| |
|
|
| Year : 2014 | Volume
: 25
| Issue : 1 | Page : 83-90 |
|
| Radiosensitizers, radioprotectors, and radiation mitigators |
|
|
Jayam Raviraj1, Vijay Kumar Bokkasam1, Venkata Suneel Kumar2, Uday Shankar Reddy3, Venkata Suman1
1 Department of Oral Medicine and Radiology, CKS Theja Dental College, Hospital and Research Centre, Tirupati, Andhra Pradesh, India
2 Department of Oral Medicine and Radiology, Narayana Dental College and Hospital, Nellore, Andhra Pradesh, India
3 Department of Oral Medicine and Radiology, Pulla Reddy Dental College and Hospital, Kurnool, Andhra Pradesh, India
Click here for correspondence address and email
| Date of Submission | 25-Apr-2012 |
| Date of Decision | 25-Jan-2013 |
| Date of Acceptance | 16-Jan-2014 |
| Date of Web Publication | 21-Apr-2014 |
|
|
 |
|
 Abstract | | |
Radiotherapy is regarded as one of the most important therapeutic modality for the treatment of malignant lesions. This field is undergoing rapid advancements in the recent times. With the use of radiosensitizers and radioprotective agents, the course of radiotherapy has improved the sensitization of tumor cells and protection of normal cells, respectively. The aim of this paper was to critically review and analyze the available compounds used as radiosensitizers, radioprotectors, and radiation mitigators. For reviewing, the author used the electronic search for the keywords 'Radiosensitizers', 'Radioprotectors', 'Radiation mitigators' on PubMed for inclusion of previously published articles and further search of reference papers on individual radiosensitizing and radioprotecting agents was done. Radiosensitizers are 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. Radioprotectors are compounds that are designed to reduce the damage in normal tissues caused by radiation. These compounds are often antioxidants and must be present before or at the time of radiation for effectiveness. Other agents, termed mitigators, may be used to minimize toxicity even after radiation has been delivered. This article tries to discuss the various aspects of radiosensitizers, radioprotectors, and radiation mitigators including the newer agents. Keywords: Radiation mitigators, radioprotectors, radiosensitizers, radiotherapy
How to cite this article:
Raviraj J, Bokkasam VK, Kumar VS, Reddy US, Suman V. Radiosensitizers, radioprotectors, and radiation mitigators. Indian J Dent Res 2014;25:83-90 |
How to cite this URL:
Raviraj J, Bokkasam VK, Kumar VS, Reddy US, Suman V. Radiosensitizers, radioprotectors, and radiation mitigators. Indian J Dent Res [serial online] 2014 [cited 2023 Sep 23];25:83-90. Available from: https://www.ijdr.in/text.asp?2014/25/1/83/131142 |
The goal of radiation therapy is to achieve maximum tumor cell killing while minimizing injury to normal tissues (therapeutic ratio). Local tumor failure is the cause of 40% to 60% of cancer deaths and may occur in 60% to 80% of cancer patients at the time of death. [1] 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.
The objective of successful radiation therapy, therefore, is to maximize the radiation damage in tumor cells and at the same time minimize the same in normal cells. This may be possible either by better localization of radiation dose or by using differential radioprotectors for normal cells and/or radiosensitizers of tumor cells.
Radiosensitizers are 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. [2]
Radioprotectors are compounds that are designed to reduce the damage in normal tissues caused by radiation. These compounds are often antioxidants and must be present before or at the time of radiation for effectiveness. Other agents, termed mitigators, may be used to minimize toxicity even after radiation has been delivered. [3]
For reviewing, the author used the electronic search for the keywords 'Radiosensitizers', 'Radioprotectors', and 'Radiation mitigators' on PubMed for inclusion of previously published articles and further search of reference papers on individual radiosensitizing and radioprotecting agents was done.
With the increasing demand for better patient care globally, a lot of research is ongoing in the field of oral oncology regarding radiosensitizers and radioprotectors. However, the literature is scanty regarding the same. Hence, this article tries to discuss the various aspects of radioprotectors and radiosensitizers like mechanism of action, clinical trials, and side effects of these agents.
Radiosensitizers are compounds that sensitize the tumor cells to radiation during radiotherapy. A list of radiosensitizing agents are given in [Table 1].
| Hyperbaric Oxygen | |  |
Oxygen is known to increase the radiosensitivity of cells. The reactions of oxygen with aqueous as well as organic-free radicals induced by ionizing radiations may lead to the production of very toxic and relatively stable peroxy radicals and hydrogen peroxide resulting in the damage to biomolecules and structures. Therefore, the simplest approach to enhance the radiosensitivity of hypoxic tumor cells would be to increase the oxygen tension in the tumor. First clinical trials by keeping the patient in a high-pressure oxygen tank just before tumor irradiation were carried out by Churchill-Davidson and Foster, et al. [4] Subsequent studies showed an increase in the 5-year survival of patients with cancers of uterine cervix [5] and head and neck. [6] Hyperbaric oxygen has been observed to be effective in relatively small tumors, whereas the advanced tumors do not show an increased radiosensitization. [7],[8] The procedure of putting the patient in high-pressure oxygen tank during every fraction is, however, cumbersome and increases complications.
| Carbogen | | |
The notion of improving tumor oxygenation by breathing highly oxygenated air has been revived recently by experiments in which subjects 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 | | |
Hypoxic cell radiosensitizers such as the nitro-imidazoles were designed primarily to overcome chronic hypoxia that is diffusion-limited hypoxia resulting from the inability of oxygen to diffuse further than 100 μm through respiring tissue. However, hypoxia also arises through acute mechanisms (intermittent blockage of blood vessels). Nicotinamide, a B3 analog, has been shown in mouse tumors to prevent the transient fluctuations in tumor blood flow that lead to the development of acute hypoxia.
The combination of nicotinamide to overcome acute hypoxia with carbogen breathing to overcome chronic hypoxia is the basis of the trials underway in several European centers. [9]
| Metronidazole and its Analogs | | |
The knowledge of oxygen effect led to the development of compounds that mimic the radiosensitizing property of oxygen. Radiosensitizing abilities of the hypoxic cell sensitizers have been observed to correlate with electron affinity. [10] Metronidazole and its analogues such as misonidazole, etanidazole, and nimorazole have been found to be effective in sensitizing hypoxic tumor cells. [11],[12]
The 'oxygen fixation' hypothesis has been proposed to explain the mechanism of action of this class of sensitizers. [13],[14],[15] They fix the radiation damage by preventing the chemical restitutions of free radicals. Misonidazole has been observed to deplete sulfhydral groups in cells, inhibit glycolysis and the repair of radiation-induced cellular potentially lethal damage. [16] Clinical trials with misonidazole have shown side effects in the form of peripheral neuropathy, convulsions, and encephalopathy. [17]
Etanidazole has been tested with encouraging results in early phase II and III trials. This member of the nimorazole group of compounds appears to be less toxic to CNS tissue than misonidazole and crosses the blood-brain barrier in limited quantity. A phase III study of this agent showed an increase survival in the 2-year local control in N0 and N1 disease with 55% in the etanidazole arm and 37% in the radiation-alone arm. [18]
Nimorazole is a member of the same structural class as metronidazole but is less toxic allowing for higher doses. A phase III study of nimorazole versus placebo in subjects with squamous cell carcinoma of the supraglottic larynx and pharynx demonstrated a statistically significant difference in improvement of loco-regional control at 5-year post-treatment. [19] In phase II, the study of nimorazole in patients with stage 3 or 4 squamous cell carcinoma of head and neck who received continuous hyperfractionated accelerated radiation therapy (CHART), it was found that local control rates were higher than in other studies using CHART, suggesting a positive effect of nimorazole.
