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T C Jenkins

Publications and source records attributed to T C Jenkins.

At least 163 records · Page 9Linked to original sources
PubMed1986

Analogues of RSU-1069: radiosensitization and toxicity in vitro and in vivo.

A series of nitroimidazoles containing aziridine and alkyl-substituted aziridine functions has been synthesized. The 2-nitroimidazole compounds examined all show greater radiosensitizing efficiency in vitro than misonidazole. The 4- and 5-nitroimidazole analogues are also more efficient than equivalent compounds which do not contain the alkylating aziridine moiety. All the compounds show increased toxicity towards hypoxic cells relative to aerobic cells, but this toxicity is reduced by alkyl-substitution of the aziridine ring. In vivo toxicity can also be reduced by modification of the aziridine function, but such alterations appear to have less effect upon the high radiosensitizing efficiency of these compounds in vivo. As a consequence of this study, compounds of potentially improved therapeutic utility compared to RSU-1069, the first reported member of this class, have been identified.

Animals↗
PubMed1986

Studies on the mechanisms of the radiosensitizing and cytotoxic properties of RSU-1069 and its analogues.

RSU 1069 is a substantially more efficient sensitizer than misonidazole when hypoxic Chinese hamster V79 cells are irradiated in vitro at room temperature; such that for 0.5 mmol dm-3 sensitizer an ER of 3.0 is obtained for RSU 1069 whereas an ER of only 1.6 is obtained for misonidazole. However, when irradiation is done at 4 degrees C, the radiosensitization caused by RSU 1069 is reduced to a level close to that obtained with misonidazole, the action remaining unaltered at the lower temperature. This temperature dependent component of sensitization for RSU 1069 suggests the involvement of a slow biochemical process that has an appreciable activation energy. The RSU 1069 analogue RB 7040 is a more efficient radiosensitizer than RSU 1069 particularly at lower concentrations. This compound has a pKa value of 8.45, in contrast to that of RSU 1069 which is 6.04. Weak bases with pKa values in excess of average intra-cellular pH can be taken up preferentially into cells from medium at pH 7.4. It is shown that RB 7040 has a 4 X higher intracellular concentration than RSU 1069 for a similar extracellular concentration. This will explain, at least in part, the greater sensitizing efficiency of this compound when compared to RSU 1069 in vitro.

Animals↗
PubMed1986

Experimental pharmacokinetics of RSU-1069 and its analogues: high tumor/plasma ratios.

The mixed-function radiosensitizer RSU-1069 and its analogues possess both alkylating and electron-affinic properties, and have been shown to be more efficient radiosensitizers than misonidazole both in vivo and in vitro. The pharmacokinetics following intraperitoneal injection of three members of this series, RSU-1069, RSU-1164, and RSU-1172 have been studied in C57BL mice bearing B16 melanoma. Peak tumor levels of each compound, and tumor/plasma ratios (T/P) were found to be high: T/P RSU-1069 = 3.8, RSU-1164 = 3.7; RSU-1172 = 4.0. In contrast, other normal tissues including brain showed tissue/plasma ratios close to 1. The mechanisms responsible for differential tumor uptake are unknown, but may depend on the basicity of the compounds, leading to preferential uptake in areas of low pH, or alternatively they may be associated with the alkylating function. This group of compounds appear to demonstrate highly favorable tissue distributions.

Animals↗
PubMed1986

The radiosensitizing and toxic effects of RSU-1069 on hypoxic cells in a murine tumor.

RSU-1069 is one of a group of compounds of particular interest in radiobiology, since it combines the nitroimidazole ring with a side chain bearing a monofunctional alkylating agent. This compound has been shown to be a potent radiosensitizer both in vitro and in vivo. Furthermore, it has recently been shown to be an effective hypoxic cell cytotoxin in vitro. Our studies have been carried out using the SCCVII squamous carcinoma implanted subcutaneously in C3H mice, using a technique we recently developed which facilitates isolation of tumor cell subpopulations from known locations relative to the tumor blood supply. The response of the separated tumor subpopulations was assessed using a soft agar clonogenic assay. For radiosensitization studies, RSU-1069 was administered i.p. at 0.5 mumol/g 20 min before irradiation and the tumors excised 20 min after irradiation. For toxicity studies, tumors were excised 16-18 hr after RSU-1069 administration. The results obtained to date clearly demonstrate that RSU-1069 is an efficient hypoxic cell radiosensitizer and cytotoxin in this murine tumor and has little effect on well perfused (i.e., oxic) cells.

