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PubMed1984

[Platinum complexes as radiosensitizers in radiotherapy].

The authors study the radiosensitizing effect of cisplatinum, cis-dichloroethylenediamine platinum (II), and cis-dichlorobis-cyclohexylamine platinum (II) by the of TC-SV40 cells radiated under aerobic and hypoxic conditions. Cis-platinum shows the highest radiosensitizing activity but is very toxic. Perhaps cis-dischloro-bis-cyclohexylamine platinum (II) could be assayed as a less toxic radiosensitizing agent. On the other hand, DNA synthesis is studied in mouse spleen and TC-SV40 cells labeled with tritiated thymidine. Cis-platinum inhibitory activity is related to the preincubation time, cis-dichloroethylenediamine platinum(II) does not inhibit the semiconservative synthesis and stimulates the repair synthesis of DNA, and cis-dichloro-bis-cyclohexylamine platinum (II) produces a 60 per 100 inhibition of the semiconservative synthesis and a smaller inhibition of the repair synthesis.

Anaerobiosis↗

PubMed1980

[Recent data on biological and clinical properties of radiosensitizers (author's transl)].

In the pursuit of a way to reduce the radioresistance due, among others, to hypoxia in solid tumors, research on radiosensitizers (notably the electron-affinic sensitizers) has been active for many years. The radiosensitization efficiency and the cytotoxic and transforming effects of a great number of substances was first studied in vitro. Then two drugs, metronidazole and misonidazole, were tested especially in vivo in animals; this research concerned their effect both on tumors and on normal tissues. After presenting an overview of the experimental results, we summarize the preliminary results of the first clinical trials with misonidazole. The general tolerance to this drug is now well known: its local influence on tumors and also normal tissues radiosensitivity is the object of most of the present clinical trials.

Animals↗

PubMedDate not supplied

[Recent data on biological and clinical properties of radiosensitizers (author's transl)].

In order to reduce the radioresistance due, among others, to hypoxia in solid tumors, research on radiosensitizers (especially the electron-affinic sensitizers) has been active for many years. The radiosensitization efficiency and the cytotoxic and transforming effects of a great number of substances was first studied in vitro. Then two drugs, metronidazole and misonidazole, were tested especially in vivo in animals; this research concerned their effect both on tumors and on normal tissues. After presenting an overview of the experimental results, we summarize the preliminary results of the first clinical trials with misonidazole. The general tolerance to this drug is now well known: its local influence on tumors and also normal tissues radiosensitivity is the object of most of the present clinical trials.

Animals↗

PubMed1983

[Recent advances in hypoxic cell radiosensitizer].

The comparative studies on the radiosensitizing efficacy of misonidazole (MISO) and SR-2508, a new 2-nitroimidazole which is less neurotoxic than MISO, were performed using C3H/He mouse mammary tumors. The enhancement ratios of 1.42 for 0.5 mmole/kg of MISO and 1.82 for 1.5 mmole/kg of SR-2508, the equitoxic dose to MISO, were obtained when each drug was administered in combination with a single dose of radiation. When the radiation was delivered in three and five fractions, enhancement ratios decreased to 1.15 and 1.11 for MISO while they remained at 1.40 and 1.34 for SR-2508 respectively. Potentiating effect of diethyl maleate (DEM) on the radiosensitization of MISO was also studied using the same experimental tumor. Although DEM, in itself, has a radiosensitizing effect in the dose range of more than 600mg/kg combined use of DEM and MISO showed more efficient synergism, e.g., the enhancement ratio of 0.5 mmole/kg of MISO increased from 1.42 to 2.06 when it was given in combination with 760 mg/kg of DEM. However, synergistic effects of MISO and DEM observed were dependent upon given dose of each drug. i.e.

Animals↗

PubMed1983

Metabolic potentiation of the radiosensitization of hypoxic bacterial cells afforded by nitroaromatic compounds.

Prolonged preirradiation incubation of nitroaromatic radiosensitizers with Escherichia coli cells has been found to increase the degree of radiosensitization of the cells in anoxia. Studies with E. coli strains which differ in their nitroreductase activity indicate that the increase in sensitization arises from the action of metabolites produced by the nitroreductase system of the cell. The metabolites alone appear to decrease the extrapolation number of irradiated hypoxic cells and when combined with the parent compound give a biphasic survival curve. The combination of misonidazole (1 mmole dm-3) and its metabolites (1 mmole dm-3) gave initial and final enhancement ratios of 2.4 and 1.4, respectively. The final enhancement ratio is that expected for 1 mmole dm-3 misonidazole alone, whereas the initial enhancement ratio indicates that the metabolites potentiate the action of misonidazole. The preirradiation incubation effect is removed by dithiothreitol at concentrations which do not affect the radiosensitization level of the nitroaromatic sensitizer. This result indicates that the active metabolite probably depletes a certain amount of the free-thiol compounds inside the cell which assist in the repair of radiation-induced damage.