| Hypoxic Cell Cytotoxic Agents | | |
Hypoxic cell cytotoxic agents include Mitomycin-C and Tirapazamine. Mitomycin-c is a bioreductive alkylating agent that has been studied in pancreatic and head and neck cancer. Tirapazamine is another bioreductive agent that is preferentially cytotoxic to hypoxic cells in vitro. It differs from oxygen mimetic sensitizers in which it requires metabolic activation and enhancement is seen when this agent is given prior to or after radiotherapy. [20] Studies in lung and head and neck cancer have shown positive results. Side effects include nausea, muscle cramps, and hematologic toxicities. [21] While under hypoxic conditions tirapazamine is reduced to a highly reactive radical that produces strand breaks in the DNA, under aerobic conditions, the radical is back-oxidized to the nontoxic parent compound with a concomitant production of the superoxide radical, which is much less toxic than the tirapazamine radical. Phase II trials with tirapazamine in combination with radiotherapy and/or cisplatin have been performed primarily in carcinomas of the head, neck, and lung. The results of the trials indicate that tirapazamine can improve outcome in advanced carcinomas when combined with cisplatin monotherapy. [22],[23]
| Membrane Active Drugs | | |
Cell membranes, besides DNA, could also be critical targets for cell killing. [24] Membrane-specific drugs, such as local anesthetic (procaine and lidocaine hydrochloride) and tranquilizers, for example chlorpromazine etc., interact with cell membranes and alter their structural and functional organization. These drugs were observed to increase the radiosensitivity of bacterial cells ( Escherichia More Details coli) under hypoxic conditions. [25] Membrane-specific drugs have been observed to enhance radiosensitivity of hypoxic mouse lymphoma cells and radioprotect these cells under euoxic conditions. Inhibition of the rejoining of radiation induced DNA strands breaks by chlorpromazine has been observed in mammalian and human cancer cells. [26]
| Radiosensitizing Nucleosides | | |
Fluoropyrimidines
5-Fluorouracil (FUra) and Fluorodeoxyuridine (FdUrd) are analogues of uracil and deoxyuridine, respectively. Randomized trials have demonstrated local control and survival advantages with systemic FUra and radiation compared with radiation alone in patients with rectal cancer, esophageal cancer, and pancreatic cancer. [27]
FUra and FdUrd, through their metabolites lead to cell cycle redistribution, DNA fragmentation, and cell death. [28] Whereas clinically achievable concentrations of FdUrd produce only DNA-mediated cytotoxic effects, FUra can also kill cells by RNA-dependent mechanisms. [29]
Thymidine analogs
The thymidine analogs bromodeoxyuridine (BrdUrd) and iododeoxyuridine (IdUrd) have been used as radiosensitizers in the treatment of a number of cancers including head and neck cancers, [30] malignant gliomas, brain metastases, soft tissue sarcomas, intrahepatic cancers, and cervical cancers.
BrdUrd and IdUrd produce radiosensitization by incorporation into DNA. Their incorporation increases the susceptibility of the DNA to single-strand breaks from radiation-produced free radicals. [31] Analog incorporation produces both an increase in radiation-induced DNA damage and a decrease in the rate of DNA repair.
However, the toxic side effects such as myelosuppression and normal tissue toxicity within the radiation field have been observed. [32]
Hydroxyurea
Although hydroxyurea is not a nucleoside analog, its primary mechanism of cytotoxicity is related to its inhibition of ribonucleotide reductase, a key enzyme for the transformation of ribonucleotides to deoxyribonucleotides. Its role in the treatment of hematologic malignancies and myeloproliferative disorders is well established. [33] The use of hydroxyurea as a radiosensitizer has been investigated in the clinic since the 1960s in patients with head and neck cancer, [34] malignant glioma, and cervical cancer. Since hydroxyurea has little or no activity as a chemotherapeutic agent in patients with advanced squamous cell carcinoma of the cervix, it has been assumed that any positive result would represent radiosensitization rather than additive effects.
Gemcitabine
Gemcitabine is an analog of deoxycytidine that has demonstrated effectiveness as a single agent against solid tumors, including pancreatic cancer, non-small-cell lung cancer, head and neck cancer, [35] and breast cancer. The mechanism by which gemcitabine radiosensitizer tumor cells is not yet clear. Our preliminary studies indicate that the observed radiosensitization is not associated with either an increase in the radiation-induced DNA double-strand breaks or with a slowing of DNA double-strand break repair. This suggests that radiosensitization by gemcitabine is unlike that produced by the fluoropyrimidines and the thymidine analogs. The relationships between gemcitabine radiosensitization and DNA incorporation, alterations in DNA synthesis, or alteration in cell cycle kinetics remain to be investigated. In addition, it would be logical to investigate the role of apoptosis in gemcitabine-mediated radiosensitization, since this mechanism of cell death has been shown to be the pathway by which the drug exerts its cytotoxic action, at least in lymphoid cell lines. [36]
Fludarabine
Fludarabine is a well-studied DNA damage repair inhibitor. [37] The incorporation of the corresponding nucleotides into DNA results in potent inhibition of DNA synthesis. Fludarabine has clinical activity against hematologic cancers such as chronic lymphocytic leukemia and follicular non-Hodgkin's lymphoma. [38] The mechanism of cytotoxicity has been attributed to inhibition of enzymes critical for DNA synthesis and repair, including DNA polymerases, ribonucleotide reductase, DNA primase, and DNA ligase. [39] Incorporation of fludarabine at the DNA chain terminus results in gene deletions and increased mutational frequency. Fludarabine also inhibits RNA synthesis and induces apoptosis.
| Motexafin Gadolinium | | |
Motexafin gadolinium, which is currently being studied in clinical trials, is the first in a class of pharmaceuticals known as texaphyrins to reach human testing. Texaphyrins accumulate inside cancer cells due to their high rate of metabolism and induce programmed cell death. A phase-1 study of patients who are receiving hyperfractionated irradiation and concurrent 5-flourouracil/cisplatin for head and neck cancer reported interim results recently. [40] Nine of the ten evaluable patients demonstrated a complete tumor response and eight of these remained in complete remission with a median follow-up of 1 year. Side effects reported include mucositis and radiation dermatitis. A randomized phase III trial is currently investigating the use of motexafin in patients with brain metastases who receive whole body radiation therapy. [40],[41]
| Suppressors of Sulfhydral Groups | | |
Intracellular compounds containing sulfhydral (thiol) groups are known to protect biomolecules against radiation damage. The depletion of intracellular thiol groups may therefore increase the radiosensitivity of cells. N-Ethylmalemide, diamide, and diethylmaleate have been observed to lower the intracellular glutathione content, which is the major intracellular sulfhydral compound. [42] The depletion of intracellular glutathione content may increase the radiation sensitivity of cells [42] due to a reduction in the radioprotective reaction. Decrease in the glutathione content has also been observed to correlate with inhibition of repair of DNA single strand breaks, induced under aerobic conditions.