Animals↗
PubMed1986

The phosphate-group of DNA as a potential target for RSU-1069, a nitroimidazole-aziridine radiosensitizer.

Strand breakage of plasmid DNA by parent and radiation-reduced RSU-1069 (2.0-8.0 mmol dm-3) has been measured in air over 4 hr at 310K. Reduced RSU-1069 was shown to be approximately 4 times as efficient as the parent compound at causing strand breakage. The aziridine moiety of both parent and reduced RSU-1069 is required for strand break production and, furthermore, is capable of alkylating inorganic phosphate (k = 1.0 X 10(-3) dm3 mol-1 s-1) and a series of nucleotides (k = 0.8 - 2.1 X 10(-3) dm3 mol-1 s-1) at pH 7.0. From the determined rate constants and the nature of the adducts observed, it was shown that phosphate is a target on nucleotides, although additional sites probably exist particularly, on dGMP and dAMP. The mechanism of action of RSU-1069 is discussed in terms of its ability to act as a cytotoxic agent, radiosensitizer and bioreductive drug.

DNA, Bacterial↗
PubMed1986

Effect of dietary fat and calcium source on insoluble soap formation in the rumen.

Diets with and without added fat and with different amounts of soluble and insoluble calcium were fed to rumencannulated cows to determine roles of fat and calcium in formation of insoluble calcium soaps in the rumen. Percent of total fatty acids in soap was increased only by addition of soluble calcium (CaCl2). The amount of fatty acid in soap was highly dependent on amount of fat in the rumen and was not changed by calcium addition. Concentration of ionized calcium in rumen content was halved by fat addition and was inversely correlated with rumen pH, whereas proportion of fatty acid in soap was directly related to pH. Rumen pH was lower 8 to 12 h postfeeding when calcium was added to the diet, which was related nonsignificantly with total volatile fatty acid concentration. Addition of fat to diets tended to lower the ratio of acetic to propionic acids in the rumen; this trend was reversed by calcium addition. Beneficial effects of added calcium in high fat diets were not caused by increased calcium soap formation in the rumen.

Animal Feed↗
PubMed1985

Induction of DNA strand breaks by RSU-1069, a nitroimidazole-aziridine radiosensitizer. Role of binding of both unreduced and radiation-reduced forms to DNA, in vitro.

[2-14C]-RSU-1069 [1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol], either as a parent (unreduced) or following radiation reduction, binds to calf thymus DNA in vitro. Radiation-reduced RSU-1069 binds to a greater extent and more rapidly than the parent compound. RSU-1137, a nonaziridino analogue of RSU-1069, binds following radiation reduction. Radiation-reduced misonidazole (1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol) exhibits binding ratios a thousand-fold less than those of reduced RSU-1069. There is no evidence for binding of parent misonidazole. Both parent and reduced RSU-1069 cause single strand breaks (ssbs) in pSV2 gpt plasmid DNA with the reduced compound causing a greater number of breaks. Parent and reduced RSU-1137 and misonidazole do not cause ssbs. It is inferred that the aziridine moiety present in both parent and reduced RSU-1069 is required for ssb production. RSU-1069 reacts with inorganic phosphate probably via nucleophilic ring-opening of the aziridine fragment. Incubation of plasmid DNA with reduced RSU-1069 in the presence of either phosphate or deoxyribose-5-phosphate at concentrations greater than 0.35 mol dm-3 prevents strand breakage, whereas 1.2 mol dm-3 deoxyribose does not protect against strand breakage formation. From these findings it is proposed that the observed binding to DNA occurs via the aziridine and the reduced nitro group of RSU-1069 and that these two have different target sites. Binding to DNA via the reduced nitro group may serve to increase aziridine attack due to localization at or near its target.

Acetates↗
PubMed1985

Polyfunctional radiosensitizers. VII. Radiosensitization by conformationally-restricted isomers of a nitroxyl biradical in vitro.

