Selectively enhancing radiosensitivity of cancer cells

The radiotherapy modulators used in clinic have disadvantages of high toxicity and low selectivity. For the first time, we used the

Application of dextran-coated iron oxide nanoparticles in enhancing the radiosensitivity of cancerous cells in radiotherapy with high-energy electron beams

Purpose: Nowadays, cancer is one of the most important causes of morbidity and mortality in the world. The ideal aim of radiotherapy is delivering a lethal radiation dose to tumor cells while minimizing radiation exposure to healthy tissues around the tumor. One way to increase the dose in the tumor cells is the use of high-atomic number nanoparticles as radiosensitizer agents in these cells. The aim of this in vitro study was investigating the radiosensitization enhancement potential of the dextran-coated iron oxide nanoparticles (IONPs) on HeLa and MCF-7 cell lines in irradiations with high-energy electron beams. Materials and Methods: In this in vitro study, the cytotoxicity level of dextran-coated IONPs at different concentrations (10, 40, and 80 μg/ml) was assessed on HeLa and MCF-7 cell lines. To evaluate the radiosensitivity effect, the nanoparticles were incubated with the cells at different concentrations for 24 h and afterward irradiated with different doses (0, 2, 4, 6, and 8 Gy) of 6 and 12 MeV electron beams. The cells survival fractions were obtained by the methylthiazoletetrazolium assay. Results: Toxicity results of the nanoparticles at 10 and 40 μg/ml concentrations showed no significant cytotoxicity effect. The cells survival rates in groups receiving radiation in the absence and presence of IONPs showed a significant difference. The radiosensitivity enhancement induced by the nanoparticles in MCF-7 cell line was more than it in HeLa cell line. The average of radiosensitization enhancement factor at 10, 40, and 80 μg/ml concentrations and under 6 MeV irradiations obtained as 1.13, 1.19, 1.25, and 1.26, 1.28, 1.29 for HeLa, and MCF-7 cells, respectively. When 12 MeV electron beams were carried out, the values of 1.17, 1.26, 1.32, and 1.29, 1.32, 1.35 were obtained for the cells at the mentioned concentrations, respectively. Furthermore, the significant differences were observed in radiosensitization enhancement between 6 and 12 MeV electron beams irradiations. Conclusion: Use of dextran-coated IONPs can increase radiosensitivity and consequently at a given absorbed dose more cell killing will occur in cancerous cells. In other words, these nanoparticles can improve the efficiency of electron therapy

Application of radiosensitizers in oncotherapy / 中华放射医学与防护杂志

Radiotherapy is one of the important methods for treating malignant tumors. However, due to the limitation of normal tissue tolerance dose, it is impossible to give a sufficient irradiation dose to the tumor, which causes treatment failure. Therefore, how to improve the sensitivity of the tumor to radiation is a prominent problem in tumor radiotherapy. Radiosensitizers can enhance the sensitivity of tumor radiotherapy and improve the efficacy of radiotherapy, through accelerating DNA damage, producing free radicals and regulating key molecular targets. This paper summarized the applications of radiosensitizers in radiotherapy, the development status of radiosensitizers and research progresses in the related fields.Furthermore, the possible mechanisms of how radiosensitizers enhance the sensitivity of tumors were also briefly reviewed. This review will elucidate the detailed molecular mechanisms of radiosensitization regulation, promote the development of radiosensitizers, and facilitate the development of new strategies to improve radiotherapy efficiency.

Application of radiosensitizers in oncotherapy / 中华放射医学与防护杂志

Radiotherapy is one of the important methods for treating malignant tumors. However, due to the limitation of normal tissue tolerance dose, it is impossible to give a sufficient irradiation dose to the tumor, which causes treatment failure. Therefore, how to improve the sensitivity of the tumor to radiation is a prominent problem in tumor radiotherapy. Radiosensitizers can enhance the sensitivity of tumor radiotherapy and improve the efficacy of radiotherapy, through accelerating DNA damage,producing free radicals and regulating key molecular targets. This paper summarized the applications of radiosensitizers in radiotherapy, the development status of radiosensitizers and research progresses in the related fields. Furthermore, the possible mechanisms of how radiosensitizers enhance the sensitivity of tumors were also briefly reviewed. This review will elucidate the detailed molecular mechanisms of radiosensitization regulation, promote the development of radiosensitizers, and facilitate the development of new strategies to improve radiotherapy efficiency.