| Hyperthermia | | |
Hyperthermia alone or in combination with ionizing radiation has been used in the treatment of radioresistant tumors. It has been observed to enhance cell killing. [43] Cells with higher radioresistance such as chronically hypoxic cells with a low intracellular Ph, and those in S-phase of cell cycle are more susceptible to thermal killing and radiosensitization. [44] Hyperthermia could lead to radiosensitization of cells by the following mechanisms:
· Elevated temperatures increase the fluidity of membranes and this critically determines survival after thermal insult [45]
· Inhibition of energy metabolism
· Inhibition of macromolecular (DNA, RNA, and protein) synthesis
· Inhibition of DNA repair as well as the repair of sublethal, [46] and potentially lethal cellular damage.
| Novel Radiosensitizers | | |
Taxanes
This group of anticancer agents have a novel mechanism of action, broad clinical activity, and potential as clinical radiosensitizers. Paclitaxel is the prototype of taxanes. Docetaxel is another agent in this group. Paclitaxel may be the most efficacious single chemotherapy agent for head and neck cancer with a 40% response rate for patients with recurrent disease. As it is possible to achieve durable control with radiotherapy of locally advanced head and neck cancer in only a minority of cases, chemotherapy drugs, such as paclitaxel, are being used with radiotherapy in an attempt to improve tumor control. Paclitaxel stabilizes microtubules and leads to accumulation of cells at the G2/mitosis phase of the cell cycle, which is a necessary condition for its antitumor effect, and also the phase with the greatest relative radiosensitivity. Paclitaxel has been shown to be a radiosensitizer in vitro for some but not all cell lines studied. [47]
Irinotecan
It is a camptothecin derivative that is thought to exert its cytotoxic effects by targeting topoisomerase I. It is believed that irinotecan stabilizes a DNA-topoisomerase I cleavable complex, and that interactions between this complex and the replication machinery may lead to cell death. There is a significant volume of in-vitro and in-vivo data demonstrating that irinotecan acts as a radiosensitizer. The exact mechanism of this radiosensitization is currently unknown. The increasing amount of data demonstrating improved outcomes with concurrent chemoradiation treatment of malignancies like lung cancer and head and neck cancer provides impetus for pursuing the addition of other drugs as radiosensitizers to improve local control further. [48]
Radioprotectors are chemical compounds that protect the nontumor (normal) cells from radiation during radiotherapy. A list of radioprotectors is given in [Table 2].
Amifostine
Amifostine (WR-2721) is one of today's most widely studied protectors. [49] Amifostine selectively protects a broad range of normal tissues, including the oral mucosa, salivary glands, lungs, bone marrow, heart, intestines, and kidneys. 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. [50] A phase III study of patients who received radiotherapy for head and neck cancer demonstrated that those who received 200 mg/m [2] of amifostine, IVP 15-30 min prior to radiation daily, had a statistically significant decrease in acute (P < 0.001) and late (P < 0.0001) grade 2 × erostomia. Patients also experienced a statistically significant improvement (P = 0.0001) in the time of onset of grade 2 × erostomia (30 days vs 45 days). [51] Amifostine may be administered intravenously or subcutaneously and should be dosed daily before radiation therapy. Side effects of this agent include nausea, vomiting and hypotension. Amifostine was the first FDA approved radioprotector. Clinical trials with patients receiving head and neck, thoracic, and pelvic radiation therapy are ongoing. [2]
A major mechanism underlying the radioprotective effect of WR2721 is the scavenging highly reactive free radicals induced by ionizing radiation. Since damage inflicted by free radicals is a major event responsible not only for killing mammalian cells by radiation, but also for malignant transformation of these cells. [52]
Amifostine also protects against the cytotoxic effects of chemotherapeutic agents. It offers significant protection against the nephrotoxicity, ototoxicity, and neuropathy associated with cisplatin and hematologic toxicity associated with cyclophosphamide. [49]
Nitroxides
Amifostine is the only radioprotector currently in clinical use. A number of other compounds are in various stages along the pathway of clinical development as radiation protectors. Nitroxides are among the most promising agents for future use as radiation protectors.
Laboratory studies have shown that stable nitroxide-free radicals and their one-electron reduction products, hydroxylamines, are recycling antioxidants that protect cells when exposed to oxidative stress, including superoxide and hydrogen peroxide. [53] Likewise, preclinical studies have shown that the oxidized form of a nitroxide is a radioprotector in both in vitro (cell survival) and in vivo (lethal total body radiation) models. [54] Although the hydroxylamine exhibits antioxidant activity, it is incapable of protecting against radiation damage. The lead compound from this class for radioprotection is Tempol.
Tempol protects against radiation-induced damage to salivary glands and does not alter tumor growth after irradiation suggesting that delivery of the agent prior to irradiation would not alter tumor control. [55] In the oxidized form, tempol is paramagnetic and provides T1 contrast on magnetic resonance imaging (MRI). [56] Because of this unique property, the active, radioprotective form of tempol can therefore be followed temporally using MRI. Tumors were grown on the neck region of a mouse that would allow a single MRI slice to include the tumor, salivary gland area, and normal leg muscle. These preclinical findings provide feasibility to evaluate tempol as a radioprotector in clinical trials for cancer patients treated with radiation. Coupling MRI with such a trial would permit a novel dimension that could provide extremely important information with respect to the timing of tempol administration and radiation treatment.
Other antioxidants
With the understanding that free radicals perpetuate a significant amount of the damage caused by ionizing radiation, multiple vitamin antioxidants have been tested as a method to reduce the toxicity of radiotherapy. Antioxidant compounds such as glutathione, lipoic acid, and the antioxidant vitamins A, C, and E have been evaluated in this context. A great deal of preclinical and clinical information has been accumulated that describes the effects of combining radiotherapy with antioxidants. In general, the efficacy of these naturally occurring agents as radioprotectors is less than that for the synthetic agents previously described. One of the major concerns with the use of supplemental nutritive antioxidants or other antioxidants during the course of radiotherapy is the possibility of tumor protection through nonselective free radical scavenging. As described earlier for agents such as amifostine, selective uptake, or activity in tumor tissue is essential to realize a gain in the therapeutic ratio.
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, [57] mucositis, pulmonary fibrosis, cystitis, and alopecia.
Unfortunately, the use of antioxidant vitamins, such as alpha-tocopherol and beta carotene, during the course of radiotherapy was associated with evidence of poorer tumor control in randomized trials. [58] The lower toxicity associated with the use of these agents is appealing, but not at the cost of poorer tumor control. These findings reinforce the importance of preclinical testing of radioprotectors to verify a lack of tumor protection. Topical application has been used to minimize the possibility of systemic absorption and interference with tumor response to radiation; however, caution is advised because even topical applications for the prevention of mucositis in head and neck cancers have been associated with evidence of poorer tumor control. [59]
When discussing antioxidants as radioprotectors, it is worth mentioning the use of superoxide dismutase (SOD) as a method to prevent radiotherapy-induced toxicity. Ionizing radiation results in the formation of superoxide radicals that are highly reactive and potentially damaging to cells. 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 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, [60] esophagitis, pneumonitis, and fibrosis in animal models.
Melatonin
Melatonin is thought to act as an antioxidant itself, but also acts to increase the expression of antioxidant enzymes such as SOD and glutathione peroxidase. [61] Radioprotection with melatonin and melatonin analogs has been documented in a number of animal models. Importantly, melatonin has also been shown to have direct antitumor effects and has been described as a radiation sensitizer for tumors in animal models. 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. [62] 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.