Bothtrans-N,N'-bis(2,2,6,6-tetramethyl-1-oxyl-4-piperidinyl)-1, 2-diaminocyclopropane[Ro31-2269] and its cis isomer [Ro 31-2778] selectively sensitized hypoxic Chinese hamster cells, line V-79-753B, to radiation by decreasing both the D0 value and extrapolation number, whereas a related dibasic monoradical Ro 31-2655 decreased D0 alone. Although sensitization was maximal after a 1-hr cell-drug contact time, cells continued to accumulate both Ro 31-2269 and Ro 31-2778 when this contact time was increased up to 3 hr. There was no evidence for competition between either biradical and 2,2,6,6-tetramethyl-4-piperidinol-N-oxyl (TMPN) at equimolar concentration or biradical and 0.82 microM oxygen when cells were equilibrated with the biradicals for 3 hr prior to irradiation in the presence of mixtures of either oxygen and biradical, TMPN and biradical, or TMPN alone. Furthermore, when cells were equilibrated with an equimolar radical concentration of the trans isomer Ro 31-2269 and TMPN for 1 hr prior to irradiation in the presence of the mixture, there was no appreciable effect on sensitization of the slope of the hypoxic cell survival curve, but shoulder modification was reduced. When cells were equilibrated with the trans isomer Ro 21-2269 prior to irradiation in combination with 2.92 microM oxygen, cell survival was similar to that seen for cells irradiated with this concentration of oxygen alone. Examination of the plasma membrane from cells equilibrated with the trans biradical Ro 31-2269 showed that the drug accumulated in the membrane when compared with the concentration found in whole cells. Experiments with the conformationally-unrestricted biradical bis(2,2,6,6-tetramethyl-1-oxy-4-piperidinyl) succinate [Ro 03-6061] showed that when cells were equilibrated with the compound for 1 hr prior to irradiation in hypoxia in the presence of a mixture containing an equimolar radical concentration of TMPN, there was an increase in both the slope and the extrapolation number compared with values for hypoxic cells irradiated in the presence of this biradical alone. Furthermore, when cells which had been equilibrated with Ro 03-6061 were washed free of the drug, there was a residual decrease in both the D0 and extrapolation number of the hypoxic cell survival curve for at least 3 hr after removal of the compound. The results are discussed in terms of a model to account for sensitization by these compounds.

Animals↗
PubMed1985

The VER as a predictor of normal visual acuity in the adult human eye.

The ability of the evoked potential to predict conventional visual acuity, as measured with a Landolt C test, was investigated for subjects with normal acuities. Both peak-to-trough and Fourier-analysed amplitudes were used. The extrapolation technique assumed curvilinear regression and produced correlations no better than did a method employing amplitude measurements of a single check size of 5.5 min arc (r = 0.67). Assessment of Landolt C acuity by subjective use of the evoked potential stimulus was unable to produce a higher correlation.

Adolescent↗
PubMed1985

Radiosensitizers of hypoxic mammalian cells. 1-(Hydroxyaminoalkyl)-substituted nitroimidazoles.

A series of novel 1-(hydroxyaminoalkyl)-substituted nitroimidazoles has been synthesized as potential radiosensitizers for hypoxic mammalian cells. These compounds were synthesized via N-(hydroxyalkyl)phthalimide nitroimidazole intermediates which, on reaction with hydrazine hydrate, yielded the corresponding amines. The intermediates were prepared by reacting the epoxide derived from nitroimidazole with phthalimide and/or the epoxide derived from phthalimide with the nitroimidazole. The method was used successfully for the preparation of 2-, 4- and 5-nitroimidazole derivatives. In a modification of this procedure, 1-(2-aminoethyl)-2-nitroimidazole has been prepared by a new route which avoids the use of aziridine. These agents were tested for cytotoxicity and radiosensitizing ability in vitro using Chinese hamster V79 cells. All of the 2-nitroimidazoles tested showed toxicity similar to that previously reported for misonidazole and Ro 03-8799 (1-(2-hydroxy-3-piperidinopropyl)-2-nitroimidazole), two compounds currently undergoing clinical evaluation. In addition, all the novel primary amines were shown to function as hypoxic cell radiosensitizers. The 2-nitroimidazole derivatives were the most efficient compounds to be examined and showed at least as much activity as misonidazole.

Animals↗
PubMed1984

Empty body component gain of rats grown at different rates to a range of final weights.