Efficacy of bodyγ-knife with radiosensitizer and/or hyperthermia for recurrent soft tis-sue sarcoma / 中国肿瘤临床

Objective:This study investigates the clinical effect of bodyγ-knife combined with radiosensitizer and/or hyperthermia. for the recurrence of soft tissue sarcoma. Methods:Sixty-three patients with recurrent soft tissue sarcoma from January 2012 to March 2014 were treated by bodyγ-knife combined with radiosensitizer and/or hyperthermia. The patients were exposed to radiation dose levels of 4-5.5 Gy/fraction (10-13 fractions) with total doses of 44-55 Gy and 55%-70%isodose, including 95%PTV. The radiosensitizer, sodium glycodidazolum (CMNa), was administered to all patients at 1.00-1.50 g V.D qod at 5-6 fractions 0-3 h before bodyγ-knife treat-ment. Hyperthermia for 30 patients was delivered during the bodyγ-knife treatment with two fractions/week for a total of six frac-tions. Results:The total response rate was 77.7%three months after the treatment. The one and two year local control rates were 78.8%and 63.6%, respectively, while the survival rates of patients treated with bodyγ-knife with radiosensitizer at one and two years were 75.7%and 63.6%, respectively. The local control rates at one and two years were 83.6%and 70.0%, respectively, while the surviv-al rates at one and two years for bodyγ-knife combined with radiosensitizer and hyperthermia treatments were 80.0%and 63.3%, re-spectively. Serious complications of radiotherapy were not observed. Conclusion:Bodyγ-knife combined with radiosensitizer and/or hyperthermia is effective for recurrent soft tissue sarcoma.

Research progress of RRx-001 as a sensitizer for radiotherapy / 天津医药

Radiotherapy is one of the most important methods to treat malignant tumors. Due to the presence of radiation resistance, the effect of radiotherapy is not entirely satisfactory. To alleviate radiation resistance and improve the radiotherapy effect, radiosensitizers have emerged. As a newly discovered radiosensitizer, RRx-001 has a good clinical application prospect. This paper reviewed the research progress of RRx-001 in source, safety, radiotherapy sensitizing activity and related mechanisms.

Targeting the AKT pathway: Repositioning HIV protease inhibitors as radiosensitizers.

Cellular resistance in tumour cells to different therapeutic approaches has been a limiting factor in the curative treatment of cancer. Resistance to therapeutic radiation is a common phenomenon which significantly reduces treatment options and impacts survival. One of the mechanisms of acquiring resistance to ionizing radiation is the overexpression or activation of various oncogenes like the EGFR (epidermal growth factor receptor), RAS (rat sarcoma) oncogene or loss of PTEN (phosphatase and tensin homologue) which in turn activates the phosphatidyl inositol 3-kinase/protein kinase B (PI3-K)/AKT pathway responsible for radiation resistance in various tumours. Blocking the pathway enhances the radiation response both in vitro and in vivo. Due to the differential activation of this pathway (constitutively activated in tumour cells and not in the normal host cells), it is an excellent candidate target for molecular targeted therapy to enhance radiation sensitivity. In this regard, HIV protease inhibitors (HPIs) known to interfere with PI3-K/AKT signaling in tumour cells, have been shown to sensitize various tumour cells to radiation both in vitro and in vivo. As a result, HPIs are now being investigated as possible radiosensitizers along with various chemotherapeutic drugs. This review describes the mechanisms by which PI3-K/AKT pathway causes radioresistance and the role of HIV protease inhibitors especially nelfinavir as a potential candidate drug to target the AKT pathway for overcoming radioresistance and its use in various clinical trials for different malignancies.

The Role of Celecoxib as a Cox-2 Inhibitor Increasing the Radiosensitivity of Tumor Tissue.

One of the major causes of death in the world is cancer. Due to significant advances in molecular and cellular biology, previous approaches in cancer treatment have progressed, applying new strategies. Identification and use of chemotherapy and radiation sensitizers and their effect on the further destruction of the cancer cells have received a lot of attention in medical studies. The main objectives of this Review Article are to identify the inhibitors of the enzyme COX -2 and mechanisms that are known to inhibit the enzyme in order to increase the sensitivity of tumour cells to radiation. COX-2 enzyme inhibition with Celecoxib and the prevention of the restoration of this tumour have been a major challenge for researchers. Evidence Acquisition: The mechanism by which the cells are radio sensitized can increase the initial damage, inhibiting the restoration and redistribution of the cell cycle as well as blocking in the more radio sensitized zone. Enhanced response to treatment would be initiated by identifying enzymes that are involved in increasing tumour growth and followed by inhibiting tumour growth and restoration. COX-2 is one of the enzymes expressed highly in tumour growth. Inhibiting this enzyme will enhance the response rate of treatment followed by the death of tumour cells. High expression of COX-2 gene in tumours is more related to tumour aggressive behaviour and a worse prognosis. Results: There are five mechanisms that the COX-2 enzyme applies to develop tumours and increase the malignant phenotype of tumour cells: 1- Apoptosis inhibition 2- Angiogenesis increase 3- Invasion rise 4- Inflammation modulation/weakened immunity, suppression 5- Procarcinogen conversion to carcinogens. Known mechanisms in increased sensitivity to radiation by Celecoxib: 1-COX-2 inhibition and subsequent reduction in PGE2 production result in increasing apoptosis and decreasing angiogenesis proliferation-2. The mechanism of COX-2 inhibition by Celecoxib has not been fully recognized. The drug inhibits the COX-2 enzyme through TNF-α signalling by nuclear transfer inhibition of growth factor. It also inhibits NF-KB transcription factor activation. Apoptosis inhibition is one of the mechanisms implemented by COX-2 that increases tumourigenesis. Cell cycle arrest at G1-S is one of the most sensitized areas to radiation. Studies in the field of pancreatic and ovarian carcinoma cells show cell cycle arrest at G1-S; the mechanism by which this arrest happens is not fully understood. Conclusions: Celecoxib, as a COX-2 inhibitor that affects and inhibits some enzymes and creates changes in the cell cycle process, has the role of a radiosensitizer. Celecoxib prevents cancer. Celecoxib inhibits tumour growth delay and the amount is insignificant. Simultaneous application of radio sensitzers such as celecoxib and chemo radiotherapy procedures will have a more damaging effect on the tumour cells.