Novel radioprotectors
Tetracyclines and fluoroquinolones, which share a common planar ring moiety, were found to be radioprotective by Kwanghee Kim et al. 2009. [63] Tetracycline protected murine hematopoietic stem and progenitor cell populations from radiation damage and allowed 87.5% of mice to survive when given before and 35% when given 24 h after lethal TBI. Interestingly, tetracycline did not alter the radiosensitivity of Lewis lung cancer cells. Tetracycline and ciprofloxacin also protected human lymphoblastoid cells, reducing radiation-induced DNA double-strand breaks by 33% and 21%, respectively. The effects of these agents on radiation lethality are not due to the classic mechanism of free radical scavenging but potentially through activation of the Tip60 histone acetyltransferase and altered chromatin structure.
| Radiation Mitigators | | |
Radiation-induced late normal tissue toxicity is increasingly being appreciated as a phenomenon of ongoing changes in tissue after radiation but prior to the manifestation of toxicity. These events include ongoing mitotic cell death and perpetually active cytokine cascades that can lead to vascular damage, tissue hypoxia, and excessive extracellular matrix deposition. Radiation mitigators aim to interrupt these cascades or intervene to prevent the perpetuation of damage and thus reduce the expression of toxicity. Various agents have been documented in the literature. [64],[65],[66]
Alternatively, 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 has been in the field of developing chemopreventatives to reduce carcinogenesis of total body exposures. [Table 3] enlists several promising radiation mitigators.
In conclusion, radiosensitizers and radioprotectors have a special role in the treatment of malignancies by radiotherapy. Every agent has its own application, mode of action, and adverse effects. 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.
| References | | |
| 1. | Wasserman TH, Chapman JD. Radiation response modulation. Part A. Chemical sensitizers and protectors. In: Perez CA, Brady LW, Halperin EC, Schmidt-Ullrich RK, Editors. Principles and practice of radiation oncology, 4 th ed. Philadelphia: Lippincott Williams and Wilkins; 2004. p. 663-98. 
|
| 2. | Gosselin-Acomb TK. Principles of radiation therapy. In: Yarbro CH, Goodman M, Frogge MH, editors. Cancer nursing: Principles and practice, 6 th ed. Sudbury: Jones and Bardett Publishers; 2005. p. 230-49.
|
| 3. | Citrin D, Cotrim AP, Hyodo F, Baum BJ, Krishna MC, Mitchell JB. Radioprotectors and Mitigators of Radiation-Induced Normal Tissue Injury. Oncologist 2010;15:360-71.
|
| 4. | Churchill-Davidson I, Foster CA, Wiernik G, Collins CD, Pizey NC, Skeggs DB, et al. The place of oxygen in radiotherapy. Br J Radiol 1966;39:321-31.
[PUBMED] |
| 5. | Dische S, Anderson PJ, Sealy R, Watson ER. Carcinoma of cervix, anaemia, radiotherapy and hyperbaric oxygen. Br J Radiol 1983;56:251-6.
[PUBMED] |
| 6. | Henk JM, Smith CW. Radiotherapy and hyperbaric oxygen in head and neck cancer. Lancet 1977;2:104-5.
[PUBMED] |
| 7. | Henk JM. Late results of a trial of hyperbaric oxygen and radiotherapy in head and neck carcinomas: A rationale for hypoxic cell sensitizers. Internat J Radiat Oncol Biol Phys 1986;12:1339-41.
|
| 8. | Rockwell S, Dobrucki IT, Kim EY, Marrison ST, Vu VT. Hypoxia and radiation therapy: Past history, ongoing research and future promise. Curr Mol Med 2009;9:442-58.
|
| 9. | Hall EJ, Cox JD. Physical and biological basis of radiation therapy. In: Cox JD, Ang KK, Editors. Radiation oncology: Rationale, technique, results. 8 th ed. Missouri: Mosby; 2003. p. 3-62.
|
| 10. | Adams GE, Dewey DL. Hydrated electrons and radiobiological sensitisation. Biochem Biophys Res Commun 1963;12:473-7.
[PUBMED] |
| 11. | Asquith JC, Foster JL, Willson RL, Ings R, McFadzean JA. Metronidazole ("Flagyl"). A radiosensitizer of hypoxic cells. Br J Radiol 1974;47:474-81.
[PUBMED] |
| 12. | Brown JM. Selective radiosensitization of hypoxic cells of mouse tumor with the mitomidazoles, metronidazole and RO-07-0582. Radiat Res 1975;64:633-47.
[PUBMED] |
| 13. | Alper T. The modification of damage caused by primary ionization of biological targets. Radiat Res 1956;5:573-86.
[PUBMED] |
| 14. | Howard-Flanders P. Effect of oxygen on the radiosensitization of bacteriophage in the presence of sulfhydryl compounds. Nature 1960;186:485-7.
[PUBMED] |
| 15. | Chapman JD, Greenstock CL, Reuvers AP, McDonald E, Dunlop I. Radiation chemical studies with nitrojurazone as related to its mechanism of radiosensitization. Radiat Res 1973;53:190-203.
[PUBMED] |
| 16. | Guichard M, Malaise EP. Radiosensitizing effects of misonidazole and SR 2508 on a human melanoma transplanted in nude mice: Influence on repair of potentially lethal damage. Int J Radiat Oncol Biol Phys 1982;8:465-8.
[PUBMED] |
| 17. | Dische S, Saunders MI, Lee ME, Adams GE, Flockhart IR. Clinical testing of radiosensitizer RO-07-0582. Experience with multiple doses. Br J Cancer 1977;35:567-79.
[PUBMED] |
| 18. | Lee DJ, Cosmatos D, Marcial VA, Fu KK, Rotman M, Cooper JS, et al. Results of an RTOG phase III trial comparing radiotherapy plus etanidazole with radiotherapy alone for locally advanced head and neck carcinomas. Int J Radiat Oncol Biol Phys 1995;32:567-76.
|
| 19. | Overgaard J, Hansen HS, Overgaard M, Bastholt L, Berthelsen A. A randomized double blind phase III study of nimorazole as hypoxic radiosensitizer of primary radiotherapy in supra-glottic larynx and pharynx carcinoma. Radiother Oncol 1998;46:135-46.
|
| 20. | Von Pawel J, Von Roemeling R, Gatzemeier U, Boyer M, Elisson LO, Clark P, et al. Tirapazamine plus cisplatin versus cisplatin in advanced non-small cell lung cancer: A report of the international CATAPULT study group, cisplatin and tirapazamine in subjects with previously untreated non-small cell lung tumors. J Clin Oncol 2000;18:1351-9.
|
| 21. | Lee DJ, Trotti A, Spencer S, Rostock R, Fisher C, von Roemeling R, et al. Concurrent tirapazamine and radiotherapy for advanced head and neck carcinomas: A Phase II study. Int J Radiat Oncol Biol Phys 1998;42:811-5.
|
| 22. | Kovacs MS, Hocking DJ, Evans JW, Siim BG, Wouters BG, Brown JM. Cisplatin anti-tumour potentiation by tirapazamine results from a hypoxia-dependent cellular sensitization to cisplatin. Br J Cancer 1999;80:1245-51.
|
| 23. | Treat J, Johnson E, Langer C, Belani C, Haynes B, Greenberg R, et al. Tirapazamine with cisplatin in patients with advanced non-small-cell lung cancer: A phase II study. J Clin Oncol 1998;16:3524-7.
|
| 24. | Yau TM, Kim SC. Local anaesthetics as hypoxic radiosensitizers, oxic radioprotectors and potentiators of hyperthermic killing in mammalian cells. Br J Radiol 1980;53:687-92.