Acetophenones↗

PubMed1983

[X-ray-induced breaks in the X chromosomes in Drosophila lines of various radiosensitivities].

The frequency of X-ray induced X-chromosome breaks has been studied in females of the line rad (2) 201G1 hypersensitive to radiation and in females of the control line selected from the same population. The frequency of X-chromosome breaks was judged based on the frequency of X0 males occurrence. Synergism of the effects of X-rays (at doses 0.1, 0.5 and 1.0 kr) and of hyperthermia (+37 degrees C, 5.5 hours) applied after irradiation served as an indirect evidence for the functioning of DNA repair systems. It is demonstrated that radiosensitivity of mature oocytes of the lines compared was equal and that hyperthermia applied after irradiation increased the latter effect in both lines. Young oocytes of the control line were radioresistant, and hyperthermia applied after irradiation enhanced its effect. Opposite to them, young oocytes of the rad line females were radiosensitive. They did not differ from mature oocytes in the frequency of X-chromosome losses. Synergism of the two factors (irradiation and hyperthermia) was not registered in young oocytes. On the basis of the results obtained, it may be concluded that radiosensitivity of young oocytes in the hypersensitive line is conditioned by the failure of DNA repair systems and that the rad (2) 201G1 gene may be considered, in relation to the genes controlling DNA repair, as a suppressor functioning selectively at a certain stage of oogenesis.

Animals↗

PubMed1980

Radiosensitive, thymic hormone-sensitive peripheral blood suppressor cell activity in cancer patients.

Suppressor cell activity which was radiosensitive in most subjects and thymic hormone sensitive in some was identified in patients with cancer, and compared to simultaneously studied normal controls. Suppressor cell activity was measured in cocultures of normal lymphocytes with patient lymphocytes added in microwells using the blastogenic response to phytohemagglutinin and concanavalin A as the measure of activity. Thirty-five patients (lung cancer, 21; leukemia in remission, seven; and various solid tumors, seven) and an equal number of controls were studied. Suppressor cell activity was identified in 71% of the patients. In approximately 75% of these, the suppressor cell activity was radiosensitive (4000 to 6000 rads). For the phytohemagglutinin response, suppressor cell activity was thymic hormone sensitive in approximately 40% (Thymosin Fraction 5 or thymic humoral factor), and for the concanavalin A response, it was thymic hormone sensitive in about 25% of the cases. There was a significant correlation between the presence of immunodeficiency (defined as a phytohemagglutinin response < 35,000 or a concanavalin A response < 12,000 cpm) and the presence of the suppressor cell activity. The suppressor cell activity was heterogenous relative to its radiosensitivity and thymic hormone sensitivity. Suppressor cell activity was observed in all the patient categories. These results indicate that certain available therapeutic manipulations may have significant effects on suppressor cell activity and should be an important subject for further investigation.

Antineoplastic Agents↗

PubMedDate not supplied

[Circadian and seasonal rhythms in the radiosensitivity of mongrel white rats].

From experiments in albino mongrel rats it is shown that the radiosensitivity of gamma-irradiated (60Co) animals follows a daily rhythm. A synchronization of the daily rhythms in radiosensitivity was noted in winter and during the first spring month which was impaired in April. Established were the rhythms of radiosensitivity for three seasons, i. e. winter, spring and summer, with the extremes in the dependence upon mean annual values varying significantly.

Animals↗

PubMedDate not supplied

[Radiosensitivity of pluripotent stem cells detectable by cloning in the spleen of irradiated mice].

It was shown that the dose--effect curves describing the radiosensitivity of CFUc of the bone marrow irradiated in vitro (0.04-3.7 Gy) and treated with normal rabbit serum (NRS) and anti-mouse-brain serum (AMBS) has two differently sloping portions indicating that two CFUc populations differing in radiosensitivity are present in the bone marrow. D0 was 0.93 Gy after irradiation with doses of 0.04-0.75 Gy and treatment with NRS, and 0.33 Gy after incubation of the bone marrow with AMBS. The addition of thymus cells "straightened" the dose--effect curve for the bone marrow treated with AMBS: in this case D0 was 1.81 Gy exceeding considerably the values of D0 for intact bone marrow. The CFUc population is suggested to be heterogeneous in radiosensitivity.

Animals↗

PubMed1984

Thermal sensitivity and radiosensitization in V79 cells after BrdUrd or IdUrd incorporation.