Progress in radiosensitization of hypoxia-inducible factor-1 inhibitors / 中国药理学与毒理学杂志

Hypoxia-inducibIe factor-1(HIF-1)is a main nucIear transcription factor for response to intratumor hypoxia. RecentIy,it has become a hot spot to attempt to improve hypoxia by inhibiting HIF-1. HIF-1 inhibitors' mechanisms of action are wide,which infIuences the two signaI transduction pathways that are phosphatidyIinositoI-3-kinase/ protein kinase B/ mammaIian target of rapamycin and Ras/ Raf/ mitogen-activated protein kinase kinase1-2/ extraceIIuIar signaI-reguIated kinase1-2,inhibits the function of heat shock protein 90,and reduces transcriptionaI activity of HIF-1. In combination with radiation,HIF-1 inhibi-tors significantIy enhance radiosensitivity and weaken radioresistance of hypoxia ceIIs,which contributes to the therapeutic effect of tumor irradiation.

Derris scandens benth extract radiosensitizes HT-29 colon cancer cells.

Objective: To evaluate the radiosensitizing potential of Derris scandens extract in a human colon cancer cell model. Methods: The radiosensitizing effect of D., scandens extract on human colon cancer cells (HT-29) and non-cancerous human retinal epithelial cells (RPE) was determined by cell survival and micronuclei analysis after irradiation. Cell cycle distribution was analyzed by a flow cytometer. Results: D. scandens extract powerfully increases the radiosensitivity of HT-29 cells, but is less toxic and does not affect the radiosensitivity of RPE cells. Furthermore, the extract was found to reduce radiation-induced G2/M phase arrest in HT-29 cells, but not in RPE cells. Conclusion: D., scandens extract may have potential as a radiosensitizer for cancer treatment.

Advances in research on ATM as a target for novel radiosensitizers / 中国癌症杂志

Patients with ataxia-telangiectasia ( A-T) syndrome were charachaterized by profound hypersensitivity to ionizing radiation in clinic. Many studies have shown that this hypersensitivity possibly attributed to ATM gene whose critical compartment was ATM kinase. So inhibitors of the ATM kinase such as caffeine, pentoxifylline, methyl xanthines and 7-hydroxystaurosporine (UCN-01) were developed and have achieved a few encouraging results in basic and clinical stuides.

Effects of REtinoic Acid and Radiation on the Growth of Cell Lines of Human Head and Neck Squamous Cell Carcinoma / 대한암학회지

PURPOSE: Mammalian tumor cells differ in their response to ionizing radiation to a degree that some patients are readily curable with conventional doses of radiation, while others are rarely controlled. In experimental systems, it is possible to demonstrate differences between cell lines both in intrinsic radiosensitivity and in the apparent capacity to repair damage. Retinoic acid is a substance that has previously been reported to increase radiosensitivity, but at concentrations likely to have cytostatic effects or induce cellular differentiation. We chose several head and neck cancer cell lines to investigate radiation sensitivity and synergism in combination with retinoic acid. Material and Methods: Seventeen head and neck cancer cell lines (MDA886, P1, P13, A-431, PCI-50, UMSCC-10A, UMSCC-10B, UMSCC-11A, UMSCC-11B, UMSCC-17A, UMSCC-17B, UMSCC-19, UMSCC-22B, UMSCC-30, UMSCC-38, 1YA, 1YB) are irradiated with variable dose of radiation (1 Gy, 5 Gy, 9 Gy) for determination of radiosensitivity of each cell lines. The less radiosensitive cell lines are treated with retinoic acid for evaluation of the effects of retinoic acid on cellular X-ray sensitivity and recovery from X ray-induced potentially lethal damage. RESULTS: Lowest growth inhibition rates are seen UMSCC-11A and 1YA cell lines in 1 Gy, so that we treated with retinoic acid such cell lines. We obtained the following RESULTS: 1) two cell lines appear not inhibitory effect on recovery from X-ray induced potentially lethal damage but growth inhibition synergism when irradiated with retinoic acid in 1 Gy of radiation dose. 2) two cell lines were little effect on radiosensitivity and inhibitory effect on recovery from X-ray damage in 0.5 Gy radiation dose. CONCLUSION: We found that direct radiosensitizing effects of retinoic acid on 1 Gy of radiation dose may act synergistically for cell growth inhibition in vitro study(three cell lines: UMSCC-11A, 1YA, UMSCC-11B). Further in vitro and in vivo experiments are now necessary to evaluate retinoic acid as radiosensitizer for head and neck cancer radiation therapy.