[PUBMED] |
| 25. | Shenoy MA, Singh BB, Gopal-Ayengar AR. Enhancement of radiation lethality of E. coli B-r by procaine hydrochloride. Nature 1974;248:415-6.
[PUBMED] |
| 26. | Djordjevic B. Differential effect of procaine on irradiated mammalian cells in culture. Radiology 1979;131:515-9.
[PUBMED] |
| 27. | Pu AT, Robertson JM, Lawrence TS. Current status of radiation sensitization by fluoropyrimidines. Oncology 1995;9:707-14.
|
| 28. | Pinedo HM, Peters GF. Fluorouracil: Biochemistry and Pharmacology. J Clin Oncol 1988;6:1653-64.
|
| 29. | Herrick D, Kufe DW. Lethality associated with incorporation of 5-fluorouracil into preribosomal RNA. Mol Pharmacol 1984;26:135-40.
[PUBMED] |
| 30. | Epstein AH, Lebovics RS, Goffman T, Teague D, Fuetsch ES, Glatstein E, et al. Treatment of locally advanced cancer of the head and neck with 5'- iododeoxyuridine and hyperfractionated radiation therapy: Measurement of cell labelling and thymidine replacement. J Natl Cancer Inst 1994;86:1775-80.
|
| 31. | Zimbrick JD, Ward JF, Myers LS Jr. Studies on the chemical basis of cellular radiosensitisation by 5-bromouracil substitution in DNA. Int J Radiat Biol Relat Stud Phys Chem Med 1969;16:525-34.
[PUBMED] |
| 32. | Erikson RL, Szybalski W. Molecular radiobiology of human cell lines I. Comparative sensitivity to x-rays and UV light of cells containing halogen substituted DNA. Biochem Biophys Res Commun 1961;4:258-61.
[PUBMED] |
| 33. | Donehower RC. An overview of the clinical experience with hydroxyurea. Semin Oncol 1992;19:11-9.
[PUBMED] |
| 34. | Lerner HJ. Concomitant hydroxyurea and irradiation. Clinical experience with 100 patients with advanced head and neck cancer at Pennsylvania hospital. Am J Surg 1977;134:505-9.
[PUBMED] |
| 35. | Catimel G, Vermorken JB, Clavel M, de Mulder P, Judson I, Sessa C, et al. A phase II study of Gemcitabine (LY 188011) in patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol 1994;5:543-7.
|
| 36. | Huang P, Plunkett W. Fludarabine and gemcitabine induced apoptosis: Incorporation of analogs into DNA is a critical event. Cancer Chemother Pharmacol 1995;36:181-8.
|
| 37. | Plunkett W, Gandhi V, Huang P, Robertson LE, Yang LY, Gregoire V, et al. Fludarabine: Pharmacokinetics, mechanisms of action, and rationales for combination therapies. Semin Oncol 1993;20:2-12.
|
| 38. | Weiss B, Richardson CC. Enzymatic breakage and joining of deoxyribonucleic acid, I. Repair of single-strand breaks in DNA by an enzyme system from Escherichia coli infected with T4 bacteriophage. Proc Natl Acad Sci 1967;57:1021-8.
[PUBMED] |
| 39. | Jordheim LP, Galmarini CM, Dumontet C. Metabolism, mechanism of action and resistance to cytotoxic nucleoside analogues. Bull Cancer 2005;92:239-48.
|
| 40. | Evens AM. Motexafin gadolinium: A redox-active tumor selective agent for the treatment of cancer. Curr Opin Oncol 2004;16:576-80.
[PUBMED] |
| 41. | Xu S, Zakian K, Thaler H, Matei C, Alfieri A, Chen Y, et al. Effects of Motexafin gadolinium on tumor metabolism and radiation sensitivity. Int J Radiat Oncol Biol Phys 2001;49:1381-90.
|
| 42. | Hayon E, Simic M. Radiation sensitization reactions of N-ethylmaleimide with model compounds. Radiat Res 1972;50:464-78.
[PUBMED] |
| 43. | Horsman MR, Overgaard J. Hyperthermia: A potent enhancer of radiotherapy. Clin Oncol (R Coll Radiol) 2007;19:418-26.
|
| 44. | Westra A, Dewey WC. Variation in sensitivity to heat shock during cell cycle of Chinese hamster cells in vitro. Int J Radiat Biol Relat Stud Phys Chem Med 1971;19:467-77.
[PUBMED] |
| 45. | Dennis WH, Yatvin MB. Correlation of hyperthermic sensitivity and membrane viscosity in E. coli K 1060. Int J Radiat Biol Relat Stud Phys Chem Med 1981;39:265-71.
[PUBMED] |
| 46. | Ben-Hur E, Elkind MM, Bronk BV. Thermally enhanced radioresponse of cultured Chinese hamster cells: Inhibitor of repair of sub-lethal damage and enhancement of lethal damage. Radiat Res 1974;58:38-51.
[PUBMED] |
| 47. | Rosenthal DI, Carbone DP. Taxol plus radiation for head and neck cancer. J Infus Chemother 1995;5:46-54.
|
| 48. | Choy H, MacRae R. Irinotecan and radiation in combined-modality therapy for solid tumors. Oncology 2001;15:22-8.
|
| 49. | Brown JM. Sensitizers and protectors in radiotherapy. Cancer 1985;55:2222-8.
[PUBMED] |
| 50. | Blumberg AL, Nelson DF, Gramkowski M, Glover D, Glick JH, Yuhas JM, et al. Clinical trials of WR-2721 with radiation therapy. Int J Radiat Oncol Biol Phys 1982;8:561-3.
[PUBMED] |
| 51. | Brizel DM, Wasserman TH, Henke M, Strnad V, Rudat V, Monnier A, et al. Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 2000;18:3339-45.
|
| 52. | Phillips TL. Rationale for initial clinical trials and future development of radioprotectors. Cancer Clin Trials 1980;3:165-73.
[PUBMED] |
| 53. | Soule BP, Hyodo F, Matsumoto K, Simone NL, Cook JA, Krishna MC, et al. Therapeutic and clinical applications of nitroxide compounds. Antioxid Redox Signal 2007;9:1731-43.
|
| 54. | Mitchell JB, DeGraff W, Kaufman D, Krishna MC, Samuni A, Finkelstein E, et al. Inhibition of oxygen-dependent radiation-induced damage by the nitroxide superoxide dismutase mimic, tempol. Arch Biochem Biophys 1991;289:62-70.
|
| 55. | Cotrim AP, Hyodo F, Matsumoto K, Sowers AL, Cook JA, Baum BJ, et al. Differential radiation protection of salivary glands versus tumor by Tempol with accompanying tissue assessment of Tempol by magnetic resonance imaging. Clin Cancer Res 2007;13:4928-33.
|
| 56. | Matsumoto K, Hyodo F, Matsumoto A, Koretsky AP, Sowers AL, Mitchell JB, et al. High-resolution mapping of tumor redox status by magnetic resonance imaging using nitroxides as redox-sensitive contrast agents. Clin Cancer Res 2006;12:2455-62.
|
| 57. | Chitra S, Shyamala Devi CS. Effects of radiation and alpha-tocopherol on saliva flow rate, amylase activity, total protein and electrolyte levels in oral cavity cancer. Indian J Dent Res 2008;19:213-8.
