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Results for “Radiosensitivity”

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At least 649 records · Page 36Linked to original sources

PubMed1991

Aziridinyl nitropyrroles and nitropyrazoles as hypoxia-selective cytotoxins and radiosensitizers.

A series of 1- and 2-substituted 4- and 5-nitropyrroles and 3- and 4-nitropyrazoles has been prepared and evaluated in vitro as radiosensitizers of hypoxic cells and as bioreductively-activated cytotoxins. Both the nitropyrroles and the nitropyrazoles were considerably less effective, based upon the differential between hypoxic and aerobic toxicity, than were similar 2-nitroimidazoles bearing alkylating moieties. The trends in radiosensitizing efficiency observed for both classes of drugs corresponded with their one-electron reduction potentials (E1(7] as measured by pulse radiolysis, although they were generally more effective than predicted from previous correlations of E1(7] with sensitizing efficacy and reactivities. Furthermore, the enhancement of sensitizing efficiency by the incorporation of alkylating groups is considerably greater than has been observed for nitroimidazoles. alpha-[(1-Aziridinyl)methyl]-3-nitropyrazole- 1-ethanol (10, E1(7) = -456 mV) and methyl 5-nitro-1-(cyclopropylcarbonyl)pyrrole-2-carboxylate (25, E1(7) = -326 mV) were the most effective radiosensitizers in vitro. Only 3-[cis-2,3-dimethyl-1-aziridinyl) methyl)-1-oxo-3,4-dihydro-6-nitro-1-H-pyrrolo [2,1-c] oxazine (22) and methyl 5-nitro-1-(cyclopropylcarbonyl)pyrrole-2-carboxylate (25) showed significant bioreductively-activated cytotoxicity, with differentials of 3.5. Although these differential toxicities were coupled with significantly lower aerobic toxicity compared with similar 2-nitroimidazoles, this series was not deemed effective enough to warrant further evaluation. The electron affinity and radiosensitization could be manipulated by chemical design but hypoxia-selectivity was not clearly related to these properties.

Animals↗

PubMed1991

Targeting radiosensitizers to DNA by attachment of an intercalating group: nitroimidazole-linked phenanthridines.

The nitroimidazole-linked phenanthridine series of compounds (NLP-1, 2, and 3) were synthesized under the assumption that it should be possible to enhance the molar efficiency of 2-nitroimidazoles as hypoxic cell radiosensitizers and cytotoxins by targeting them to their likely site of action, DNA. The targeting group chosen was the phenanthridine moiety, the major component of the classical DNA intercalating compound, ethidium bromide. The sole difference between the compounds is the length of the hydrocarbon chain linking the nitroimidazole to the phenanthridine. The phenanthridine group with a three-carbon side chain, P-1, was also synthesized to allow studies on the effect of the targeting group by itself. The ability of the compounds to bind to DNA is inversely proportional to their linker chain length with binding constant values ranging from approximately 1 x 10(5) mol-1 for NLP-2 to 6 x 10(5) mol-1 for NLP-3. The NLP compounds show selective toxicity to hypoxic cells at 37 degrees C at external drug concentrations 10-40 times lower than would be required for untargeted 2-nitroimidazoles such as misonidazole in vitro. Toxicity to both hypoxic and aerobic cells is dependent on the linker chain: the shorter the chain, the greater the toxicity. In addition, the NLP compounds radiosensitize hypoxic cells at external drug concentrations as low as 0.05 mM with almost the full oxygen effect being observed at a concentration of 0.5 mM. These concentrations are 10-100 times lower than would be required for similar radiosensitization using misonidazole. Radiosensitizing ability is independent of linker chain length. The present compounds represent prototypes for further studies of the efficacy and mechanism of action of 2-nitroimidazoles targeted to DNA by linkage to an intercalating group.

Animals↗

PubMed1990

[Analysis of the frequency of spontaneous and induced autosomal recessive lethal mutations in the oogenesis of the radiosensitive mutant rad(2)201G1 of Drosophila melanogaster].

The frequency of spontaneous and gamma-ray induced autosomal recessive lethals has been studied in chromosomes 2 and 3 at different stages of Drosophila melanogaster radiosensitive mutant rad (2) 201G1 oogenesis. The frequency of spontaneous lethals in radiosensitive mutant was higher by the order of magnitude as compared with wild-type flies (9.3 and 0.6%, respectively). Germ cells of radiosensitive mutant were of high mutability at all stages of oogenesis studied. The irradiation of flies by 1.29 x 10(-1) Kl/kg results in decrease of lethals frequency in radiosensitive mutant as compared with the spontaneous level, whereas under irradiation by 7.74 x 10(-2) Kl/kg no change in mutability was revealed.

Animals↗

PubMed1989

Bone marrow toxicity of total-body irradiation combined with radiosensitizers.

The effect of the addition of radiosensitizers to low-dose total-body irradiation was studied. SR2508 (1 g/kg) or misonidazole (0.35 g/kg) was given 30 min prior to single-dose total-body irradiation, delivered at 0.1 Gy/min. Six dogs received either SR2508 or misonidazole and 2 Gy irradiation, and 14 dogs served as controls, receiving no drug and either 2 or 3 Gy of total-body irradiation. All dogs had a decline in their white blood cell and platelet counts and were supported with prophylactic antibiotics and platelet transfusions. High plasma levels of both radiosensitizers were achieved. The degree of cytopenia with 2 Gy total-body irradiation when combined with either radiosensitizer was not significantly greater than that seen with 2 Gy alone, and the neutropenia was significantly less than that seen with 3 Gy alone. The only observed toxicity of the drugs was vomiting, which started shortly after the infusion of SR2508 and before the radiation treatment. A single high-dose infusion of a radiosensitizer combined with total-body irradiation appears to cause a mild increase in bone marrow toxicity but is otherwise well tolerated.

Animals↗

PubMed1987

In vitro IgM and IgM rheumatoid factor production in response to Staphylococcus aureus Cowan I: evidence for the role of Leu-2-positive T suppressor cells and radiosensitive T helper cells.

Staphylococcus aureus Cowan I (SAC) is a potent stimulus of B cell proliferation and differentiation, the latter being T cell-dependent. It has been suggested that immunoglobulin and IgM rheumatoid factor (RF) production in response to SAC involves radiosensitive T helper cells. We studied normal peripheral blood mononuclear cell (PBMC) cultures to assess the roles of radiosensitive T cells and Leu-2 positive suppressor cells in the cellular control of SAC-stimulated IgM and IgM RF responses. Depletion of Leu-2 positive T cells from reconstituted autologous PBMC cultures resulted in an increase in SAC-stimulated IgM production in the majority of individuals, implying the involvement of Leu-2 positive suppressor T cells in this system. Suppression by Leu-2 positive cells is less evident in the SAC-induced IgM RF response, suggesting qualitative differences between IgM and IgM RF SAC-stimulated responses in PBMC cultures from the same normal individuals. Irradiation (1000 rads) of the T cell-enriched subpopulation, either with or without Leu-2 positive cell depletion, resulted in statistically significant decreases in IgM and IgM RF production in response to SAC in reconstituted autologous cultures, providing further evidence of a Leu-2 negative radiosensitive sheep-cell rosetting cell active in in vitro SAC responses. In contrast, PWM-stimulated PBMC cultures showed almost exclusively increases in total IgM and IgM RF production when T cells were irradiated (1000 rads) before culture, consistent with the radiosensitive T suppressor cell involved in the in vitro immunoglobulin responses to PWM. The same five out of nine individuals produced IgM RF, under different culture conditions, in response to PWM and SAC, suggesting that the ability of an individual to produce IgM RF lies intrinsically within the B cell.

Adult↗

PubMedDate not supplied

[Dependence of the radiosensitivity of yeast cells on the LET of radiations. Experiments on haploid cells].

The previously developed model was used to study the dependence of radiosensitivity (D0(-1) of Saccharomyces cerevisiae (the wild type and radiosensitive mutant) on linear energy transfer (LET) of ionizing radiation. D0(-1) (L) of haploid yeasts was shown to be associated, to a certain extent, with the capacity of radiation damages repair. As to the wild-type cells, the above function was represented by a curve showing a maximum, while a descending curve was characteristic of the radiosensitive mutant cells deficient in radiation damages repair. The influence of the repair processes on cell radiosensitivity decreased with increasing LET.

Alpha Particles↗

PubMed1986

DNA polymerase activity in heat killing and hyperthermic radiosensitization of mammalian cells as observed after fractionated heat treatments.

Possible relations between hyperthermic inactivation of alpha and beta DNA polymerase activity and hyperthermic cell killing or hyperthermic radiosensitization were investigated. Ehrlich Ascites Tumor (EAT) cells and HeLa S3 cells were treated with fractionated doses of hyperthermia. The heating schedules were chosen such that the initial heat treatment resulted in either thermotolerance or thermosensitization (step-down heating) for the second heat treatment. The results show that for DNA polymerase activity and heat radiosensitization (cell survival) no thermotolerance or thermosensitization is observed. Thus hyperthermic cell killing and DNA polymerase activity are not correlated. The correlation of hyperthermic radiosensitization and DNA polymerase activity was substantially less than observed in previous experiments with normotolerant and thermotolerant HeLa S3 cells. We conclude that alpha and beta DNA polymerase inactivation is not always the critical cellular process responsible for hyperthermic cell killing or hyperthermic radiosensitization. Other possible cellular systems that might determine these processes are discussed.

Animals↗

PubMed1986

Radiosensitization by tinidazole: pharmacokinetic study.

In previous study on cell-cultures, the authors have proved that tinidazole had radiosensitizing properties on hypoxic cells similar to those of metronidazole. The radiosensitizing activity of tinidazole becomes useful in vitro using a concentration of 1 millimol. The purpose of this study was to determine the dose of tinidazole necessary to produce a useful radiosensitizing effect in patients cured by radiotherapy. The pharmacokinetic properties of tinidazole were studied by treating patients with 1.5-3-4.5 g of the drug per day, using single doses for two consecutive days. The plasma concentration was determined by 15 series samples during a period of 48 h. Moreover endotumoural concentrations of tinidazole were studied in a group of patients using high pressure liquid chromatography techniques. The results showed that a dose of 4.5 g of tinidazole was sufficient to reach plasmatic and endotumoural concentrations similar to those which provide a radiosensitizing effect in vitro with an enhancement factor ratio of approximately 1.5. The initial dose and the accumulation factor were also determined in order to maintain the above-mentioned concentrations for a time sufficient to be able to apply multiple daily fractions of radiotherapy. The tolerance of the drug throughout the study was excellent.

Drug Administration Schedule↗

PubMed1986

Influence of buthionine sulfoximine and misonidazole on glutathione level and radiosensitivity of human tumor xenografts.

We have studied the effect of buthionine sulfoximine (BSO; a gamma-glutamylcysteine synthetase inhibitor) administration, either alone or combined with misonidazole (MISO), on five human tumor xenografts (three melanomas: Bell, Mall, and Nall; and two rectocolic adenocarcinomas: HT29 and HRT18) transplanted into mice. Two criteria were used, the nonprotein bound sulfhydryl (NPSH) level (glutathione (GSH) and cysteine (CYS] and the fraction of surviving tumor cells after gamma irradiation. GSH and CYS were estimated by HPLC and cell survival by in vivo-in vitro clonogenic assay. Administration of BSO alone (three injections of 10 mumol/g) prior to irradiation always produced a significant reduction in the GSH level while MISO administration (1 mg/g) did not consistently influence the NPSH level. While BSO had little or no radiosensitizing effect, MISO always induced radiosensitization (enhancement ratio between 1.6 and 1.8). This effect did not depend on the fraction of surviving hypoxic cells. An increase in MISO-induced radiosensitization produced by BSO was cell-line dependent. Results do not seem to support the hypothesis of a relationship between the GSH level at the time of irradiation and the radiosensitization induced by BSO or BSO + MISO. However, BSO treatment may not have been able to reduce endogenous thiols to a low enough level to test the hypothesis.

Adenocarcinoma↗

PubMed1979

Photosensitizers and radiosensitizers in dermatology and oncology.

Two therapeutic modalities are currently of great interest, namely photo- and radiosensitization. Whereas photosensitizers only function in combination with ultraviolet (UV) light, radiosensitizers act only in combination with ionizing radiation. Because of the small UV penetration, up to a maximum of 0,5 mm, photosensitization can take place only at the surface of the body, ie. the skin. Photosensitizers are applied in dermatology in order to optimize and improve the UV therapy of certain diseases (mainly psoriasis, mycosis fungoides and vitiligo). Radiosensitizers lead to an increase in sensitivity of the hypoxic and therefore radioresistant parts of tumours against X- and gamma-radiation. With sufficient concentration within the tumour, they can act where the radiation can reach, even in the deeper parts of the body. They represent a modern and useful aid to radiation oncology. Because of neurotoxic effects, however, their practical use is limited. A short review of the history, mechanisms of action, application and side-effects of these photo- and radiosensitizers is presented.

Brain Neoplasms↗

PubMed1982

Superoxide dismutase levels in various radioresistant and radiosensitive tissues of irradiated rats.

The activity of superoxide dismutase (E.C. 1.15.1.1; SOD) was determined in male Wistar rats in order to evaluate the possible relationship between both the enzyme content in tissue and the resistance of this tissue to ionizing radiation (8,0 Gy, 60Co). Our results showed that some non-irradiated radioresistant organs (liver) had a high SOD activity and on the contrary, in some radiosensitive tissue (bone marrow) the SOD content was low. In spite of this observation it is not possible to generalize the statement that the radiosensitivity is directly conditioned by the SOD level without any exception. The SOD content in the spleen was higher than in the brain, but the spleen is remarkably radiosensitive, whereas the brain is not. The radiosensitivity of individual tissues probably reflected the changes of SOD activity after the irradiation.

Animals↗

PubMed1983

Different radiosensitivities of mast-cell precursors in the bone marrow and skin of mice.

Although tissue mast cells are derived from the bone marrow, some descendants of bone marrow-derived precursors retain the ability to proliferate and differentiate into mast cells even after localization in the skin. The purpose of the present study was to determine the D0 values for mast-cell precursors in the bone marrow and those localized in the skin. Bone marrow cells were removed from (WB X C57BL/6)F1-+/+ mice after various doses of irradiation and injected into the skin of the congenic W/Wv mice which were genetically without mast cells. Radiosensitivity of mast-cell precursors in the bone marrow was evaluated by determining the proportion of the injection sites at which mast cells did not appear. For the assay of the radiosensitivity of mast-cell precursors localized in the skin, pieces of skin were removed from beige C57BL/6 (bgJ/bgJ. Chediak-Higashi syndrome) mice after various doses of irradiation and grafted onto the back of the normal C57BL/6 mice. Radiosensitivity of mast-cell precursors in the skin was evaluated by determining the decrease of beige-type mast cells which possessed giant granules. Mast-cell precursors in the bone marrow were much more radiosensitive than those localized in the skin. D0 value was about 100 rad for the former and about 800 rad for the latter.

Animals↗

PubMed1984

Glutathione depletion, radiosensitization, and misonidazole potentiation in hypoxic Chinese hamster ovary cells by buthionine sulfoximine.

Buthionine sulfoximine (BSO) inhibits the synthesis of glutathione (GSH), the major nonprotein sulfhydryl (NPSH) present in most mammalian cells. BSO concentrations from 1 microM to 0.1 mM reduced intracellular GSH at different rates, while BSO greater than or equal to 0.1 mM (i.e., 0.1 to 2.0 mM), resulting in inhibitor-enzyme saturation, depleted GSH to less than 10% of control within 10 hr at about equal rates. BSO exposures used in these experiments were not cytotoxic with the one exception that 2.0 mM BSO/24 hr reduced cell viability to approximately 50%. However, alterations in either the cell doubling time(s) or the cell age density distribution(s) were not observed with the BSO exposures used to determine its radiosensitizing effect. BSO significantly radiosensitized (ER = 1.41 with 0.1 mM BSO/24 hr) hypoxic, but not aerobic, CHO cells when the GSH and NPSH concentrations were reduced to less than 10 and 20% of control, respectively, and maximum radiosensitivity was even achieved with microM concentrations of BSO (ER = 1.38 with 10 microM BSO/24 hr). Furthermore, BSO exposure (0.1 mM BSO/24 hr) also enhanced the radiosensitizing effect of various concentrations of misonidazole on hypoxic CHO cells.

Animals↗

PubMed1984

The effect on the Km for radiosensitization at 0 degree C of thiol depletion by diethylmaleate pretreatment: quantitative differences found using the radiation sensitizing agent misonidazole or oxygen.

Pretreatment of V79- WNRE cells with 150 microM diethylmaleate for 1 hr at 37 degrees C caused a decrease in intracellular glutathione levels to approximately 10-15% of control levels (0.5 vs 5.0 nmol/10(6) cells). The cells could be washed free of diethylmaleate and held at 0 degree C for several hours without toxicity and with no increase in glutathione concentration, although the glutathione concentration rapidly increased to normal levels at higher temperatures. Survival curves were determined as a function of oxygen or misonidazole concentration (the latter in the absence of oxygen). A new "thin-film" technique was used to avoid changes in oxygen concentration because of radiochemical or cellular oxygen consumption. Glutathione depletion itself caused a small but consistent radiosensitization of hypoxic cells (dose enhancement ratio of 1.2). However, glutathione depletion caused a profound change in the radiosensitizing efficiency of misonidazole, with a decrease in Km of about sevenfold from 0.6 to 0.09 mM. In contrast, only a 2.5-fold decrease was found in the Km for radiosensitization by oxygen with diethylmaleate pretreatment. These results suggest a fundamental problem with the conventional theory of radiosensitivity whereby one considers a first-order competition for reaction with target radicals between radical-fixing versus radical-repairing species. It also suggests difficulties in the interpretation of glutathione as the only endogenous protective species.

Animals↗

PubMed1983

Evaluation of the factors influencing the radiosensitivity of mouse ascites tumors.

Factors influencing the radiosensitivity of the newly established mouse ascites tumor TMT-3 line were studied. In vivo radiosensitivity of the tumor cells decreased with the progression of the growth phase in mice. Oxygen depletion was the major cause of the decreased radiosensitivity. Polarographic measurement of the oxygen dissolved in suspension of various cell densities suggested that high cell density such as in the ascites might well cause severe hypoxia. Humoral factors in the ascites and cell-to-cell contact had no effect on tumor cell radiosensitivity when the influence of the repair of potentially lethal damage was excluded.

Animals↗

PubMed1981

Combination of radiosensitizers and hyperthermia in tumour radiotherapy.

Specific metabolic properties of hypoxic (and therefore radio-resistant) tumour cells are responsible for the selective effect of radiosensitizers (such as misonidazole) and hyperthermia upon these cells in respect of radiosensitization as well as cytotoxicity. Radiosensitizers and hyperthermia should therefore be used to improve the results of tumour radiotherapy; enhancement ratios of 2-4 have already been attained experimentally with this combined treatment. In spite of these good results, certain problems exist, and up to now the combination of radiosensitizers and hyperthermia has not been used to any great extent for tumours in humans.

Animals↗

PubMed1995

Lack of dependence of 5-fluorodeoxyuridine-mediated radiosensitization on cytotoxicity.

It has been proposed that fluoropyrimidine-mediated cytotoxicity and radiosensitization are closely correlated. We have shown that HT29 human colon cancer cells transfected with the E. coli dUTPase gene are resistant to 5-fluorodeoxyuridine (FdUrd)-mediated cytotoxicity, presumably through more effective elimination of dUTP. We used these cells to assess the association between radiosensitization and cytotoxicity produced by FdUrd. The radiation sensitivities of the clones expressing elevated dUTPase activity (dutE clones) were similar to those of untransfected HT29 cells or HT29 cells which had been transfected with only the expression vector for the E. coli gene (con clones). We found that FdUrd produced similar increases in radiation sensitivity regardless of dUTPase activity. Levels of dUTPase in the dutE clones remained elevated during the entire period of FdUrd exposure, demonstrating that the lack of difference between dutE and Con clones was not a reflection of down-regulation of dUTPase activity by FdUrd. Flow cytometry showed that all clones progressed past the G1/S-phase boundary and into early S phase during FdUrd treatment. These data suggest that the mechanisms of FdUrd-mediated cytotoxicity and radiosensitization are not closely linked. These findings, combined with our previous investigations, are consistent with the hypothesis that radiosensitization occurs in cells which progress past the G1/S-phase boundary in the presence of FdUrd.

Cell Survival↗

PubMed1993

Design and synthesis of N-(pyridylacryl) amino acid derivatives as potential radiosensitizers against HeLa-S3 cells in vitro.

A new series of N-(pyridylacryl) amino acid derivatives have been designed and synthesized as potential radiosensitizers in an effort to increase therapeutic efficacy with less toxicity. Radiosensitization and cytotoxicity of the newly synthesized compounds upon HeLa-S3 cells were measured. The main effects of the reduction of the shoulder width and Do value of the survival curve by 3-pyridylacrylsarcosine (3A) and 4-pyridylacrylsarcosine (4A) were observed. This work has demonstrated that this series of compounds, especially 3A and 4A, or their structurally related compounds, showed great clinical potential as radiosensitizers if significant radiosensitizing activity in vivo could be achieved.

HeLa Cells↗