Search PubMed⌕ Search

Biomedical subjects

J F Ward

Publications and source records attributed to J F Ward.

At least 109 records · Page 6Linked to original sources
PubMed1981

Mice, men, mustard and methylated xanthines: the potential role of caffeine and related drugs in the sensitization of human tumours to alkylating agents.

The relationships between DNA damage from UV radiation, alkylating drugs and the methylated xanthines (MX) have been studied in normal and malignant rodent and human cells. A comparison of the level of DNA excision repair (repair replication and unscheduled DNA synthesis) confirms that some forms of alkylating-agent damage (probably mono-filar DNA adducts) are less completely removed by both normal and malignant rodent cells than by their human counterparts, rendering rodent cells more susceptible to the toxic potential of unexcised lesions. The toxicity of alkylating agents can be increased by the presence of several MXs during the period of DNA replication which follows infliction of the damage. Human cells appear capable of excising more DNA damage, rendering them somewhat less susceptible to enhancement of cytotoxicity by MX. This resistance of human cells is only quantitative, however, since 2 human cancer cell lines (HeLa and HT-29) could be sensitized to a variety of alkylating agents by appropriate concentrations of MX. Trimethylxanthine (caffeine) and the 2 clinically useful dimethylxanthines (theophylline and theobromine) appeared equally effective in sensitizing cells. The sensitization was dependent upon a slightly cytotoxic concentration of the MX and a suitably prolonged period of post-damage MX exposure. Of these 3 classic MXs, only theobromine might be clinically useful. The levels required for alkylating-agent sensitization exceed the clinically tolerable level of theophylline, and probably approach the tolerance of man to caffeine. The most likely mechanism by which MX sensitization is achieved is reversal of the inhibition of DNA replicon initiation which follows the infliction of significant DNA damage. Through the selection of suitable clinically useful alkylating agents (those dependent on active cellular transport for cell penetration) and appropriate MX scheduling, an enhanced therapeutic ratio might be achieved, potentially increasing the clinical usefulness of these alkylating agents. MX would thus form a useful class of agents adjuvant to conventional anti-cancer drugs.

Alkylating Agents↗
PubMed1981

DNA polymerase alpha and beta activity in gamma-irradiated HeLa S3 cells.

The acute effects (less than 2 hours) of gamma-irradiation on DNA polymerase alpha and beta activity in HeLa S3 cells were studied. The enzyme activities were measured in sonicates of the irradiated cells, using an exogenous DNA as template. Both DNA alpha- and beta-polymerase activities decreased following irradiation of the cells. Doses as low as 100 rad significantly reduced the activities of the enzymes. While the activities of both DNA polymerases decreased as the dose received by the cells increased, the major reduction in enzyme activity occurred with doses of 100--200 rad. The reduction in DNA alpha- and beta-polymerase activities was maximal by 30 min post-irradiation and recovered to control values by 2 hours post-irradiation.

Cell Division↗
PubMed1980

Effects of methylated xanthines on mammalian cells treated with bifunctional alkylating agents.

Caffeine has been previously reported to enhance the lethal potential of many DNA-damaging agents in rodent cells1-5. This effect has most commonly been ascribed to the binding of caffeine to single-stranded DNA6, and the resulting inhibition of post-replication repair7-10, which is associated with the synthesis of abnormally small nascent DNA fragments7, 11-13. However, certain aspects of this theory remain unclear:(1) why does the addition of caffeine to damaged cells elevate the level of DNA synthesis when it supposedly blocks post-replication repair10,14, and (2) as pointed out by Cleaver15, why does caffeine continue to exert its synergistic lethal effects until completion of the S phase16, 17, even though the size of newly synthesized DNA seems normal much earlier18-20? The present studies with nitrogen mustard (HN2) fail to demonstrate any effect of non-lethal concentrations of methylated xanthines (MXs) on removal of DNA damage or post-replication repair in conditions producing synergistic lethal effects. We demonstrate an influence by MXs on initiation of DNA synthesis in damaged replicons, and propose that this effect is primarily responsible for the synergistic lethal properties of these drugs.

Animals↗
PubMed1980

Amyloidoma of the stomach.

Localized amyloid deposit in the gastric antrum presented as an ulcerated mass on upper gastrointestinal series. Radiographic and autopsy findings are correlated and the literature is reviewed.

Amyloidosis↗
PubMed1978

Radiation damage to DNA in aqueous solution: effects of radiosensitizers.

Systems are described for examining the molecular mode of action of anoxic radiosensitisers with DNA-OH radicals. Pulse radiolysis showed that NPPN reacts with these radicals even in the presence of 0.5 mM oxygen. Analysis of low molecular weight products liberated from DNA by irradiation showed that NPPN does not act in an oxygen-like way but that misonidazole does. Thus a molecular rationale exists for the use of combinations of radiosensitizers.

Alkaloids↗