[PUBMED]  |
| 58. | Prasad KN, Cole WC, Kumar B, Prasad KC. Pros and cons of antioxidant use during radiotherapy. Cancer Treat Rev 2002;28:79-91.
|
| 59. | Ferreira PR, Fleck JF, Diehl A, Barletta D, Braga-Filho A, Barletta A, et al. Protective effect of alpha-tocopherol in head and neck cancer radiation-induced mucositis: A double-blind randomized trial. Head Neck 2004;26:313-21.
|
| 60. | Guo H, Seixas-Silva JA Jr, Epperly MW. Prevention of radiation induced oral cavity mucositis by plasmid/liposome delivery of the human manganese superoxide dismutase (SOD2) transgene. Radiat Res 2003;159:361-70.
|
| 61. | Kaya H, Delibas N, Serteser M, Ulukaya E, Ozkaya O. The effect of melatonin on lipid peroxidation during radiotherapy in female rats. Strahlenther Onkol 1999;175:285-8.
|
| 62. | Berk L, Berkey B, Rich T, Hrushesky W, Blask D, Gallagher M, et al. Randomized phase II trial of high-dose melatonin and radiation therapy for RPA class 2 patients with brain metastases (RTOG 0119). Int J Radiat Oncol Biol Phys 2007;68:852-7.
|
| 63. | Kim K, Pollard JM, Norris AJ, McDonald JT, Sun Y, Micewicz E, et al. High-Throughput Screening Identifies Two Classes of Antibiotics as Radioprotectors: Tetracyclines and Fluoroquinolones. Clin Cancer Res 2009;15:7238-45.
|
| 64. | Finch PW, Rubin JS. Keratinocyte growth factor/fibroblast growth factor 7, a homeostatic factor with therapeutic potential for epithelial protection and repair. Adv Cancer Res 2004;91:69-136.
|
| 65. | Beaven AW, Shea TC. Recombinant human keratinocyte growth factor palifermin reduces oral mucositis and improves patient outcomes after stem cell transplant. Drugs Today 2007;43:461-73.
|
| 66. | Xavier S, Piek E, Fujii M, Javelaud D, Mauviel A, Flanders KC, et al. Amelioration of ra diation-induced fibrosis: Inhibition of transforming growth factor-beta signalling by halofuginone. J Biol Chem 2004;279:15167-76.
|
Correspondence Address:
Jayam Raviraj
Department of Oral Medicine and Radiology, CKS Theja Dental College, Hospital and Research Centre, Tirupati, Andhra Pradesh
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0970-9290.131142
[Table 1], [Table 2], [Table 3] |
|
| This article has been cited by | | 1 |
Therapeutic implications of exosomes in the treatment of radiation injury |
|
| Shijie Dai, Yuzhong Wen, Peng Luo, Le Ma, Yunsheng Liu, Junhua Ai, Chunmeng Shi | | Burns & Trauma. 2022; 10 | | [Pubmed] | [DOI] | | | 2 |
Robust radiosensitization of hemoglobin-curcumin nanoparticles suppresses hypoxic hepatocellular carcinoma |
|
| Ruoling Gao, Yuan Gu, Ying Yang, Yuping He, Wenpeng Huang, Ting Sun, Zaixiang Tang, Yong Wang, Wei Yang | | Journal of Nanobiotechnology. 2022; 20(1) | | [Pubmed] | [DOI] | | | 3 |
Differential Radiosensitizing Effect of 50 nm Gold Nanoparticles in Two Cancer Cell Lines |
|
| Miguel Ángel Pérez-Amor, Leonardo Barrios, Gemma Armengol, Joan Francesc Barquinero | | Biology. 2022; 11(8): 1193 | | [Pubmed] | [DOI] | | | 4 |
Interruptin C, a Radioprotective Agent, Derived from Cyclosorus terminans Protect Normal Breast MCF-10A and Human Keratinocyte HaCaT Cells against Radiation-Induced Damage |
|
| Nipha Chumsuwan, Pasarat Khongkow, Sireewan Kaewsuwan, Kanyanatt Kanokwiroon | | Molecules. 2022; 27(10): 3298 | | [Pubmed] | [DOI] | | | 5 |
Intracellular Signaling Responses Induced by Radiation within an In Vitro Bone Metastasis Model after Pre-Treatment with an Estrone Analogue |
|
| Jolene Helena, Anna Joubert, Peace Mabeta, Magdalena Coetzee, Roy Lakier, Anne Mercier | | Cells. 2021; 10(8): 2105 | | [Pubmed] | [DOI] | | | 6 |
Ring-Selective Fragmentation in the Tirapazamine Molecule upon Low-Energy Electron Attachment |
|
| Eugene Arthur-Baidoo, Joao Ameixa, Milan Oncák, Stephan Denifl | | International Journal of Molecular Sciences. 2021; 22(6): 3159 | | [Pubmed] | [DOI] | | | 7 |
Synergistic Tumoricidal Effects of Alpha-Lipoic Acid and Radiotherapy on Human Breast Cancer Cells via HMGB1 |
|
| Hoon Sik Choi, Jin Hyun Kim, Si Jung Jang, Jeong Won Yun, Ki Mun Kang, Hojin Jeong, In Bong Ha, Bae Kwon Jeong | | Cancer Research and Treatment. 2021; 53(3): 685 | | [Pubmed] | [DOI] | | | 8 |
Determination of radioprotective and genotoxic properties of sulfamide derivatives |
|
| Bünyamin Aygün, Burak Alaylar, Akin Akincioglu, Bünyamin Alim, Ebu Talip Kocaman, Mehmet Karadayi, Mohammed Ibrahim Abu Al-Sayyed, Seyma Aksu, Erdem Sakar, Özgür Firat Özpolat, Süleyman Göksu, Medine Güllüce, Abdulhalik Karabulut | | Radiochimica Acta. 2021; 109(12): 891 | | [Pubmed] | [DOI] | | | 9 |
Radioprotective Potential of Nutraceuticals and their Underlying Mechanism of Action |
|
| Shabnoor Iqbal, Muhammad Ajmal Shah, Azhar Rasul, Malik Saadullah, Sobia Tabassum, Shujat Ali, Muhammad Zafar, Haji Muhammad, Md Sahab Uddin, Gaber El-Saber Batiha, Celia Vargas-De-La-Cruz | | Anti-Cancer Agents in Medicinal Chemistry. 2021; 22(1): 40 | | [Pubmed] | [DOI] | | | 10 |
Contemporary biomedical engineering perspective on volitional evolution for human radiotolerance enhancement beyond low-earth orbit |
|
| Alexander M Borg, John E Baker | | Synthetic Biology. 2021; 6(1) | | [Pubmed] | [DOI] | | | 11 |
A review on radiation induced nausea and vomiting: “Current management strategies and prominence of radio sensitizers” |
|
| Meenu Vijayan, Sherin Joseph, Emmanuel James, Debnarayan Dutta | | Journal of Oncology Pharmacy Practice. 2021; 27(5): 1061 | | [Pubmed] | [DOI] | | | 12 |