Chinese hamster V79 cells were exposed to 10(-5) moles/liter bromodeoxyuridine (BrdUrd) or iododeoxyuridine (IdUrd) for 16 or 29 hr and then tested for thermal sensitivity, radiosensitivity, and sensitivity to the combined treatments of heat and radiation. BrdUrd and IdUrd treatment of cells resulted in enhanced radiosensitivity which increased with exposure time but had little or no effect on thermal sensitivity. For 42.0 degrees C heating, no effect was observed, while for 45.0 degrees C heating, a small decrease in thermal sensitivity occurred for both 16- and 29-hr exposure times, in the combined treatment of heat and radiation, the presence of BrdUrd or IdUrd resulted in about the same thermal enhancement in radiosensitivity. BrdUrd and IdUrd uptake into cellular DNA were measured using high-pressure liquid chromatography and, after a 29-hr exposure to 10(-5) moles/liter of BrdUrd or IdUrd, approximately 40% of the thymidine was substituted.

Acclimatization↗

PubMed1984

[Radiosensitization by oxygen in Ehrlich tumor receiving artificial blood substitute (FOB 20%)].

To enhance tissue PO2 of radioresistant hypoxic cells of tumor, artificial blood substitute (FOB) was applied, because it is excellent solvent for oxygen and allows the blood circulation system to recover and consequently increase the oxygen supply from blood to the tissue. When trasplanted Ehrlich tumor of mice on thigh grew about 1,000 mm3 in volume, those were divided into three groups, group 1: 60Co gamma-ray irradiation alone, group 2: irradiation under breathing oxygen, and group 3: irradiation under breathing oxygen after exchange transfusion with FOB. The radiosensitization of FOB was studied by comparing with the OER values of three groups for 50% TGD time, 50% SD time, and 50% and 75% TCP. The OER values of 50% TGD time, 5, 10 and 50% SD time 10 of oxygen group were 1.46, 1.29, and 1.22, respectively, and oxygen effect was observed in this group. Those values of FOB group were 2.02, 1.56, and 1.56, respectively and oxygen effect of FOB group was greater than those of oxygen effect of FOB group was greater than those of oxygen group. Animals receiving FOB were apparently radiosensitized by oxygen against animals breathing oxygen at small doses irradiation effect (50% TGD time, and 50% SD time). The OER values of 50% and 75% TCP at 30 days and 90 days after irradiation of oxygen group were about 1.5 (1.46-1.61) and these of FOB group about 1.3 (1.15-1.38). Radiosensitization by oxygen of animals receiving FOB was not clearly recognized against animals breathing oxygen in TCP effect at high dose irradiation. These results indicate that radioresistant hypoxic cells of tumor receiving artificial blood substitute (FOB) increase the sensitivity of 60Co gamma-ray irradiation, especially at small dose irradiation.

Animals↗

PubMed1984

Radiosensitization by derivatives of isoindole-4,7-dione.

New derivatives of isoindole -4,7-dione have been synthesized and their radiation sensitization and chemical behavior have been studied. One-electron reduction potentials have been determined by pulse radiolysis and found to be in the range of -0.45 to -0.36 V vs NHE . Radiosensitization effects were tested in vivo using soft tissue sarcoma transplanted in mice. All the isoindole -4,7-diones tested were found to exert considerable radiosensitization, approaching that of misonidazole tested under comparable conditions. The derivatives which contain a carbethoxy group on the pyrrolic ring were found to have more positive reduction potentials and to act as more efficient sensitizers. Further development of this class of radiosensitizers is underway.

Animals↗

PubMedDate not supplied

[Age-related changes in the radiosensitivity of animals and critical cell systems. Survival of stem cells of the small intestine epithelium 4-5 days after death in mice of various ages].

Mice of three strains exhibited similar changes in radiosensitivity tested with a reference to "intestinal" death: juvenile and old animals were more radiosensitive. No age-related changes were detected in radiosensitivity of stem cells of the small intestine epithelium estimated with a reference to average lethal dose D0.

Aging↗

PubMedDate not supplied

[Seasonal radiosensitivity of rats and dogs].

The data are submitted obtained on 10.5 thousands Wistar rats and 350 mongrel dogs exposed to gamma-radiation (LD40-LD100) in different seasons. The radiosensitivity of both animal species was the highest in autumn (August and September) and the lowest in winter (February and January). The seasonal DMF for rats and dogs with LD16, LD50 and LD84 was 1.24 and 1.31, 1.13 and 1.17 and 1.04 and 1.07, respectively. The curves for seasonal radiosensitivity of dogs with LD84, LD50 and LD16, exhibited a single--phase character throughout a year. For rats, the seasonal radiosensitivity curves with LD84 were single-phase, and the curve with LD50, and particularly LD16, exhibited the second peak of radioresistance in June. The increase in radioresistance of rats and dogs correlated with the increase in number of leukocytes in the peripheral blood of animals.

Animals↗

PubMed1983

Influence of heat on the intracellular uptake and radiosensitization of 2-nitroimidazole hypoxic cell sensitizers in vitro.

The effect of elevated temperature (44 degrees) on the intracellular uptake of the 2-nitroimidazole hypoxic cell radiosensitizer, misonidazole (MIS), and analogues more hydrophilic than MIS was studied in Chinese hamster ovary cells. It was found that the intracellular uptake of these compounds which enter cells by restricted passive diffusion can be enhanced approximately 4-fold when incubated at 44 degrees compared to the uptake at 37 degrees. Peak intracellular uptake (expressed as the ratio of intracellular concentration to extracellular concentration) following incubation of cells in 2 mM MIS was 100% at 44 degrees but only 25% at 37 degrees. Furthermore, a short-term nonlethal heat pulse (44 degrees for 15 min) with MIS present caused a 2-fold enhancement in uptake which was sustained for an additional 45 min at 37 degrees. This same nonlethal heat pulse was found to induce a similar enhancement in uptake even when MIS was added at subsequent time intervals at 37 degrees. The heat pulse induced a time-related enhancement of uptake at 37 degrees which increased for 1 hr and persisted for at least 6 hr. Finally, in vitro radiosensitization studies of hypoxic Chinese hamster ovary cells showed that the nonlethal heat pulse of 44 degrees for 15 min could greatly enhance the sensitization by low concentrations (0.5 mM) of MIS added after heating due to increased intracellular concentrations of the drug. MIS (0.5 mM) alone achieved a radiosensitization enhancement ratio of 1.29 (compared to irradiated hypoxic cells alone), while the addition of the short-term heat pulse, which had only a minor effect itself, achieved an enhancement ratio of 1.78.

Animals↗

PubMed1983

[Hyperthermia and radiosensitization].

The effects of hyperthermia on tumor cells and the mechanism of radiosensitization by hyperthermia were analysed. The clinical application of hyperthermia to cancer treatment was also discussed. The heat sensitivity of cells was dependent on the exposed period and temperature. The increase in one degree Celsius of temperature enhanced twice the heat sensitivity of cells. The target of cell killing might be proteins which are associated with the membrane-energy system. The heat sensitivity was increased at low pH. A large tumor (e. g., 800 mm3 of volume) responded more to hyperthermia than a small tumor (e. g., 30 mm3). This could be explained that the large tumor contains nencosis and many low-pH cells. Repeated treatment of hyperthermia induced heat-tolerance. The same effects of hyperthermia to the tumor cells were observed on normal tissues as well. The clinical application of hyperthermia can be evaluated by the therapeutic ratio. With animal tumors, 1.5 of the therapeutic ratio was obtained. By combining hyperthermia with irradiation, the radiation effect of cell killing was enhanced. The radiosensitization increased with the temperature of hyperthermia. The mechanism of radiosensitization is due to inhibition of repair from sublethal damage and potentially lethal damage. Clinical evaluation of the combination of two modalities was done by the therapeutic gain factor. Irradiation followed by hyperthermia resulted in more than unity of the therapeutic gain factor. It might be concluded that hyperthermia can be applied to large tumor clinically, and that the treatment of hyperthermia can be applied after 2 to 4 hours of irradiation when combined.

Animals↗

PubMed1981

Analysis of differentiated T-cell subpopulations: difference in radiosensitivity of immune responses to allogeneic antigen.

The radiosensitivity of immune responses to allogeneic tumor cells was compared. Delayed hypersensitivity as demonstrated by macrophage migration inhibition and antibody production as detected by immune adherence test were extremely radiosensitive. The radiosensitive nature of macrophage migration inhibition was in marked contrast to he radioresistance of the delayed footpad reaction. The generation of cytotoxicity was relatively radioresistant.

Animals↗

PubMed1982

Radiosensitizing ability and cytotoxicity of some 5(4)-substituted 2-methyl-4(5)-nitroimidazoles.

Radiosensitizing efficiency and cytotoxicity of three 2-methyl-4(5)-nitroimidazoles substituted with electron-withdrawal groups -NO2, -Cl and -OCH3 in 5(4)-position ("ortho" position) have been evaluated in vitro on V 79-379 A cells under aerobic as well as under hypoxic conditions. It has been established that 2-h incubation of cells at 37 degrees C in the presence of increasing (up to 2 mM) concentration of the compounds causes a moderate cytotoxicity for P7(2-methyl-5(4)-chloro-4(5)-nitroimidazole) and P5(2-methyl-4,5-dinitroimidazole). Cytotoxicities of these compounds are much stronger under hypoxic than under aerobic conditions. The compound P9(2-methyl-5(4)-methoxy-4(5)-nitroimidazole) is practically completely nontoxic. The radiosensitizing efficiency of P5, P7, and P9 at 2 mM concentration expressed by ER (enhancement ratio) equals 1.75, 1.57 and 1.14 respectively. A discussion regarding the features of electron-affinity, cytotoxicity and radiosensitizing ability of the compounds studied is presented.

Animals↗