Enhanced Radiosensitivity of Tumor Cells Treated with Vanadate in Vitro / 대한치료방사선과학회지

Intracellular ions which have a major role in cellular function have been reported to affect repair of radiation damage. Recently it has been reported that ouabain sensitizes A549 tumor cells hut not CCL-120 normal cells to radiation. Ouabain inhibits the Na+-K+-pump rapidly thus it increases intracellular Na concentration. Vanadate which is distributed extensively in almost all living organisms in known to be a Na+-K+-ATPase inhibitors. This study was performed to see any change in radiosensitivity of tumor cell by vanadate and any role of Na+-K+-ATPase in radiosensitization. Experiments have been carried out by pretreatment with vanadate in human cell line(A549, JMG) and mouse cell line(L1210, spleen). For the cell survival MTT assay was performed for A549 and JMG cell and trypan blue dye exclusion test for L120, and spleen cells. Measurements of Na+-K+-ATPase activity in control, vanadate treated cell, radiation treated cell (9 Gy for A549 and JMG, 2 Gy for L1201, spleen), and combined 10-6 M vanadate and radiation treated cells were done. The results were summarized as follows. 1. L1210 cell was most radiosensitive, and spleen cell and JMG cell were intermediate, and A549 cell was least radiosensitive. 2. Minimum or cytotoxicity was seen with vanadate below concentration of 10-6 M. 3. In A549 cells there was a little change in radiosensitivity with treatment of vanadate. However radiation sensitization was shown in low dose level of radiation i. E. 2-Gy. In JMG cells no change in radiosensitivity was noted. Both L1210 and spleen cell had radiosensitization but change was greater in tumor cell. 4. Na+-K+-ATPase activity was inhibited significantly in tumor cell by treatment of vanadate. 5. Radiation itself inhibited Na+-K+-ATPase activity of tumor cell with high Na+- K+-ATPase concention. Increase in radiosensitivity by vanadate was closely associated with original Na+-K+-ATPase contents. From the above results vanadate had little cytotoxicity and it sensitized tumor cells to radiation. Inhibitory effect of vanadate on Na+-K+-ATPase activity might be one of the contributing factors for radiosensitization to tumor cells which has greater enzyme activity than that of normal cell. It was suggested vanadate could be used as a potential radiosensitizer for tumor cells.

EFFECTS OF METRONSDAZOLE DERIVATIVE ON MEMBRANE PERMEABILITY OF~51Cr LABELLED L_7712 CELLS / 第二军医大学学报

This report describes the effects of a new radiosensitizer, metronidazole derivative (CM) synthesized in our laboratory, on membrane permeability of 51Cr labelled L7712 cells.It was found that CM could be incorporated into the cancer cells easily, and resulted in increased membrane permeability.Under aerobic condition, the release rate of 51Cr was increased when the cells were irradiated with more than 40 Gy Y-rays.At a dose of 0-80 Gy, the sensitization effects of CM on membrane permeability of irradiated cells were not found.

COMPARISON OF THE SENSITIZING EFFECT OF METRONIDA-ZOLE DERIVATIVE (CMCa) ON TUMOR BEARING MICE BETWEEN TWO FRACTIONATED RADIOTHERAPY SCHEDULES / 第二军医大学学报

The sensitizing effects of radiosensitizer CMCa on S180 bearing mice in two f rac- tionated radiotherapy schedules were compared. The restlts showed that CMCa had the sensitizing effects in both fractionated schedules. The SER value of 2F/7D schedule was higher than that of 5F/7D. The TCD50(90) dose of 2F/7D was also decreased obviously. There was a significant difference of regression coefficients of dose-response curves between the experimental group and control one. The total radiation dose which was required for disapperance of tumor in all drug treated animals was reduced. The results indicate.that radiosensitizing effect of CMCa with 2F/7D schedule is better than that with 5F/7D.