Antitumor and Radiosensitizing Effects of Zinc Oxide-Caffeic Acid Nanoparticles against Solid Ehrlich Carcinoma in Female Mice |
|
| Hayam M. Sayed, Mahmoud M. Said, Nadia Y. S. Morcos, Mona A. El Gawish, Amel F. M. Ismail | | Integrative Cancer Therapies. 2021; 20: 1534735421 | | [Pubmed] | [DOI] | | | 13 |
Radiosensitizing Effect of Bromelain Using Tumor Mice Model via Ki-67 and PARP-1 Inhibition |
|
| Mai H. Mekkawy, Hanan A. Fahmy, Ahmed S. Nada, Ola S. Ali | | Integrative Cancer Therapies. 2021; 20: 1534735421 | | [Pubmed] | [DOI] | | | 14 |
Obtaining radioactivated strains of microorganisms and studying their antiradiation efficiency |
|
| T R Caynutdinov, R N Nizamov, A M Idrisov, G I Rakhmatullina, V A Guryanova | | IOP Conference Series: Earth and Environmental Science. 2021; 723(4): 042008 | | [Pubmed] | [DOI] | | | 15 |
Radiation proteome: a clue to protection, carcinogenesis, and drug development |
|
| Sandeep Kumar Shukla, Ajay Kumar Sharma, Sania Bajaj, M.H. Yashavarddhan | | Drug Discovery Today. 2021; 26(2): 525 | | [Pubmed] | [DOI] | | | 16 |
Studies on imidazo[2,1-b][1,3]benzothiazole derivatives as new radiosensitizers |
|
| Krishnakishore Majalakere, Sarojini Balladka Kunhana, Shama Rao, Bhuvanesh Sukhlal Kalal, Narayana Badiadka, Ganesh Sanjeev, Bantwal Shivaram Holla | | SN Applied Sciences. 2020; 2(11) | | [Pubmed] | [DOI] | | | 17 |
Protective effect of N-acetyl cysteine against radiotherapy-induced cardiac damage |
|
| Songul Barlaz Us, Ozden Vezir, Metin Yildirim, Gülsen Bayrak, Serap Yalin, Ebru Balli, Ali Erdinç Yalin, Ülkü Çömelekoglu | | International Journal of Radiation Biology. 2020; 96(5): 661 | | [Pubmed] | [DOI] | | | 18 |
Radiation Induced Metabolic Alterations Associate With Tumor Aggressiveness and Poor Outcome in Glioblastoma |
|
| Kshama Gupta, Ivan Vuckovic, Song Zhang, Yuning Xiong, Brett L. Carlson, Joshua Jacobs, Ian Olson, Xuan-Mai Petterson, Slobodan I. Macura, Jann Sarkaria, Terry C. Burns | | Frontiers in Oncology. 2020; 10 | | [Pubmed] | [DOI] | | | 19 |
Neoadjuvant Treatment Options in Soft Tissue Sarcomas |
|
| Mateusz Jacek Spalek, Katarzyna Kozak, Anna Malgorzata Czarnecka, Ewa Bartnik, Aneta Borkowska, Piotr Rutkowski | | Cancers. 2020; 12(8): 2061 | | [Pubmed] | [DOI] | | | 20 |
Recent advances in radiotherapy and its associated side effects in cancer—a review |
|
| Gomathi Mohan,Ayisha Hamna T P,Jijo A J,Saradha Devi K M,Arul Narayanasamy,Balachandar Vellingiri | | The Journal of Basic and Applied Zoology. 2019; 80(1) | | [Pubmed] | [DOI] | | | 21 |
Recent advances in radiotherapy and its associated side effects in cancer—a review |
|
| Gomathi Mohan,Ayisha Hamna T P,Jijo A J,Saradha Devi K M,Arul Narayanasamy,Balachandar Vellingiri | | The Journal of Basic and Applied Zoology. 2019; 80(1) | | [Pubmed] | [DOI] | | | 22 |
Iron-oxide nanoparticles target intracellular HSP90 to induce tumor radio-sensitization |
|
| Neena G. Shetake,Amit Kumar,Badri N. Pandey | | Biochimica et Biophysica Acta (BBA) - General Subjects. 2019; 1863(5): 857 | | [Pubmed] | [DOI] | | | 23 |
Iron-oxide nanoparticles target intracellular HSP90 to induce tumor radio-sensitization |
|
| Neena G. Shetake,Amit Kumar,Badri N. Pandey | | Biochimica et Biophysica Acta (BBA) - General Subjects. 2019; 1863(5): 857 | | [Pubmed] | [DOI] | | | 24 |
Radiosensitizing effects of Oroxylum indicum extract in combination with megavoltage radiotherapy beams |
|
| Wan Nordiana Rahman,Nor Fazila Che Mat,Nurin Afiqah Che Long,Raizulnasuha Ab Rashid,Norhayati Dollah,Reduan Abdullah | | Materials Today: Proceedings. 2019; 16: 2072 | | [Pubmed] | [DOI] | | | 25 |
Radiosensitizing effects of Oroxylum indicum extract in combination with megavoltage radiotherapy beams |
|
| Wan Nordiana Rahman,Nor Fazila Che Mat,Nurin Afiqah Che Long,Raizulnasuha Ab Rashid,Norhayati Dollah,Reduan Abdullah | | Materials Today: Proceedings. 2019; 16: 2072 | | [Pubmed] | [DOI] | | | 26 |
Silencing of heat shock protein 27 increases the radiosensitivity of non-small cell lung carcinoma cells |
|
| Liping Xu, Xuemei Lin, Yihua Zheng, Hua Zhou | | Molecular Medicine Reports. 2019; | | [Pubmed] | [DOI] | | | 27 |
Mitigation of radiation-induced oxidative stress by methanolic extract of Tragia involucrata in swiss albino mice |
|
| NivyaMachettira Thimmaiah,ChandrashekharGajanan Joshi,RajashekharK Patil,AjayS Khandagale,HM Somashekarappa,D Ananda,HM Manjunath | | Pharmacognosy Research. 2019; 11(3): 236 | | [Pubmed] | [DOI] | | | 28 |
Mitigation of radiation-induced oxidative stress by methanolic extract of Tragia involucrata in swiss albino mice |
|
| NivyaMachettira Thimmaiah,ChandrashekharGajanan Joshi,RajashekharK Patil,AjayS Khandagale,HM Somashekarappa,D Ananda,HM Manjunath | | Pharmacognosy Research. 2019; 11(3): 236 | | [Pubmed] | [DOI] | | | 29 |
Multidirectional Efficacy of Biologically Active Nitro Compounds Included in Medicines |
|
| Dorota Olender,Justyna Zwawiak,Lucjusz Zaprutko | | Pharmaceuticals. 2018; 11(2): 54 | | [Pubmed] | [DOI] | | | 30 |
Multidirectional Efficacy of Biologically Active Nitro Compounds Included in Medicines |
|
| Dorota Olender,Justyna Zwawiak,Lucjusz Zaprutko | | Pharmaceuticals. 2018; 11(2): 54 | | [Pubmed] | [DOI] | | | 31 |
Natural radioprotectors and their impact on cancer drug discovery |
|
| Vinutha Kuruba,Pavan Gollapalli | | Radiation Oncology Journal. 2018; 36(4): 265 | | [Pubmed] | [DOI] | | | 32 |
Natural radioprotectors and their impact on cancer drug discovery |
|
