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Biomedical subjects

M E Watts

Publications and source records attributed to M E Watts.

At least 37 records · Page 2Linked to original sources
PubMed1983

A rapid-mix study on the effect of lipophilicity of nitroimidazoles on the radiosensitization of mammalian cells in vitro.

A liquid flow rapid-mixing apparatus has been used to study the role of lipophilicity (octanol: water partition coefficient, P) in the sensitization of hypoxic V79 cells by nitroimidazoles. Sensitization by seven neutral 2-nitroimidazoles of similar reduction potential but widely differing partition (0.11-77) and one basic 2-nitroimidazole (pKa=8.9; p=8.5 (of free base)) was studied as a function of pre-irradiation contact time ca. 3-40 ms. With increasing P, sensitization occurs at increasingly shorter pre-irradiation contact times. The results suggest that even though factors other than passive diffusion control the sensitization observed with the base Ro 03-8799 it is able to diffuse to the target site faster than midonidazole.

Animals↗
PubMed1981

Use of solubilizing agents to study radiosensitization in vitro by compounds of low water solubility.

A major disadvantage in studying the effects of chemicals on the radiation response of mammalian cells in vitro can be the poor water solubility of the chemicals. Using Chinese hamster cells we have overcome this problem by using dimethyl sulphoxide and ethanol as co-solvents. From studies using these co-solvents and misonidazole as a standard we have demonstrated that these co-solvents have no effect on sensitizing efficiency and cytotoxicity. A number of poorly water soluble 2-nitroimidazoles of promising structure have been studied. The results, together with those from studies on misonidazole and the co-solvents are presented.

Animals↗
PubMed1980

Structure-activity relationships in the development of hypoxic cell radiosensitizers. III. Effects of basic substituents in nitroimidazole sidechains.

The effects of substituting 2-nitroimidazoles with groups carrying basic functions were studied. Prototropic, redox, lipophilicity and protein-binding properties were compared with the efficiency in radiosensitizing hypoxic Chinese hamster V79-379A cells in vitro and the cytotoxicities of the compounds after chronic aerobic exposure. Seventeen compounds were (2-nitro-1-imidazolyl)alkylamines in which the effects of changes in the terminating base and of alkyl chain length were investigated. About an order of magnitude increase in sensitization efficiency could be observed in some compounds without any increase in the aerobic cytotoxicity compared to simple, uncharged 2-nitroimidazoles such as misonidazole. The behaviour of five hydrazones was similar to that of uncharged analogues. The methiodide quaternary salts of two of the (2-nitro-1-imidazolyl)alkylamines showed that quaternization considerably reduced sensitization efficiency. (Nitro-1-imidazolyl)alkylamines appear worthy of further investigation as hypoxic cell radiosensitizers in vivo.

Animals↗
PubMed1980

Toxicity of nitro compounds toward hypoxic mammalian cells in vitro: dependence on reduction potential.

Fifteen nitroaromatic and nitroheterocyclic compounds that can act as "radiosensitizers" were tested for their cytotoxicity toward hypoxic Chinese hamster V79 cells in vitro. The cytotoxicity increased markedly as the electron affinity, measured as a one-electron reduction potential, increased. Non-nitro-containing compounds of similar electron affinities (such as quinones) that also act as radiosensitizers did not exhibit this specific toxicity toward hypoxic cells. The implications of the presence of the nitro group as a prerequisite for the hypoxic cell toxicity were discussed, and the mechanism of the cytotoxicity was compared with that of hypoxic cell radiosensitization.

Animals↗
PubMed1979

Structure-activity relationships in the development of hypoxic cell radiosensitizers. I. Sensitization efficiency.

The efficiency of 35 nitroaromatic and nitroheterocyclic compounds in radiosensitizing hypoxic Chinese Hamster cells in vitro was determined. The concentration C of the compound required to achieve an enhancement ratio of 1.6 was measured, and the redox and partition properties were quantified as the one-electron reduction potential at pH 7, E, and the octanol: water partition coefficient, P, respectively. Most of the compounds studied were 2-nitroimidazoles, but some 4- and 5-nitromidazoles, 5-nitrofurans and nitrobenzenes were investigated for comparison. Together with data for nine nitroimidazoles previously reported, the results were fitted to a structure-activity relationship of the form -log C = b0 + b1E + b2 log P + b3 (log P)2 using multiple linear regression analysis. Statistical tests showed that the coefficients b2 and b3 were not significantly different from zero and the simpler equation, obtained by omitting the terms in log P, explained 85 per cent of the variance in log C. Earlier reports that the radiosensitization efficiency of nitro compounds in vitro largely depends on the reduction potential were confirmed. The conclusive demonstration that P is unimportant in vitro is valuable in interpreting the results of experiments in vivo, where P is expected to have a much greater influence on biological response.

Animals↗
PubMed1979

Structure-activity relationships in the development of hypoxic cell radiosensitizers. II. Cytotoxicity and therapeutic ratio.

