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Biomedical subjects

B C Millar

Publications and source records attributed to B C Millar.

At least 127 records · Page 7Linked to original sources
PubMed1984

Do prostaglandins affect cellular radiosensitivity in vitro?

We have been unable to detect any change in the in vitro radiation response of mouse fibrosarcoma cells, HSDM1C1, which secrete 2 micrograms PGE2/mg cell protein/24 h, in the presence of the prostaglandin biosynthesis inhibitor flurbiprofen. Furthermore, addition of exogenous PGE1 or PGA2 to cultures of Chinese hamster cells was similarly without effect on radiation response. Although a high concentration of PGA2 inhibited the growth of Chinese hamster cells in vitro this effect disappeared upon removal of the prostaglandin. The implications of these results for radiotherapy are discussed.

Animals↗
PubMed1983

In vitro inhibition of misonidazole toxicity and melphalan chemopotentiation by metyrapone.

Overnight exposure of Chinese hamster cells, V-79-753B, to 10(-3)M metyrapone protected them against the hypoxiamediated toxicity of 10(-2)M misonidazole. This protection was accompanied by an increase in radiation resistance. There was no appreciable change in the oxygen-enhancement ratio, nor in the amount of sensitisation produced by 10(-3)M misonidazole. Treatment of cells with metyrapone (10(-3)M) or dexamethasone (1 microgram ml-1 [approximately 2 X 10(-6)M]) prior to exposure first to 5 X 10(-3)M misonidazole in hypoxia and then to melphalan in air, substantially decreased the amount of chemopotentiation produced by the sensitiser, although the toxicity of melphalan alone was not affected in cells treated with either compound. Cells pretreated with either metyrapone or dexamethasone had 2-3 times more glutathione than control cells. This increase in GSH could not explain the change in radiation response, since cells pretreated with 5 X 10(-5)M flurbiprofen, a non-steroidal anti-inflammatory agent, had similarly high GSH levels, but their radiation response is similar to that of untreated cells (Millar et al, 1981). Neither dexamethasone nor flurbiprofen affected cell growth, whilst metyrapone markedly decreased the growth of cells. The results are discussed in terms of possible mechanism(s).

Animals↗
PubMed1983

Polyfunctional Radiosensitizers. VI. Dexamethasone inhibits shoulder modification by uncharged nitroxyl biradicals in mammalian cells irradiated in vitro.

Overnight exposure of Chinese hamster cells (V. 79-753B) in vitro to 1 micrograms/ml dexamethasone increases the radiation resistance of the cells by about 20% both in air and in hypoxia, while having no appreciable effect on the oxygen enhancement ratio (OER). This is accompanied by substantially higher levels of glutathione. When dexamethasone-treated hypoxic cells are irradiated in the presence of nitroxyl biradicals there is no effect on the slope ratio of of the exponential portion of the survival curves. In the case of uncharged biradicals, Ro.03-6061 and RSU-4072. which have been shown to modify the shoulder region of the hypoxic cell survival curve, there is an increase in extrapolation number in dexamethasone-treated cells. When hypoxic cells are exposed to the charged biradical RSU-4073, which does not exhibit shoulder modification, there is no change in extrapolation number. Experiments to examine the effect of concentration of these compounds on radiosensitization show that lower concentrations of both RSU-4072 and RSU-4073 are required to mediate changes in the slope of the hypoxic cell survival curve than to mediate shoulder modification, in the case of RSU-4072. Quantitative ESR data comparing the uptake of RSU-4072 and RSU-4073 with the monoradical TMPN into cells suggest that the cell membrane may act as a barrier to the incorporation of biradicals, and that this is greater for charged than for uncharged compounds. Treatment of cells with dexamethasone does not affect the uptake of the compounds. The data suggest, however, that the cell membrane may be an important site for localization of uncharged biradicals and that this may be important in determining shoulder modification.

Air↗
PubMed1981

Flurbiprofen, a non-steroid anti-inflammatory agent, protects cells against hypoxic cell radiosensitizers in vitro.

Overnight exposure of Chinese hamster cells (V79-753B) to 5 x 10(-5) M flurbiprofen (2-(2-fluoro-4-biphenyl)propionic acid) in vitro reduced the cytotoxic effects of misonidazole, 1-methyl-4-nitro-5-phenoxysulphonylimidazole (NSC 38087) and nitrofurantoin, both in air and in hypoxia at 37 degrees C. Flurbiprofen did not alter the cells' uptake of 14C-misonidazole, nor did it affect the radiosensitivity of aerobic or anaerobic cells, or the degree of hypoxic-cell radiosensitization produced by the sensitizers. When flurbiprofen-treated cells were exposed to melphalan there was no protection against cytotoxicity. These data suggest that flurbiprofen may inhibit the catabolism of radiosensitizers to toxic products and indicate the need to examine whether it will protect against misonidazole-induced toxicity in vivo.

Animals↗
PubMed1981

Radiosensitization of hypoxic mammalian cells in vitro by some 5-substituted-4-nitroimidazoles.

The efficiencies of various 5-substituted-4-nitroimidazoles as radiation sensitizers have been determined in hypoxic Chinese hamster cells irradiated in vitro. Compared with published data on the sensitizing properties of substituted 2-nitro- and 5-nitroimidazoles, some of the 4-nitro derivatives show unusually high sensitizing efficiencies defined as the concentrations required to give an enhancement ratio of 1.6. The equilibrium one-electron reduction potentials of the compounds (E17) were measured by a pulse radiolysis technique and the results show that although sensitizing efficiencies are unexpectedly high, based on considerations of electron affinity, they still increase with increasing values of E17. Enhancement ratios were determined in two V79 cell lines for combinations of one of these compounds (a 4-nitroimidazole containing the group SO2.O.phenyl in the 5-position, NSC 38087) with various concentrations of misonidazole. The sensitization observed suggests that the two compounds may be operating by different mechanisms.

Animals↗
PubMed1981

The effect of dexamethasone on the radiation survival response and misonidazole-induced hypoxic-cell cytotoxicity in Chinese hamster cells V-79-753B in vitro.

Overnight exposure of Chinese hamster cells, V-79-753B, to microgram quantities of the synthetic corticosteroid, dexamethasone, resulted in a decrease in sensitivity towards radiation, both in air and in hypoxia. The effect was dose-modifying and the oxygen enhancement ratio did not change appreciably. Similarly, when dexamethasone-treated hypoxic cells were irradiated in the presence of misonidazole, a hypoxic cell radiosensitizer, there was a decrease in radiation sensitivity compared with untreated hypoxic cells irradiated with misonidazole. The effect of dexamethasone cannot be attributed to classical radioprotection since administration of the drug immediately or 4.5 h before irradiation does not alter the survival response of hypoxic cells with or without misonidazole. Neither can this increased radioresistance be attributed to synchronization to a more resistant phase of the cell cycle since pretreated cells remain more radioresistant for at least 6 h after the removal of the drug. The data suggest that dexamethasone induces metabolic changes in cells which alter their radiosensitivity. Whatever metabolic changes may be occurring there was no effect on the uptake of 14C-misonidazole into dexamethasone-treated or control cells. However, there was a pronounced decrease in hypoxic-cell cytotoxicity induced by misonidazole in cells pretreated with dexamethasone. The implications of these results are discussed.

Animals↗
PubMed1980

Enhanced killing of mammalian cells by radiation combined with m-AMSA.

m-AMSA is an intercalating agent at present on Phase II trial as a chemotherapeutic drug. A 30 min exposure of Chinese hamster (Line V79-753B) cells to submicromolar concentrations of m-AMSA killed 50% of the cells. The survivors had an enhanced sensitivity to radiation-induced cell killing. Depending upon the conditions, m-AMSA enhanced the radiation effect by either a decrease in the survival-curve shoulder or by an increase in slope. m-AMSA may act partly by suppressing the accumulation of sublethal damage but, if so, recovery from damage as measured in split-dose experiments with cells pretreated with the drug is not affected to its radiation effect from selective toxicity to cells in a radioresistant phase of the cell cycle cannot be excluded. Radiation and the drug interacted to give increased cell killing, even when the exposures to each agent were separated in time. It is concluded that m-ASMA may behave like actinomycin D and adriamycin, and enhance clinical radiation responses. In vivo testing to determine the effect of m-AMSA on the therapeutic index is recommended.

Aminoacridines↗