Modification Of Radiosensitivity Research Articles

Modification of radiosensitivity by Curcumin in human pancreatic cancer cell lines

Pancreatic cancer is one of the most aggressive malignancies and is characterized by a low 5-year survival rate, a broad genetic diversity and a high resistance to conventional therapies. As a result, novel therapeutic agents to improve the current situation are needed urgently. Curcumin, a polyphenolic colorant derived from Curcuma longa root, showed pleiotropic influences on cellular pathways in vitro and amongst others anti-cancer properties including sensitization of tumor cells to chemo- and radiation-therapy. In this study, we evaluated the impact of Curcumin on the radiosensitivity of the established human pancreatic cancer cell lines Panc-1 and MiaPaCa-2 in vitro. In contrast to MiaPaCa-2 cells, we found a significant radiosensitization by Curcumin in the more radioresistant Panc-1 cells, possibly caused by cell cycle arrest in the most radiation-sensitive G2/M-phase at the time of irradiation. Furthermore, a significant enhancement of radiation-induced apoptosis, DNA-double-strand breaks and G2/M-arrest after curcumin treatment was observed in both cell lines. These in vitro findings suggest that especially patients with more radioresistant tumors could benefit from a radiation-concomitant, phytotherapeutic therapy with Curcumin.

Effects of Nrf2 knockdown on the properties of irradiated cell conditioned medium from A549 human lung cancer cells.

The nuclear factor erythroid 2-related factor 2 (Nrf2) plays an important role in cellular defense against oxidative stress. Recent studies have demonstrated that Nrf2 is a useful target for cancer treatment, including radiation therapy. Ionizing radiation affects, not only the irradiated cells, but also the non-irradiated neighboring cells, and this effect is known as radiation-induced bystander effect. Upon exposure to radiation, the irradiated cells transmit signals to the non-irradiated cells via gap junctions or soluble factors. These signals in turn cause biological effects, such as a decrease in the clonogenic potential and cell death, in the non-irradiated neighboring cells. Nrf2 inhibition enhances cellular radiosensitivity. However, whether this modification of radiosensitivity by Nrf2 inhibition affects the radiation-induced bystander effects is unknown. In this study, we prepared an Nrf2 knockdown human lung cancer cell A549 and investigated whether the effects of irradiated cell conditioned medium (ICCM) on cell growth and cell death induction of non-irradiated cells vary depending on the Nrf2 knockdown. We found that Nrf2 knockdown resulted in a decrease in the cell growth and an increase in the radiosensitivity of A549 cells. When non-irradiated A549 cells were transfected with control siRNA and treated with ICCM, no significant difference was observed in the cell growth and proportion of Annexin V+ dead cells between ICCM from non-irradiated cells and that from 2 or 8 Gy-irradiated cells. Similarly, no significant difference was observed in the cell growth and cell death induction upon treatment with ICCM in the Nrf2 knockdown A549 cells. Taken together, these results suggest that Nrf2 knockdown decreases cell growth and enhances the radiosensitivity of A549 cells; however, it does not alter the effect of ICCM on cell growth.

Characterization of in vitro radiosensitization in mammalian cells using biomathematical modelling: implications for hypofractionated radiotherapy with a combined modality approach.

It is unclear whether radiosensitization is beneficial when radiotherapy is administered at a high dose per fraction. The aim of this study was to assess the impact of radiation dose on the effectiveness of a broad range of radiosensitizers. We analyzed 653 pairs of clonogenic survival curves in 285 published articles, in which modifications of radiosensitivity were studied using the colony-forming assay. The modifications of radiosensitivity were arbitrarily classified into 20 classes. The survival curves were fitted to two biomathematical models: the linear-quadratic model and the repair-misrepair (RMR) model. We found that radiosensitization was predominantly characterized by an increase of the α value (α-sensitization) without an increase of the β value (β-sensitization). A subset analysis revealed that all 20 classes showed significant α-sensitization. In contrast, only oxygen/hypoxic sensitizers (oxygen) and poly(adenosine diphosphate-ribose) polymerase inhibition (PARPi) exhibited β-sensitization. An analysis using the RMR model revealed two major sources of radiosensitization: an increased residual DNA lesion through repair inhibition and a shift from linear repairs to quadratic misrepairs, leading to enhanced lethal chromosomal aberrations. Oxygen and PARPi were found to show β-sensitization, which was favourable for eliciting a comparable degree of sensitization in the higher dose range. Reduced fidelity of the repair was suggested to be a possible mechanism of β-sensitization. Further study targeting β-sensitization is needed to develop a novel combined modality therapy with high-dose-per-fraction radiotherapy. Radiosensitization can be classified into two groups, α- and β-sensitizations. These two phenomena may stem from distinct underlying mechanisms.

143 Biological modification of radiosensitivity by erlotinib in glioblastoma cells depends on the sequence of treatment

143 Biological modification of radiosensitivity by erlotinib in glioblastoma cells depends on the sequence of treatment

Modification of radiosensitivity following chemotherapy exposure: potential implications for combined-modality therapy.

Treatment protocols for many tumor sites often consist of a combination of poly-chemotherapy with loco-regional radiotherapy. In many instances, these treatments are given in close temporal proximity to each other, either within a few hours (concomitant) or within a few weeks of each other (sequential). In other instances, radiotherapy may be given at some considerable time after completion of chemotherapy to achieve a measure of loco-regional control in tumors that have recurred following front-line chemotherapy. The optimum integration of chemotherapy and radiotherapy in all three situations has yet to be fully established. Careful consideration of the impact of clinically relevant chemoresistance on radiation response in these various scenarios, and appropriate adjustments, may lead to qualitative differences in patient quality of life, and hopefully quantitative improvements in disease free survival

A multidrug-resistant breast cancer cell line induced by weekly exposure to doxorubicin.

Attempts to study drug resistance in vitro have focused on continuous exposure of cell lines to cytotoxic agents that results in marked resistance. In an effort to examine drug resistance in an environment that is more typical of a clinical setting, monolayered human breast cancer cells (MCF-7) were exposed weekly for one hour to doxorubicin at a concentration that is achieved in vivo (0.1 microg/ml). After 20 weeks, the treated cell line (C20) was found to be resistant to doxorubicin by a factor of 2.0-2.5 at the 10 and 1% cell survival level compared to parent MCF-7 cells. Additionally, cross resistance to other chemotherapeutic agents including etoposide, vincristine, cisplatin, and mitomycin C was observed. Similar to other models of in vitro drug resistance, no modification of radiosensitivity was observed in C20 cells. The p170 glycoprotein was not overexpressed on C20 cells as assessed by the anti-p170 glycoprotein monoclonal antibody C219 staining nor was mRNA for the mdr-1 or MRP gene overexpressed. In addition, the mdr-blocking agent verapamil had no effect on the level of resistance encountered in tissue culture. C20 cells did not differ from the parent cell line with respect to cell cycle distribution, doubling time, GSH, GSH peroxidase, GSH reductase or GSH transferase levels. After a one-hour exposure to doxorubicin, lower intracellular doxorubicin levels were found in C20 cells compared to the parent line which provides at least a partial explanation for resistance, although the mechanism for this is unclear. Although the magnitude of resistance observed in the C20 cell line is low compared to other in vitro models of drug resistance, the modest level of drug resistance is probably sufficient to explain drug resistance seen clinically. The model of non-mdr mediated drug resistance presented may be a more relevant model for the evaluation of drug resistance in vitro.

Subadditive interaction of radiation and taxol in vitro

To examine the dependency of Taxol-radiation interactions on the scheduling of the two agents. The human laryngeal squamous cell carcinoma line SCC20 was used for this study. Cells were irradiated as subconfluent cultures using Cs-137 gamma rays at a dose rate of 1.75 Gy/min. Cultures were pretreated with Taxol (7.5 nM for 12 h, S.F. = 0.4) and then irradiated with graded doses followed by either immediate plating or holding for 6 h either in the absence or presence of 7.5 nM Taxol prior to plating for colony-forming ability. Experiments in which cells were irradiated and then exposed to 7.5 nM Taxol for both 12 and 18 h were also performed. Parallel-flow cytometric analyses of cell-cycle distribution of the various treated populations were carried out. The results indicate that pretreatment with Taxol induced a G2 block which was maintained during 6 h postirradiation holding either in the presence or absence of Taxol. No modification of radiosensitivity in the low-dose region was seen for cells treated with Taxol, irradiated, and plated immediately, with the resulting survival being compatible with an additive effect. However, for Taxol-pretreated cells held for 6 h postirradiation, either in the absence or presence of Taxol, the resulting survival reproducibly demonstrated a marked less than additive effect. This was particularly prominent for cells held in the presence of Taxol. Subsequent experiments in which Taxol was added to cells immediately postirradiation again demonstrated a less than additive effect of the two modalities. The results of this study are consistent with a dual mechanism of action involving Taxol-induced radiation resistance, possibly as a consequence of postirradiation holding in G2, and radiation-induced Taxol resistance through an as-yet-undefined mechanism.

Modulation of the effect of camptothecin in x-irradiated L5178Y-R and L5178Y-S cells by benzamide.

The L5178Y (LY) murine lymphoma subline, LY-R, is more radioresistant and more sensitive to camptothecin (CPT, inhibitor of topisomerase I) than the second subline used in our investigation, LY-S. Post-irradiation treatment with 3 microM CPT enhanced the radiosensitivity of LY-S cells (D0 decrease from 0.52 to 0.34 Gy), but did not change it in LY-R cells. Treatment with 2 mM benzamide [BZ, inhibitor of poly (ADP-ribosylation)] before x-rays and CPT increased the radiosensitivity of LY-R cells (D0 decrease from 1.15 to 0.52) without further modification of radiosensitivity of LY-S cells. Activity of topoisomerase I was diminished 10 min after x-irradiation (5 Gy) in LY-S, but not in LY-R cells. The data on DNA damage (fluorescent halo or comet assays) showed that the ultimate fate of the cells did not depend on the DNA damage pattern estimated immediately after treatment (e.g. the damage was greater in x-rays plus CPT than in BZ plus x-rays plus CPT treated LY-R cells, although the radiosensitivity was less). Aphidicolin (inhibitor of DNA polymerases alpha and delta) applied concomitantly with CPT in cells not pretreated with BZ prevented the increase in DNA damage in LY-R cells, but was without effect in LY-S cells. Taking into account the differential inhibition by x-rays of DNA synthesis in LY sublines and its reversion by BZ in LY-S but not in LY-R cells, we conclude that the pattern of DNA damage observed by the methods applied depended on the status of DNA replication.

Modification of radiosensitivity of rat thymocytes by cholesterol-enriched autoliposomes

Modification of radiosensitivity of rat thymocytes by cholesterol-enriched autoliposomes

Modification of radiosensitivity by the so-called tissue recovery stimulator. I. Radiosensitizing effects of solcoseryl.

The effect of solcoseryl on the growth, radiosensitization and ability of V79 cells to recover from X-ray-induced damage has been observed. Solcoseryl at 0.8 mg/ml was the optimal concentration for the stimulation of cell growth. Increased sensitivity to X-irradiation was found in the shoulder region of V79 cells treated before and after irradiation with solcoseryl (0.8 mg/ml). The Dq and extrapolation number (n) decreased. Solcoseryl treatment apparently does not reduce split dose recovery or inhibit the repair of potentially lethal damage. Flow cytofluorometry studies of the cell cycle distribution and mitotic index show that solcoseryl inhibits the expression of radiation-induced cell arrest in the G2 phase of the cell cycle. Although this action increases radiation sensitization, additional mechanisms probably exist.

Modification of radiosensitivity and recovery from X ray damage in vitro by retinoic acid

We studied the effects of all-trans retinoic acid (RA) combined with X-irradiation on confluent cultures of human breast cancer (MCF-7) and melanoma (C-143) cell lines, as well as in a normal human diploid fibroblast strain (AG 1522). RA in non-cytotoxic concentrations was a potent inhibitor of confluent holding recovery of potentially lethal damage (PLD repair) for all three cell types. A complete inhibition of recovery was observed at lower RA concentrations in the tumor lines than in the fibroblast strain. Exposure to RA prior to and during irradiation resulted in a radiosensitizing effect that was similar in MCF-7 and AG 1522 cells. The implications of these findings are discussed in terms of the potential value of retinoids as biological response modifiers for the clinical radiotherapy of cancer.

Porphyrin photosensitization and phototherapy.

Porphyrin photosensitization and phototherapy.

Modification of Radiosensitivity in Cancer Treatment

Modification of Radiosensitivity in Cancer Treatment

Modification of stromal radiosensitivity by misonidazole and WR-2721

The radiosensitivity of normal vascular connective tissue has been assessed by measuring the growth rate of untreated tumours implanted into pre-irradiated sites. Dose response curves have been constructed from two end-points, the latent period (time for the tumours to reach a diameter of 2 mm) and the growth rate in the macroscopic range (above 4 mm). Well defined dose response curves were obtained for both end-points, with a lower dose threshold for the macroscopic growth rate. A third end-point which combined the first two was also tested, i.e., time to reach 8 mm (23 to 76 days over the dose range tested). This was found to give the steepest dose response curves overall and was therefore judged to be the best assay. Modification of the radiosensitivity of stromal tissue by misonidazole and by WR-2721 was investigated using this assay. The dose response curve for X rays plus misonidazole was similar to that for X rays alone indicating little or no radiosensitisation. WR-2721, however, significantly reduced the X-ray response indicating radioprotection by a factor of 1.8 (range 1.4-2.7). These data show that tumour implantation is an effective way of eliciting a quantifiable response in previously irradiated stromal tissue. The assay allows resolution of dose differences as small as 1 to 2 Gy.

Use of hydrogen sulphide and N-ethylmaleimide in the post-irradiation modification of oxic and anoxic components of damage in Hordeum vulgare

The post-irradiation modification of radiosensitivity of barley seeds with about 7% water content by hydrogen sulphide and N-ethylmaleimide (NEM) applied during oxygenated or oxygen-free hydration was studied. H 2 S, which causes about 18% seedling injury to unirradiated seeds, effectively decreases the post-irradiation oxygen-dependent damage ( Powers ' class III). NEM dramatically enhances the magnitude of an O 2 -independent component of damage. It also affords a small degree of protection against the post-irradiation oxic damage. The mechanisms possibly involved are briefly discussed.

Effect of caffeine and cysteine applied during post-irradiation hydration on an oxygen-independent component of damage in barley seeds

The modification of radiosensitivity of barley seeds with 11·1 per cent water content by caffeine and cysteine applied during oxygenated and oxygen-free hydration was studied. No post-irradiation oxygen-dependent damage develops in these seeds. While cysteine has no influence at all, caffeine effectively potentiates the level of the gamma-induced oxygen-independent (Class I) component of damage. The possible reactivity of caffeine and cysteine towards the precursors of oxygen-dependent and -independent components of damage in determining the mode and magnitude of modification has been briefly discussed.

A computer analysis of the role of oxygen in the modification of radiosensitivity of self-renewing cell systems.

Information obtained by a number of investigators for mammalian cell systems has been used as a basis for a computer analysis of the effects produced by assumed oxygen distributions on radiosensitivity in simple twocompartment tissue models. At low exposures, surviving distributions are slightly better oxygenated; as dose increases the distribution shifts in the hypoxic direction. The effect of time and dose on postirradiation changes has been studied by a computer program developed to study time-dependent changes in radiosensitivity after an initial conditioning exposure. These data can be of importance in establishing fractionation regimens in radiotherapy.

Modification of radiosensitivity of Ehrlich ascites carcinoma cells in vivo. 1. Some basic experiments on the role of lethally irradiated tumor cells.

Modification of radiosensitivity of Ehrlich ascites carcinoma cells in vivo. 1. Some basic experiments on the role of lethally irradiated tumor cells.

OXYGEN UPTAKE AND CARDIOVASCULAR RESPONSE OF MICE AND RABBITS ADMINISTERED "HEMATOPORPHYRIN".

SummaryThe toxicity of several preparations of “hematoporphyrin” has been studied in female ZBC mice and in rabbits. The MLD100 in mice ranged from 0.2 to 0.7 mg per gram body weight depending on source of the porphyrin and route of administration. The intraperitoneal route was generally most toxic. A marked fall in total body oxygen uptake associated with severe hypotension and decreased blood flow occurred at lethal or near-lethal dose levels. In vitro measurement of oxygen uptake by mouse liver homogenates showed no effect at porphyrin concentrations up to 3 × 10-4M (5 mg/gram of liver in a 10% liver homogenate) at pH 7.4 to 8.9 but 50 per cent or more depression at pH 6.5 to 6.6. Associated phenomena and some implications of these results in relation to studies on the modification of radiosensitivity by porphyrins are considered.

Modification of Radiosensitivity of Mice by Inert Gases and Nitrous Oxide

Nitrous oxide and xenon, in mixture with oxygen at elevated pressure, diminish radiation sensitivity to wholebody and segmental irradiation. This protection, although correlated with anesthetic effect of these agents, does not appear to be due to anoxia of vital tissues.