Rate of gain by final weight response surfaces for gain of empty body water, protein, lipid and ash were defined with data from 62 male Sprague-Dawley rats. Rats were fed for 21 days at 100, 88, 76, 64, 52 or 40% of ad libitum intake within each of five initial weight groups ranging from 84 to 286 g. Forty additional rats were killed at the beginning of the growing period to provide initial estimates of amount and composition of empty body weight. Water in the gain decreased (P less than 0.05) and lipid increased (P less than 0.05) with increasing final weight. Gains of protein and ash were not significantly affected by final weight. Gains of water, protein and lipid increased (P less than 0.05) linearly with increasing rates of gain. The relationship between rate of gain and composition of gain was not affected by different final weights. Averaged across final weight, at all rates of gain each gram of gain was composed of about 66.9% water, 18.8% protein, 10.6% lipid and from 1.0 to 2.5% ash. Thus, each additional unit of gain per unit time was composed of the same amount of water, protein, lipid and about the same amount of ash. Therefore, over the stage of growth examined, these results demonstrate that the rates at which rats grow do not influence the composition of their gain to a particular weight.

Animals↗
PubMed1984

Effect of fatty acids or calcium soaps on rumen and total nutrient digestibility of dairy rations.

Two trials ascertained whether feeding fatty acids as preformed calcium soaps would permit normal digestibility of fiber without reducing availabilities of fatty acids or energy. Six diets contained no added fat (control) or the equivalent of 4.5% added fatty acids as tallow or soy fatty acids, tallow or soy calcium soaps, or tallow combined with the nonnutritive carrier verxite. Six cows were fed each diet in trial 1 to ascertain digestibilities of total nutrients, whereas control, tallow fatty acid, and tallow soap diets were fed to steers with duodenal cannulae in trial 2 to evaluate effects of fat source on rumen fermentation. Digestibility of total fiber in trial 1 was reduced 13% by tallow fatty acids. In trial 2, tallow fatty acids markedly reduced digestibility of dry matter and fiber in the rumen. Diets supplemented with tallow calcium soaps had normal digestibilities of fiber in the rumen and totally, but digestibility of fatty acids was reduced 6% and digestibility of energy reduced 3% compared to feeding tallow fatty acids. Efficiency of synthesis of microbial protein was 39% higher for tallow fatty acids than for control. Feeding tallow verxite also permitted normal digestibility of fiber in trial 1 but caused reduced availabilities of fatty acids and energy.(ABSTRACT TRUNCATED AT 250 WORDS)

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↗
PubMed1983

Some aspects of amblyopia.

Some of the recently suggested methods for treating amblyopes are reviewed. A survey of the success rate in 50 young amblyopes, using conventional methods, is described. Whilst 26% did not improve at all in visual acuity, 50% improved by at least two Snellen lines. The suggestion is made that the success rate in the clinic described is similar to that found elsewhere.

Afterimage↗
PubMed1982

Visually evoked responses to checkerboard patterns: check and field size interactions.

Pattern reversal visually evoked responses (VER's) at a frequency of 7 Hz were recorded from 10 subjects. Peak-to-trough amplitudes were measured at centrally fixated field sizes from 1 to 8 degrees for check sizes from 2.5 to 30 min. Check size for maximum amplitude decreased as field size was reduced. The amplitude--check size relation was not necessarily linear across its full range. When using an extrapolation technique for estimating visual acuity, a curvilinear regression may be more appropriate than the assumption of a linear regression.

Evoked Potentials, Visual↗
PubMed1982

Success rate in the treatment of amblyopia by conventional methods.

Conventional methods of treatment were given to 50 young amblyopes, with the result that 26% showed no improvement and 50% improved by at least two Snellen lines. A 0.67 correlation coefficient was found between acuity before and after treatment. Whilst there was some differences in approach to convergent squint amblyopes and to non-squinting amblyopes, the degree of success in the two subdivisions was similar.

Amblyopia↗
PubMed1982

Orthoptic treatment in teenage patients.

A survey of 100 patients who received orthoptic treatment in the Bradford University Clinic is examined to see the level of success with the different binocular anomalies, indicating what factors were common in successful cases, and the type of treatment given. A successful outcome or worthwhile improvement was achieved in enough cases to conclude that orthoptics in teenage patients is often appropriate, even in strabismus, if the cases are selected carefully. There was no indication that the actual age made any difference once the patients was between 11 and 19 years, but the starting acuity was significant.

Adolescent↗