis, and genomic instability Datta et al. Among the prosurvival pathways activated by RTKs, PI3K-AKT-mTOR signaling pathway is frequently upregulated in human tumors and regarded as one of the most challenging prosurvival pathways involved in the resistance to cancer treatment Engelman, ; Liu et al.
Furthermore, improvement in preclinical methods for the biological mechanisms involved in signaling pathway s for the treatment resistance, cell cycle checkpoints, DNA damage and repair, anti-angiogenesis could increase the therapeutic response of tumor microenvironment, while sparing the surrounding normal tissues.
Furthermore, inhibition of the cancer cell survival could also affect the radiosensitivity of normal tissues as well, thus decreasing the overall therapeutic index of radiation. Therefore, strategies to improve radiation therapy to increase the effect on tumor while less toxicity on the normal tissues should be achieved without sensitizing the normal tissues and also without protecting the tumors to the radiation treatment.
Cancer therapy usually involves exposing the body to agents that kill cancer cells more efficiently than the normal cells. Recent advances in radiation biology and oncology have demonstrated that the radiation is an effective tool to control the localized tumors. Ionizing radiation induces DNA damage in the form chromosomal aberrations were first reported not only in the directly exposed cells but also in their neighboring non-irradiated cells, termed as radiation-induced bystander effect RIBE Nagasawa and Little, Therefore, the discovery of non-targeted responses to radiation, such as the bystander response, has called the direct radiation effect paradigm into question.
Various biological effects of ionizing radiation are not restricted to only the directly irradiated cells targeted effects , but are also observed in the progeny of non-irradiated cells non-targeted effects Bensimon et al. RIBE has been demonstrated in numerous in vitro and in vivo studies using a variety of biological endpoints. These effects include various molecular and genomic instabilities as seen in the targeted cells.
Bystander effects has been extensively studied in the past two decades and reported cell death Seymour and Mothersill, , induction of sister chromatid exchanges Nagasawa and Little, ; Deshpande et al. Schematic representation of bystander effects induced by radiation to the adjacent cells and distanced organs.
Radiation can cause chromosomal aberrations arising de novo in the cell progeny, several generations after irradiation. Delayed genomic instability has been observed in many types of mammalian cells Ponnaiya et al.
Therefore, communication between cells and their microenvironment is critical for both normal tissue homeostasis and tumor growth. RIBE has important implication in tumor control and in radiation therapy, wherein the targeted directly irradiated cells transmit the damaging signals to the non-irradiated normal cells, thereby inducing a response similar to that of directly irradiated cells Mothersill and Seymour, ; Shao et al.
Two major mechanisms mediate RIBE. Recently, Jiang et al. RIBE has an important implication in radiation therapy and its impact in radiation oncology is gradually beginning Munro, RIBE is also reported using mouse model, the bystander responses of internal tumor cells or tissues were also confirmed in vivo , further cancer-associated events such as p53 alteration, MMPs Matrix metalloproteinases activity and epigenetic changes were reported in the RIBE Camphausen et al.
BE can be mediated through an increase in genomic instability, cell cycle delay, cell death apoptosis , formation of micronucleus, mutations, changes in proteins gene expression, and further by malignant transformation Nagasawa and Little, ; Hickman et al. However, the components released from the irradiated cells and further the communication signals involved between the irradiated and non-irradiated cells are still not well known.
Recently, Bensimon et al. Recently Aravindan et al. However, little is known about the type of DNA damage of the bystander cells, its radiation resistance and further damage of non-targeted normal cells contributing to tumorigenesis and how this damage can be repaired by designing novel therapeutic approaches to cancer treatment paves a way for an effective strategy to compact the disease.
Though tremendous progress has been made toward understanding the hallmarks of cancer, cancer is responsible for one in eight deaths worldwide Garcia et al. Despite the use of chemotherapy, radiation therapy and surgery, the overall outcome for cancer cure continues to be disappointing. Radiation therapy offers an effective treatment for advanced cancer and the prime goal of radiation treatment is to inhibit the cancer cells multiplication potential and eventually kill the cells.
Certain tumors are intrinsically radioresistant, while others acquire radioresistance during the treatment Seiwert et al. To overcome the tumor cell radioresistance, it will be a challenging one to identify tumor specific pathways and inhibitors.
In the past few years, enormous progress has been made in radiation therapy leading to the possibility of depositing more radiation energy proton beam radiation therapy, e. We do not have a comprehensive answer about the molecular mechanisms involved in the initiation of cancer, developing resistance to treatment and further individual variations in treatment susceptibility, especially of therapy-related beneficial or detrimental effects.
In a microenvironment, cancer cells are influenced by various growth signaling pathways to resist the radiation effects and further modify the adjacent normal tissues to impede tumor recurrence or metastasis. Overall, small increase in radioresistance will lead to a large number of cancer cell survivals and further the proliferation forms cancer mass and with a logarithmic decrease in cancer cell death after radiation treatment. Therefore, in the coming years more thrust should be given on the cancer cells radioresistance, e.
Furthermore, with a greater understanding of the tumor biology, evolution of radiation therapy will continue with the improvements in imaging, computing and engineering advancements, and potentially decimate the cancer cells with fewer side effects. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
I am indebted to Dr. Kothandharaman Subramanian for his critical editorial comments and help in the preparation of this manuscript. National Center for Biotechnology Information , U. Journal List Front Mol Biosci v. Front Mol Biosci. Published online Nov Author information Article notes Copyright and License information Disclaimer.
Louis, USA. This article was submitted to Cellular Biochemistry, a section of the journal Frontiers in Molecular Biosciences. Received Jul 11; Accepted Oct The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms. This article has been cited by other articles in PMC. Abstract Cancer is a class of diseases characterized by uncontrolled cell growth and has the ability to spread or metastasize throughout the body.
Keywords: cancer cells, radiation, direct DNA damage, bystander effect. Introduction Cancer is a complex disease, which grow locally and also possesses the capacity to metastasize to different organs in the body. Radiation and biological implications Radiation remains as most widely utilized treatment modalities in the clinical management of cancer Burnette and Weichselbaum, ; McGale et al.
Direct effects Ionizing radiation has been used for more than a century to treat the cancer based on the rationale that the rapidly proliferating cancer cells are sensitive to the radiation treatment than normal cells Bernier et al. The efficiency of radiotherapy and radioimmunotherapy has much to gain by understanding the cell death mechanisms that are induced in tumor cells following irradiation.
Strategies to use specific inhibitors that will manipulate key molecules in these pathways in combination with radiation might potentiate therapy and enhance tumor cell kill.
Abstract The main goal when treating malignancies with radiation therapy is to deprive tumor cells of their reproductive potential. Publication types Research Support, Non-U. It takes days or weeks of treatment before DNA is damaged enough for cancer cells to die. Then, cancer cells keep dying for weeks or months after radiation therapy ends. External beam radiation therapy comes from a machine that aims radiation at your cancer. The machine is large and may be noisy. It does not touch you, but can move around you, sending radiation to a part of your body from many directions.
External beam radiation therapy is a local treatment , which means it treats a specific part of your body. For example, if you have cancer in your lung, you will have radiation only to your chest, not to your whole body. Learn more about external beam radiation therapy. Internal radiation therapy is a treatment in which a source of radiation is put inside your body.
The radiation source can be solid or liquid. Internal radiation therapy with a solid source is called brachytherapy. In this type of treatment, seeds, ribbons, or capsules that contain a radiation source are placed in your body, in or near the tumor.
Like external beam radiation therapy, brachytherapy is a local treatment and treats only a specific part of your body. Learn more about brachytherapy. Internal radiation therapy with a liquid source is called systemic therapy.
Systemic means that the treatment travels in the blood to tissues throughout your body, seeking out and killing cancer cells. You receive systemic radiation therapy by swallowing, through a vein via an IV line, or through an injection. With systemic radiation, your body fluids, such as urine, sweat, and saliva, will give off radiation for a while. When used to treat cancer, radiation therapy can cure cancer, prevent it from returning, or stop or slow its growth.
When treatments are used to ease symptoms, they are known as palliative treatments. External beam radiation may shrink tumors to treat pain and other problems caused by the tumor, such as trouble breathing or loss of bowel and bladder control. Pain from cancer that has spread to the bone can be treated with systemic radiation therapy drugs called radiopharmaceuticals. Brachytherapy is most often used to treat cancers of the head and neck, breast, cervix, prostate, and eye. A systemic radiation therapy called radioactive iodine , or I, is most often used to treat certain types of thyroid cancer.
Another type of systemic radiation therapy, called targeted radionuclide therapy, is used to treat some patients who have advanced prostate cancer or gastroenteropancreatic neuroendocrine tumor GEP-NET. This type of treatment may also be referred to as molecular radiotherapy. For some people, radiation may be the only treatment you need. But, most often, you will have radiation therapy with other cancer treatments, such as surgery , chemotherapy , and immunotherapy. Radiation therapy may be given before, during, or after these other treatments to improve the chances that treatment will work.
The timing of when radiation therapy is given depends on the type of cancer being treated and whether the goal of radiation therapy is to treat the cancer or ease symptoms.
There is a limit to the amount of radiation an area of your body can safely receive over the course of your lifetime. Depending on how much radiation an area has already been treated with, you may not be able to have radiation therapy to that area a second time.
But, if one area of the body has already received the safe lifetime dose of radiation, another area might still be treated if the distance between the two areas is large enough. Radiation not only kills or slows the growth of cancer cells, it can also affect nearby healthy cells.
Damage to healthy cells can cause side effects. Radiation therapy can be expensive. It uses complex machines and involves the services of many health care providers. The exact cost of your radiation therapy depends on the cost of health care where you live, what type of radiation therapy you get, and how many treatments you need. Talk with your health insurance company about what services it will pay for.
Most insurance plans pay for radiation therapy. To learn more, talk with the business office at the clinic or hospital where you go for treatment. If you need financial assistance, there are organizations that may be able to help. To find such organizations, go to the National Cancer Institute database, Organizations that Offer Support Services and search for "financial assistance.
Radiation can cause side effects that make it hard to eat, such as nausea , mouth sores, and throat problems called esophagitis. Since your body uses a lot of energy to heal during radiation therapy, it is important that you eat enough calories and protein to maintain your weight during treatment. If you are having trouble eating and maintaining your weight, talk to your doctor or nurse. You might also find it helpful to speak with a dietitian. For more information about coping with eating problems see the booklet Eating Hints or read more about side effects.
Some people are able to work full-time during radiation therapy. Others can work only part-time or not at all. How much you are able to work depends on how you feel. Ask your doctor or nurse what you may expect from the treatment you will have. You are likely to feel well enough to work when you first start your radiation treatments. As time goes on, do not be surprised if you are more tired, have less energy, or feel weak. Once you have finished treatment, it may take just a few weeks for you to feel better—or it could take months.
You may get to a point during your radiation therapy when you feel too sick to work. Talk with your employer to find out if you can go on medical leave. Check that your health insurance will pay for treatment while you are on medical leave. Menu Contact Dictionary Search. Understanding Cancer. What Is Cancer? Cancer Statistics. Cancer Disparities. Cancer Causes and Prevention. Risk Factors. Cancer Prevention Overview.
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