Indian Journal of Oral Health and Research

REVIEW ARTICLE
Year
: 2021  |  Volume : 7  |  Issue : 1  |  Page : 1--6

Role of radiosensitizers, radioprotectors, and radiation mitigators in radiation therapy


Kanica Sharma, Neelkant Patil, Mohit Sareen, Nitesh Tyagi 
 Department of Oral Medicine and Radiology, Rajasthan Dental College and Hospital, Jaipur, Rajasthan, India

Correspondence Address:
Dr. Kanica Sharma
Vill- Bishangarh, P.O. - Bhogpur, Dehradun, Uttarakhand
India

Abstract

Radiation is used in the treatment of a broad range of malignancies. Exposure of normal tissues to radiation may result in both acute and chronic toxicities that can result in an inability to deliver the intended therapy, a range of symptoms, and a decrease in the quality of life. Radiation therapy kills cancer cells by damaging their deoxyribonucleic acid. There are different types of radiation therapy for different malignancies. Radiation therapy can also deteriorate the normal cells, leading to side effects. A radiation countermeasure that can be used before radiation exposure to protect the population from the harmful effects of radiation exposure remains a major unmet medical need and is recognized as an important area for research. There are certain compounds that act to increase the radiosensitivity of tumor cells or to protect the normal cells from the effect of radiation termed as radiosensitizers and radioprotectors. Other agents termed mitigators may be used to minimize toxicity even after radiation has been delivered. The aim of this article is to critically review the available compounds used as radiosensitizers, radioprotectors, and mitigators for different types of cancers.



How to cite this article:
Sharma K, Patil N, Sareen M, Tyagi N. Role of radiosensitizers, radioprotectors, and radiation mitigators in radiation therapy.Indian J Oral Health Res 2021;7:1-6


How to cite this URL:
Sharma K, Patil N, Sareen M, Tyagi N. Role of radiosensitizers, radioprotectors, and radiation mitigators in radiation therapy. Indian J Oral Health Res [serial online] 2021 [cited 2021 Oct 17 ];7:1-6
Available from: https://www.ijohr.org/text.asp?2021/7/1/1/321117


Full Text

 Introduction



Radiation therapy is one of the most effective tools against the treatment of cancer. High doses of radiations are used in the radiation therapy to halt growth of tumor. Ionizing radiation (IR), such as X-rays and gamma-rays, is commonly used for the treatment of cancer because it has the ability to pass through the tissues and can break chemical bonds and help in the removal of electrons from the atoms to get ionized. The ionized ions as a result damage cancer cell. Cancer cells are not killed immediately by IR; in fact, substantial time is required for killing of cancer cells.[1]

Local tumor failure is the cause of 40%–60% of cancer deaths and may occur in 60%–80% of cancer patients at the time of death. Efforts to improve the therapeutic ratio have resulted in the development of certain compounds that act to increase the radiosensitivity of tumor cells or to protect the normal cells from the effects of radiation.[2]

Deoxyribonucleic acid (DNA) lesions may result from direct damage, following the interaction of photons or ionizing particles with DNA itself, or indirect damage, which occurs through the generation of reactive-oxygen species (ROS), particularly hydroxyl radicals formed by the radiolysis of water, which may then react with DNA [Figure 1].{Figure 1}

Based on the intimate relationship between tumors and their normal host tissues and surrounding critical structures and the need to irradiate clinically uninvolved normal tissue margins that are potentially contaminated with microscopic disease, it is anticipated that normal tissue toxicity will remain a concern for therapeutic radiation. An alternative mechanism to reduce normal tissue toxicity is the use of radiation modifiers/protectors, agents that when present before or shortly after radiation exposure alter the response of normal tissues to irradiation. This approach has also been viewed as an attractive countermeasure for possible nuclear/radiological terrorism. To be useful in the radiotherapy clinic, radioprotectors should ideally have several characteristics that relate to the ability of the agent to improve the therapeutic ratio.[3]