| Vinutha Kuruba,Pavan Gollapalli | | Radiation Oncology Journal. 2018; 36(4): 265 | | [Pubmed] | [DOI] | | | 33 |
Resveratrol treatment may preserve the erectile function after radiotherapy by restoring antioxidant defence mechanisms, SIRT1 and NOS protein expressions |
|
| Tarik Emre Sener,Hasan Huseyin Tavukcu,Beste Melek Atasoy,Ozge Cevik,Ozlem Tugce Kaya,Sule Cetinel,Ayse Dagli Degerli,Ilker Tinay,Ferruh Simsek,Cem Akbal,Salvatore Butticè,Goksel Sener | | International Journal of Impotence Research. 2018; 30(4): 179 | | [Pubmed] | [DOI] | | | 34 |
Resveratrol treatment may preserve the erectile function after radiotherapy by restoring antioxidant defence mechanisms, SIRT1 and NOS protein expressions |
|
| Tarik Emre Sener,Hasan Huseyin Tavukcu,Beste Melek Atasoy,Ozge Cevik,Ozlem Tugce Kaya,Sule Cetinel,Ayse Dagli Degerli,Ilker Tinay,Ferruh Simsek,Cem Akbal,Salvatore Butticè,Goksel Sener | | International Journal of Impotence Research. 2018; 30(4): 179 | | [Pubmed] | [DOI] | | | 35 |
Transferrin as a thermosensitizer in radiofrequency hyperthermia for cancer treatment |
|
| Hea-Jong Chung,Heui-Kwan Lee,Ki Beom Kwon,Hyeon-Jin Kim,Seong-Tshool Hong | | Scientific Reports. 2018; 8(1) | | [Pubmed] | [DOI] | | | 36 |
Transferrin as a thermosensitizer in radiofrequency hyperthermia for cancer treatment |
|
| Hea-Jong Chung,Heui-Kwan Lee,Ki Beom Kwon,Hyeon-Jin Kim,Seong-Tshool Hong | | Scientific Reports. 2018; 8(1) | | [Pubmed] | [DOI] | | | 37 |
The Radiosensitizing Effect of Nanodiamonds (NDs) on HeLa Cells Under X-Ray Irradiation |
|
| Xin Chen,Hong Wang,Hao Wang,Yang Fu,Jie Liu,Runze Liu | | physica status solidi (a). 2018; 215(6): 1700715 | | [Pubmed] | [DOI] | | | 38 |
The Radiosensitizing Effect of Nanodiamonds (NDs) on HeLa Cells Under X-Ray Irradiation |
|
| Xin Chen,Hong Wang,Hao Wang,Yang Fu,Jie Liu,Runze Liu | | physica status solidi (a). 2018; 215(6): 1700715 | | [Pubmed] | [DOI] | | | 39 |
Does sterilization with fractionated electron beam irradiation prevent ACL tendon allograft from tissue damage? |
|
| T. Schmidt,D. Grabau,J. H. Grotewohl,U. Gohs,A. Pruß,M. Smith,S. Scheffler,A. Hoburg | | Knee Surgery, Sports Traumatology, Arthroscopy. 2017; 25(2): 584 | | [Pubmed] | [DOI] | | | 40 |
Does sterilization with fractionated electron beam irradiation prevent ACL tendon allograft from tissue damage? |
|
| T. Schmidt,D. Grabau,J. H. Grotewohl,U. Gohs,A. Pruß,M. Smith,S. Scheffler,A. Hoburg | | Knee Surgery, Sports Traumatology, Arthroscopy. 2017; 25(2): 584 | | [Pubmed] | [DOI] | | | 41 |
Pulmonary injury associated with radiation therapy – Assessment, complications and therapeutic targets |
|
| Rasmi Rajan Radha,Guruvayoorappan Chandrasekharan | | Biomedicine & Pharmacotherapy. 2017; 89: 1092 | | [Pubmed] | [DOI] | | | 42 |
Pulmonary injury associated with radiation therapy – Assessment, complications and therapeutic targets |
|
| Rasmi Rajan Radha,Guruvayoorappan Chandrasekharan | | Biomedicine & Pharmacotherapy. 2017; 89: 1092 | | [Pubmed] | [DOI] | | | 43 |
6,7,3',4'-Tetrahydroxyisoflavone improves the survival of whole-body-irradiated mice via restoration of hematopoietic function |
|
| Cong Liu,Jing Liu,Yuhui Hao,Ying Gu,Zhangyou Yang,Hong Li,Rong Li | | International Journal of Radiation Biology. 2017; 93(8): 793 | | [Pubmed] | [DOI] | | | 44 |
6,7,3',4'-Tetrahydroxyisoflavone improves the survival of whole-body-irradiated mice via restoration of hematopoietic function |
|
| Cong Liu,Jing Liu,Yuhui Hao,Ying Gu,Zhangyou Yang,Hong Li,Rong Li | | International Journal of Radiation Biology. 2017; 93(8): 793 | | [Pubmed] | [DOI] | | | 45 |
Functional Gene Analysis Reveals Cell Cycle Changes and Inflammation in Endothelial Cells Irradiated with a Single X-ray Dose |
|
| Bjorn Baselet,Niels Belmans,Emma Coninx,Donna Lowe,Ann Janssen,Arlette Michaux,Kevin Tabury,Kenneth Raj,Roel Quintens,Mohammed A. Benotmane,Sarah Baatout,Pierre Sonveaux,An Aerts | | Frontiers in Pharmacology. 2017; 8 | | [Pubmed] | [DOI] | | | 46 |
Dynamic analysis of an antitumor model and investigation of the therapeutic effects for different treatment regimens |
|
| Liuyong Pang,Zhong Zhao,Sanhong Liu,Xinan Zhang | | Computational and Applied Mathematics. 2017; 36(1): 537 | | [Pubmed] | [DOI] | | | 47 |
Dynamic analysis of an antitumor model and investigation of the therapeutic effects for different treatment regimens |
|
| Liuyong Pang,Zhong Zhao,Sanhong Liu,Xinan Zhang | | Computational and Applied Mathematics. 2017; 36(1): 537 | | [Pubmed] | [DOI] | | | 48 |
Synergistic efficacy of ?-radiation together with gallium trichloride and/or doxorubicin against Ehrlich carcinoma in female mice |
|
| Eman kandil,Nahed Abdel Aziz | | Tumor Biology. 2016; 37(2): 1825 | | [Pubmed] | [DOI] | | | 49 |
Synergistic efficacy of ?-radiation together with gallium trichloride and/or doxorubicin against Ehrlich carcinoma in female mice |
|
| Eman kandil,Nahed Abdel Aziz | | Tumor Biology. 2016; 37(2): 1825 | | [Pubmed] | [DOI] | | | 50 |
Nano-silymarin provides protection against ?-radiation-induced oxidative stress in cultured human embryonic kidney cells |
|
| Manish Adhikari,Rajesh Arora | | Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 2015; 792: 1 | | [Pubmed] | [DOI] | | | 51 |
Nano-silymarin provides protection against ?-radiation-induced oxidative stress in cultured human embryonic kidney cells |
|
| Manish Adhikari,Rajesh Arora | | Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 2015; 792: 1 | | [Pubmed] | [DOI] | |
|
|
|
|
|
|
|
|
|
|
Users online:
