Biomedical subjects

C Mothersill

Publications and source records attributed to C Mothersill.

114 records · Page 7Linked to original sources

PubMedDate not supplied

Effect of lactate on the recovery of CHO-KI cells from gamma radiation damage.

The effect of pre-exposure of CHO-KI cells to lactate on their capacity to recover from or repair radiation damage was examined. Prolonged pre-exposure to lactate and a number of inhibitors of glycolysis has previously been shown to reduce the cell survival after irradiation. Following a split dose of irradiation, cells pre-treated with lactate for 18 hours had a higher relative recovery factor than controls even though survival following a single dose was reduced. Where lactate was added just before irradiation it had a radiation protective effect on the single dose survival curve and no effect on recovery. To investigate a possible involvement of NADH generation via lactate dehydrogenase in the mechanism, oxamate, a non-metabolisable analogue of lactate, was investigated. It reduced the survival of irradiated CHO-KI cells following prolonged and short pre-exposure and did not significantly affect the recovery factor. It is suggested that since lactate and oxamate both inhibit glucose breakdown, their radiobiologic effects may be due to depletion of cellular energy substrates necessary for repair. In contrast, the increased recovery and short term radiation protective effect seen with lactate only may involve LDH activity.

Animals↗

PubMedDate not supplied

Radiobiologic response of CHO-KI cells treated with vitamin A.

Treatment of CHO-KI cells with vitamin A altered their response to subsequent gamma irradiation. In general longterm preincubation with low doses of the vitamin caused a relative increase in the number of cells surviving a given radiation dose. The effect resulted in an increase in the D0 of the survival curve. Long or short term exposure to high concentrations of the vitamin caused a decrease in the number of surviving cells leading to a decrease in the extrapolation number of the survival curve. Recovery of cells from radiation damage, assessed using the split dose technique, was also impaired by vitamin A pretreatment. A mechanism involving repair of potentially lethal damage may explain the protective effect of vitamin A since this was highly dependent on the cell density of cultures at the time of irradiation. However, in view of the data showing that the vitamin A concentrations necessary to alter the radiation survival curve shoulder caused a significant release of sialic acid into the medium, a mechanism involving membrane stability may account for both the reduction in repair/recovery capacity of the treated cells and the radioprotective effect.

Animals↗

PubMedDate not supplied

Genomic instability, bystander effects and radiation risks: implications for development of protection strategies for man and the environment.

The last few years has seen what people are now referring to as a "shifting Paradigm" in our way of thinking about radiation effects on biological systems. The concept of the central role of DNA damage due to double strand breaks induced by a radiation "hit" has been itself hit by many studies showing persistent effects in the distant progeny of radiation exposed cells. This phenomenon is known as radiation induced genomic instability. More recently evidence has been accumulating that not even the parent cell need be exposed to radiation (the bystander effect). The new paradigm suggests that cellular stress responses or damage signalling through a range of signal transduction pathways are involved and that cell-cell contact or secretion of damage signalling molecules can induce responses in undamaged and unirradiated cells. Are these new effects relevant to risk assessment, or does it matter HOW radiation affects cells if we have good epidemiological evidence of which to base our risk estimates? The aim of this paper is to introduce the new concepts and to consider reasons why they might alter our methods of risk estimation. The paper also considers the impact of the new concepts on environmental protection and discusses the need for research in the field of comparative radiobiology if we are to develop policies which can adequately protect biodiversity.

Animals↗

PubMedDate not supplied

Relevance of radiation-induced bystander effects for environmental risk assessment.

A novel mechanism involving a medium borne signalling factor has been identified following irradiation of populations of cells to doses ranging from 5 mGy-5 Gy gamma-rays or to as little as 1 alpha particle traversal in a culture containing hundreds of cells. The factor can be released into culture medium and can induce responses in unexposed cultures. It has been called a "radiation-induced bystander factor". The effect is obviously relevant to risk assessment as it happens at very low doses. It could also offer new avenues for development of drugs aimed not at cell destruction but at restoring the tissues own control and coordination of response following DNA damage. The effect is clearly induced by radiation and probably by other substances. While these effects are now accepted to happen both in vitro and in vivo, their relevance and function is unknown. The investigation and modelling of the mechanism and the variation in level and type of effect in relation to genetic background and clinical history are key questions which need to be addressed in the field. The key driving hypothesis of the work being done by our laboratory is that radiation-induced bystander effects (RIBE) reflect emergent control in complex tissues and communicating cell systems, which can be harnessed for therapeutic gain.

Bystander Effect↗

PubMedDate not supplied

Chemotherapy agents and the induction of late lethal defects.

Radiation is now known to be capable of producing both lethal and non lethal lesions in a variety of mammalian cells which may not be expressed for several cell divisions after the initial insult. The mechanism by which such an effect occurs is unknown. Because of the possible implications for cancer treatment, if such an effect also occurred following chemotherapy exposure, cells were exposed to various cytotoxic chemotherapy agents with known and well characterised effects on DNA or other areas of cell function or structure. The results indicate that late lethal defects are not detectable after treatment with appropriate ranges of doses of cisplatinum, vincristine, BCNU or adriamycin, but that they are induced by Bleomycin and to a lesser extent by 5-Fluorouracil. Bleomycin is known to cause strand breaks and is regarded as a radiomimetic agent. 5-Fluorouracil may act by preventing efficient and faithful synthesis of DNA, allowing mutations to become integrated into the genome. The occurrence of lethal mutations with both these agents supports previous suggestions that error-prone repair of DNA base sequence abnormalities may be fundamental to the process of late lethal damage production in mammalian cells. The cloning efficiency of cells which survived exposure to Vincristine or BCNU over a wide dose range was found to be significantly increased; this may represent an adaptive response to the drugs.

Animals↗

PubMedDate not supplied

Induction of c-myc oncoprotein and of cellular proliferation by radiation in normal human urothelial cultures.

Normal urothelial cultures were established from transplant ureters and irradiated or exposed to nitrosamines. The cells which survived the treatment were monitored for expression of c-myc oncoprotein. The cultures were also exposed to tritiated thymidine (3HTdR) to determine the total number of cells synthesizing DNA. The area of explant outgrowth was also measured. Proliferation is considered to be a fundamental precondition which has to be present before malignant change can take place or which has to accompany this change. The results indicate that the overall growth rate of the carcinogen-treated cultures is relatively faster than that of the controls. This is particularly true one to two weeks after carcinogen exposure. Certain areas of the culture develop abnormally, cells are different in size and shape to the normal uroepithelial cell and have the capacity to pile up and form characteristic foci. These foci continue to proliferate after senescence of control cultures and after senescence of normal areas of treated cultures. The cells in these foci express high levels of c-Myc oncoprotein. Control and treated but normal cells are negative for this antigen under the conditions used. N-ethyl nitrosamine (NEN) (0.005-0.05 micrograms/ml) and radiation (2.5-10.0 Gy) are both able to induce the changes described. The results suggest that radiation and/or nitrosamine treatment can induce uroepithelial cells to divide at a faster rate than usual. Certain cells within this fast growing culture attain the capacity to pile up and acquire a different morphology. These cells do not senescence at the usual time and are c-myc positive. They may represent a subpopulation which has undergone some pre or early malignant changes.

Cell Division↗