 Classification of Agents



Radiosensitizers are the agents that sensitize the tumor cells to radiation. These compounds apparently promote fixation of the free radicals produced by radiation damage at the molecular level. The mechanism of action is similar to the oxygen effect, in which biochemical reactions in the damaged molecules prevent repair of the cellular radiation damage. Free radicals such as OH + are captured by the electron affinity of the radiosensitizers, rendering the molecules incapable of repair.[4]

Radioprotectors are the compounds that are designed to reduce the damage in the normal tissues caused by radiation. These compounds are often antioxidants and must be present before or at the time of radiation for effectiveness.[3]

Agents delivered at the time of irradiation or after irradiation are complete, but prior to the manifestation of normal tissue toxicity are described as mitigators of normal tissue injury.[3]

With the increasing demand for better patient care globally, a lot of research is ongoing in the field of oral oncology regarding radio sensitizers and radioprotectors. However, the literature is scanty regarding the same. Hence, this article tries to discuss the various aspects of radio protectors, radiosensitizers, and mitigators such as mechanism of action, uses, and side effects of these agents.

 Radiosensitizers



A radiosensitizer is a drug that makes tumor cells more sensitive to radiation therapy. These compounds apparently promote fixation of the free radicals produced by radiation damage at the molecular level. Radiotherapy commonly affects DNA; mainly, it leads to DNA double strand break (DSB). Hence, to target clinically developed DNA DSB repair pathways, many radio-sensitizing agents have been formulated.[1]

Radiosensitizers are compounds that sensitize the tumor cells to radiation during radiotherapy.[2] A list of radio-sensitizing agents are given in [Table 1].{Table 1}

 Hyperbaric Oxygen



Hyperbaric oxygen (HBO) therapy is the inhalation of 100% oxygen at elevated pressure > 1.5 atmospheres absolute (ATA; 150 kPa), typically 2–3 ATA (200–300 kPa). The hyperbaric chamber is the medical tool that provides those conditions to apply very high doses of oxygen in amounts that cannot be reached by any other means.[5] The physiological effects of HBO include short-term effects such as vasoconstriction and enhanced oxygen delivery, reduction of edema, and phagocytises activation, and it has an anti-inflammatory effect. Long-term effects are neovascularization, osteogenesis as well as stimulation of collagen production by fibroblasts. The clinical results are, therefore, wound healing and recovery of radiation-injured tissue.[6]

Most tumors contain nutrient- and oxygen-deprived compartments. Sterilization of hypoxic tumor cells requires a three times higher radiation dose than for cells at normal oxygen tension. HBO therapy is an effective approach to cope with the phenomenon of hypoxia by increasing the oxygen load of the tumor, and there with to enhance the response to irradiation.[7]

 Mechanism of Action



Oxygen is known to increase the radiosensitivity of cells. The reactions of oxygen with aqueous as well as organic-free radicals induced by IR s may lead to the production of very toxic and relatively stable peroxy radicals and hydrogen peroxide resulting in the damage to bio molecules and structures. Therefore, the simplest approach to enhance the radio sensitivity of hypoxic tumor cells would be to increase the oxygen tension in the tumor.[8]

Subsequent studies showed an increase in the 5-year survival of patients with cancers of uterine cervix and head and neck. HBO has been observed to be effective in relatively small tumors, whereas the advanced tumors do not show an increased radio sensitization.[2]

 Carbogen



The notion of improving tumor oxygenation by breathing highly oxygenated air has been revived recently by experiments in which participants breathe carbogen, a mixture of 95% oxygen and 5% carbon dioxide that does not produce vasoconstriction associated with breathing 100% oxygen. Breathing carbogen at atmospheric pressure is an attempt to overcome chronic (diffusion limited) hypoxia through much simpler means than the use of hyperbaric chambers.[9]

 Nicotinamide



Nicotinamide is the amide of vitamin B3. Acute hypoxia within tumors arises from intermittent closure of blood vessels, resulting in fluctuations in the tumor microcirculation. Nicotinamide overcomes acute hypoxia by reducing these changes in the microcirculation.

Furthermore, when nicotinamide is combined with carbogen, additional tumor sensitivity to radiation has been demonstrated, with overall enhancement ratios of between 1.8 and 2.1 in animal models using clinically relevant dose schedules of 2 Gy day-'. It has therefore been proposed that the combination of carbogen and nicotinamide provides the optimal means of overcoming tumor hypoxia.[10]

Dosage administered in the tablet form to patients with advanced head and neck and non-small cell lung carcinomas. A standard 6 g dose given regardless of body weight after an overnight fast and at least 30 min before breakfast.[11]

After platinum-containing compounds, ruthenium-based complexes represent the group of metallocomplexes that have been most heavily studied for anticancer activity. The cellular mechanism of action for a representative molecule from this class was found to be G1 arrest accompanied by activation of p53/p21 DNA damage signalling pathways 72, and the majority of complexes induce high levels of apoptosis at low micromolar doses.

 Radioprotectors



Radioprotectors are the agents that are used to reduce the deterioration of normal cells during irradiation. Antioxidants may also act as radioprotector, and they must be present before or at the time of radiation for effectiveness.[1] Radioprotectors are the chemical compounds that protect the nontumor (normal) cells from radiation during radiotherapy.[2]

A list of radioprotectors is given in [Table 2].{Table 2}

 Amifostine: A Radioprotector in Use Clinically



Amifostine is a phosphorothioate that is not taken into cells until it is dephosphorylated by alkaline phosphatase.[12] Once dephosphorylated the agent freely diffuses into cells and can act as a free radical scavenger. Amifostine has been shown to concentrate more rapidly in normal tissues than in tumor tissues in studies of tumor-bearing animals, which is thought to result from several factors, including the effects of tumor blood flow, the acidosis of tumors, and the lower expression of alkaline phosphatase.[13]

 Mechanism of Action



It is actually a pro-drug, which cannot readily permeate cell membranes. Amifostine on administration undergoes metabolism and gets converted into WR-1065, which can readily permeate the cell membrane[14] [Figure 2].{Figure 2}

Other functions of Amifostine-cytotoxic effects of chemotherapeutic agents, nephrotoxicity, ototoxicity and neuropathy associated with cisplatin, hematologic toxicity with cyclophosphamide.[15]

Side effects of this agent include nausea, vomiting, and hypotension. Clinical trials with patients receiving head and neck, thoracic, and pelvic radiation therapy are ongoing.[2]

 Nitroxides



Nitroxides are among the most promising agents for future use as radiation protectors. Although a number of these agents are useful in the laboratory as radiation protectors, not all have the requisite characteristics that allow them to be used clinically.[16]

Laboratory studies have shown that stable nitroxide-free radicals and their one-electron reduction products, hydroxyl amines, are recycling antioxidants that protect cells when exposed to oxidative stress, including superoxide and hydrogen peroxide. Similarly, preclinical studies have shown that the oxidized form of a nitroxide is a radio protector in both in vitro (cell survival) and in vivo (lethal total body radiation) models. Although the hydroxylamine exhibits antioxidant activity, it is incapable of protecting against radiation damage. The lead compound from this class for radioprotection is Tempol.[2]

Tempol protects against radiation-induced damage to salivary glands and does not alter tumor growth after irradiation suggesting that delivery of the agent before irradiation would not alter tumor control. Tempol also protected salivary glands from radiation-induced damage, but did not protect the tumor tissue, suggesting that delivery of the agent before irradiation would not alter tumor control.[2]