This paper describes measurements of the aerobic cytotoxicity of 42 nitroaromatic and nitroheterocyclic compounds towards Chinese Hamster cells in vitro. The results of acute and chronic exposure were quantified, and the concentration C required to achieve a standard response estimated. Fitting the data to an equation of the form - log C = b0 + b1E, where E is the one-electron reduction potential, explained 47 and 71 per cent of the variance in the acute and chronic aerobic cytotoxicity respectively. The addition of further terms to the equation, quantifying partition properties, was not statistically significant. The coefficient b1 was similar for both acute and chronic exposure; the dependence of both cytotoxicity and radiosensitization efficiency on reduction potential was also similar. A therapeutic ratio derived from these in vitro measurements showed no dependence on redox or partition properties. The insensitivity of cytotoxicity and radiosensitization properties to variations in molecular structure, other than those which influence redox behaviour, offers exceptional flexibility in developing compounds of improved therapeutic ratio.

Animals↗
PubMed1978

Some examples of anomalous radiosensitizing behaviour of electron-affinic compounds in vitro.

Studies using V79 379A cells on about 50 nitroaromatic and nitroheterocyclic radisosensitizers have confirmed the relationship between sensitizing efficiency and electron affinity. Almost all the compounds studied behaved similarly by sensitizing hypoxic cells to X-irradiation in a dose-modifying manner whilst having no sensitizing effect on oxygenated cells. However, a small number of the radiosensitizers studied exhibited additional or atypical properties. A 4-nitroimidazole ring substituted with chlorine sensitized hypoxic cells much more efficiently than predicted from its redox potential. A 2-nitroimidazole substituted with a carboxylic acid side chain showed a low but constant level of sensitization over 5 decades of concentration. A 5-nitrofuran, in addition to sensitizing hypoxic cells by dose modification, sensitized oxygenated cells by a reduction in extrapolation number.

Cell Survival↗
PubMed1978

Sensitization of ultraviolet radiation damage in bacteria and mammalian cells.

Bacteria (Serratia marcescens) and mammalian cell (Chinese hamster V79-379A) were irradiated in monolayers with ultraviolet light at 254 nm or 365 nm in the presence or absence of radiosensitizing drugs. At 254 nm, killing is very efficient (D37 approximately 1 J m-2 exposure, or approximately 6 x 10(4) photons absorbed by DNA per bacterium), and sensitizers have no effect. At 365 nm, cells are not killed in buffer, but are inactivated in the presence of nifurpipone or misonidazole. Lethal exposures (approximately 5 x 10(3) J m-2 at 10micrometer misonidazole) correspond to about 10 (7) photons absorbed by sensitizer molecules per bacterium. Toxicity of stabel photoproducts of the drugs is not involved, nor is oxygen required. Hence the transient species formed by photo-excitation of radiosensitizer molecules are capable of killing cells in the absence of other types of radiation damage.

Cell Survival↗
PubMed1977

Radiosensitization of hypoxic cells by a nitrofuran; dose-modifying and shoulder effects.

The radiosensitizer nifurpipone dihydrochloride (5-nitro-2-furaldehyde N-methyl piperazino acetyl hydrazone dihydrochloride) sensitizes hypoxic V79 mammalian cells by at least two mechanisms. Sensitization is by a reduction of ñ in addition to an increase in slope. Both these affects are absent under oxygenated conditions. When hypoxic V79 cells are irradiated in the presence of nifurpipone dihydrochloride combined with Ro-07-0582, sensitization greater than that due to air alone is observed; this effect is due to a reduction in ñ and an increased slope. Again this effect is absent under oxygenated conditions. Rapid-mix studies using Serratia marcescens show that full senitization occurs with a pre-irradiation contact time of 4 msec; this contrasts with data for V79 cells where a pre-irradiation contact time of 40 msec is insufficient for any sensitization to occur. This sensitizer also exerts a differential toxic effect, being more toxic to hypoxic cells than to oxygenated ones. It is concluded from these results that nifurpipone dihydrochloride sensitizes by at least two mechanisms, one of which resembles that of the electron-affinic type.

Cell Line↗
PubMed1975

Studies of the mechanisms of radiosensitization of bacterial and mammalian cells by Diamide.

Diamide sensitizes bacterial and mammalian cells to radiation by at least two mechanisms. Sensitization of V79-GL1 Chinese Hamster cells is due mainly to a reduction of a reduction of the survival-curve shoulder, is observed both in oxygen and in hypoxia,and is additive to the sensitization of hypoxic cells by some nitroimidazoles. In contrast, sensitization of the radioresistant organism, Micrococcus sodonensis, which has apronounced shoulder, is entirely dose-modifying. In a rapid-mix study using Serratia marcescens, two mechanisms of sensitization have been identified. After 4 to 40 msec preirradiation contact with Daimide, the enhancement ratio is constant at 1.6; after 10min contact, it is 2.5. With V79-GL1 cells, no sensitization occurs in the short-time-range; likewise non is seen when Diamide is added to bacteria or mammalian cells 4 msec after irradiation. It is concluded that Diamide sensitizes by at least two mechanisms, one of which resembles that of the electron-affinic type.

Animals↗