 Antioxidants as Radio Protectors



Antioxidant agents, such as Vitamin A, C, and E, offer protective properties against radiation because deleterious effects of radiation mimic the oxidative damage associated with active oxygen toxicity. Selenium (as Na2SeO3) and Vitamin E have been reported to act alone and in an additive form as radio-protective and chemo-preventive agents.[17] A number of trials have been performed with antioxidants delivered during the course of radiotherapy, with the goal of reducing normal tissue toxicity, in many instances with promising results. For example, antioxidants have been delivered concurrently during the course of radiotherapy to reduce xerostomia, mucositis, pulmonary fibrosis, cystitis, and alopecia.[2]

 Vitamin E



Vitamin E (alpha tocopherol) and related analogs are nutraceuticals that can scavenge singlet oxygen and superoxide anion radicals A water-soluble Vitamin E derivative, tocopherol monoglucoside (TMG), was reported to be very effective in protecting DNA both in vitro and also in mice after oral or intraperitoneal administration against gamma irradiation. TMG ([2-a-D-glucopyranosyl] methyl-2,5,7,8-tetramethylchroman-6-ol), was efficient when administered immediately after radiation exposure at a dose of 600 mg/kg. The treatment decreased radiation-induced abnormal metaphases in mouse bone marrow chromosomes and reduced the frequency of micronucleated erythrocytes at 24 h after exposure to radiation.[17]

 Herbal Radio-Protectors



The majority of synthetic radio protectors have limited clinical application owing to their side effects and inherent toxicity. Therefore, natural herbal radio protectors, such as Ginkgo biloba, Chagas mushroom, green tea (polyphenols), dithiolthiones, Panax ginseng, Shigoka extract, and Spirulina platensis, have become an important alternative. The proposed radio-protective efficacy of plant products is due to their containing a large number of active constituents, such as antioxidants, immunostimulants, and compounds with antimicrobial activity.[18]

The doses of herbal preparations that were effective in protecting against irradiation were significantly lower than the toxic dose of synthetic compounds, and this is one of the major advantages of these agents compared to synthetic compounds. The use of plants as radio protectors has some disadvantages, such as low to mild efficacy and a short protective time-window (in most cases 30 min to 2 h before irradiation).[2]

 Superoxide Dimutase



IR results in the formation of superoxide radicals that are highly reactive and potentially damaging to cells. Superoxide dismutases (SOD) is an enzyme that is naturally present in human cells. It catalyzes the conversion of superoxide to oxygen and hydrogen peroxide and functions as an antioxidant during the normal conditions and after radiation. SOD as a radioprotector has used gene therapy to increase the levels of SOD in tissues to be irradiated to prevent or decrease radiation-induced mucositis, esophagitis, pneumonitis, and fibrosis in animal models.[19],[20]

 Melatonin



Melatonin (N-acetyl-5-methyloxytryptamine), a pineal gland hormone involved in regulating the neuroendocrine axis, is a highly efficient free-radical scavenger and antioxidant. Melatonin has been reported to be a direct free-radical scavenger and an indirect antioxidant through its stimulative effects on antioxidant enzymes, such as SOD, GSH-Px, glutathione reductase, and catalase.[17]

The use of melatonin as a radiation sensitizer for tumor cells and as a radioprotector for normal cells was tested clinically in a phase II Radiation Therapy Oncology Group trial. In that study, patients were randomized to either morning-or night-time high-dose melatonin during radiotherapy. Melatonin was continued after radiotherapy until progression or until 6 months.[2]

 Novel Oral Radio protectors



For convenience and simple administration, the development of an effective orally administered radio-protective agent is highly desirable. One particular class of immunomodulators that has been relatively well developed and studied is 5-androstene steroids, whose archetype species is 5-androstene-3b, 17b-diol (5-AED), a natural steroid hormone produced in the adrenal cortex. Multiple efficacy studies have demonstrated the hematopoietic stimulation properties of 5-AED administered by subcutaneous injection before or after irradiation. In humans, 5-AED induces elevation of blood neutrophil and platelet counts, and in mice, it causes significant increases in the levels of granulocyte colony-stimulating factor and interleukin 6.[21]

 Radiation Mitigators



Radiation-induced late normal tissue toxicity is increasingly being appreciated as a phenomenon of ongoing changes in tissue after radiation but before the manifestation of cascades that can lead to vascular damage, tissue hypoxia, and excessive extracellular matrix deposition.[22] Radiation mitigators can be agents delivered during or shortly after exposure to repopulate a critical cell compartment such as the mucosa or bone marrow. In this instance, the mitigator is used to prevent acute toxicity. For radiologic terrorism and space research, much of the focus of mitigators have been in the field of developing chemo preventatives to reduce carcinogenesis of total body exposures.[2]

 Keratinocyte Growth Factor



KGF is a growth factor that stimulates a number of cellular processes such as differentiation, proliferation, DNA repair, and detoxification of ROS.[3]These properties make KGF an attractive method to stimulate the recovery of mucosa after IR. These properties make KGF an attractive method to stimulate the recovery of mucosa after IR. Accordingly, delivery of KGF in animal models prevents radiation-induced xerostomia and mucositis.[3]

 Palifermin



Palifermin is a recombinant human KGF that is approved for use in decreasing the incidence and duration of severe oral mucositis in patients with hematologic malignancies who receive high doses of chemotherapy and radiation therapy followed by stem cell rescue. The success of palifermin in patients with mucositis after cytotoxic therapy led to attempts to evaluate its use in patients with head and neck cancers receiving chemoradiotherapy, in whom mucositis can be severe and prolonged. The success of palifermin in patients with mucositis after cytotoxic therapy led to attempts to evaluate its use in patients with head and neck cancers receiving chemoradiotherapy, in whom mucositis can be severe and prolonged.[23]

 Transforming Growth Factor and Halofuginone



Transforming growth factor beta (TGF-γ) plays a critical role in the development of radiation-induced fibrosis. It is therefore not surprising that many of the agents that have been used to prevent the development of radiation fibrosis directly or indirectly inhibit the TGF-γ signalling pathway. TGF-γ receptor inhibition has shown the ability to prevent lung fibrosis after radiation exposure in the animal models. An alternative mechanism is the use of halofuginone, a small molecule that inhibits TGF-γ signalling, which has been shown in animal models to inhibit radiation-induced fibrosis.[3]

 Angiotensin Converting Enzyme Inhibitor



ACE inhibitors have been shown to mitigate radiation-induced lung injury in the preclinical models. The exact mechanisms of action have not been completely elucidated. ACE inhibitors may decrease the incidence of radiation pneumonitis in patients receiving thoracic radiation. These findings are consistent with preclinical evidence and should be prospectively evaluated.[24]

 Cyclooxygenase-2 Inhibitors/Nonsteroidal Anti-Inflammatory Drugs



Cyclooxygenase-2 (COX-2) is associated with ROS production and inflammatory signs in normal tissues. These effects further amplify radiation toxicity in irradiated cells as well as adjacent cells through a phenomenon known as Bystander effect. Increased COX-2 expression in distant nonirradiated tissues causes oxidative DNA damage and elevated cancer risk. Moreover, in tumors, the activation of this enzyme can increase the resistance of malignant cells to radiotherapy. Hence, the inhibition of COX-2 has been proposed for better therapeutic response and amelioration of normal tissues. Celecoxib is one of the most studied COX-2 inhibitors for radio sensitization and radioprotection, while some other inhibitors have shown interesting results.[25]

 Conclusion



Radiation therapy is frequently used in the definitive management and palliative care of patients with cancer. These agents termed as radiosensitizers and radioprotectors have a special role in the treatment of malignancies by radiotherapy. The novel agents are exhibiting promising results. In majority of instances, the success rate of radiotherapy is related to radiosensitizers and the patient's quality of life is dependent on the radioprotectors and radiation mitigators. The emerging application of new compounds such as nanoparticles as radiosensitizers and a steroid as a radioprotector and mitigator helps to reduce the cancer death.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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