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Biomedical subjects

E J Hall

Publications and source records attributed to E J Hall.

At least 199 records · Page 11Linked to original sources
PubMed1986

Response of cells of human origin, normal and malignant, to acute and low dose rate irradiation.

Dose response curves were obtained for normal human fibroblasts and for several cell lines derived from human tumors, including melanomas and an osteosarcoma. Most of the tumor lines are similar in radiosensitivity to the normal fibroblasts, except for the melanoma lines, which are significantly more resistant. The two melanoma lines differ, one being much more radioresistant than the other. Potentially lethal damage repair (PLDR) has been studied in these cell lines as well. The extent of PLDR does not appear to correlate with radioresistance; for example, the most resistant melanoma line shows very little repair of PLD. In addition, the normal fibroblasts repair PLD at least as well as any of the tumor derived lines, which casts doubts on the wisdom of introducing into clinical practice inhibitors of PLD until a clear differential between normal tissues and tumors has been demonstrated in vivo. Low dose-rate studies with normal human fibroblasts indicate a smaller dose-rate effect than for most established cell lines of rodent origin. Indeed, in the human cells studied, the effect of sublethal damage repair is quantitatively similar to the repair of potentially lethal damage. Dose response curves for acute and protracted exposures have been obtained for cells derived from patients with cancer-prone syndromes including ataxia telangiectasia (AT) and Bloom's syndrome. Both cell lines are much more radiosensitive than normal human fibroblasts; the AT cells show a dose-rate effect, while Bloom's syndrome cells do not.

Animals↗
PubMed1986

Oxygen dependence for chemosensitization by misonidazole.

Misonidazole (MISO) potentiates the cell killing effect of certain chemotherapy agents, but only under hypoxic conditions. The purpose of the present study was to define the range of oxygen concentrations over which chemosensitization by MISO takes place using mammalian cells cultured in vitro, and to compare this with the oxygen levels required for radiosensitization. V-79 hamster cells, attached to permanox dishes, were gassed with known concentrations of oxygen (less than 10 to 200,000 ppm) and treated with 1 and 5 mM MISO for 4 h previous to exposure to the chemotherapy agent, melphalan. In a parallel series of experiments, under the same gassing conditions, cells were irradiated with graded doses of X-rays at various oxygen concentrations. The K factor i.e. the oxygen concentration which defined half the maximum effect was found to be approximately 4776 ppm for radiosensitization and approximately 400 ppm for chemosensitization by MISO. It is evident that a significantly more stringent level of hypoxia is required for chemosensitization by MISO to take place than for radiosensitization.

Animals↗
PubMed1986

Low dose-rate effects of cesium-137 and iodine-125 on cell survival, cell progression, and chromosomal alterations.

Chinese hamster ovary (CHO-AA8) cells in exponential growth were exposed to graded doses of radiation from iodine-125 (I-125) or cesium-137 (Cs-137) at various low dose rates, then monitored for cell number and clonogenic integrity. Cellular kinetics and the induction of sister chromatid exchanges and chromosomal aberrations were evaluated in cells after irradiation. Dose rates within the range 3-23 cGy/h had little effect on these fast growing cells but there was significant cell killing at dose rates of 33-70 cGy/h. The relative biological effectiveness (RBE) values for I-125 relative to Cs-137, calculated from the cell growth curves and the percentage of plating efficiencies of irradiated cells as a fraction of control, were 1.28 and 1.5., respectively, and did not vary over the dose-rate range from 3 to 70 cGy/h. The percentage of mitoses with chromosomal aberrations increased as a function of dose, but showed little if any change with dose rate. Cells passing through two cell cycles after irradiation also showed dose-dependent increases in the frequency of sister chromatid exchanges. That is, viable cells continue to show the effects of low dose-rate irradiation at the DNA level long after irradiation is concluded. Frequencies of cells in mitosis (mitotic index) and of cells incorporating bromodeoxyuridine (BrdU) (cycling S phase cells) indicated that low dose-rate I-125 irradiation produced a much more profound delay than low dose-rate of Cs-137 irradiation. This more pronounced inhibition may play a significant role in enhancing the effect of low dose rate I-125 in a clinical situation.

Animals↗
PubMed1985

Cutaneous cryptococcosis in three cats.

Cutaneous cryptococcosis was diagnosed in 3 cats. No other organ involvement was found. One cat has remained healthy after surgical excision of the cryptococcal skin lesion. One cat was euthanatized after diagnosis. The third cat was treated successfully with a 5-month course of ketoconazole.

Animals↗
PubMed1985

Radiation biology.

On a few occasions in the past, radiobiological experiments profoundly influenced the practice of radiotherapy. For example, it was shown in the 1920s that animals could be sterilized without damage to the skin of the scrotum if the testes were irradiated in multiple fractions, whereas in a single dose, sterilization was not possible without significant skin damage. These experiments led to the fractionation patterns used in conventional radiotherapy today. Few experiments have had such a dramatic impact, but since World War II, studies with mammalian cells in culture, transplantable animal tumors, and normal tissue systems produced an impressive body of experimental data. Conventional radiotherapy techniques now can be understood in terms of the basic principles of radiobiology. New horizons in radiotherapy are also suggested. These include the following: (1) altered fractionation schedules, including hyperfractionation and accelerated treatment; (2) the selection of groups of patients likely to benefit from neutrons; and (3) The use of hyperthermia alone or as an adjunct to radiation.

Animals↗
PubMed1985

In vitro assessment of the oncogenic potential of nitroimidazole radiosensitizers.

Two hypoxic cell radiosensitizers, RSU-1069 and Ro-03-8799 were investigated for their in vitro cytotoxicity and ability to induce oncogenic transformation and sister chromatid exchanges in the C3H 10T1/2 cell system. Their effects were then compared to those of the clinically used sensitizer misonidazole. Equitoxic doses of Ro-03-8799 and RSU-1069 were approximately 3-fold and 150-fold less than misonidazole, respectively, with both agents exhibiting dose and contact time dependence for cell killing. Both sensitizers appeared no more oncogenic than misonidazole when administered at equitoxic dosages. At doses of equivalent sensitizing efficiencies relative to misonidazole, RSU-1069, but not Ro-03-8799, induced significantly higher transformation incidence. In conjunction with gamma-irradiation, both Ro-03-8799 and misonidazole induced an additive transformation response. Preliminary studies also indicate that RSU-1069, at a concentration of 0.03 mM, induced significantly higher sister chromatid exchanges (SCE) per chromosome than either Ro-03-8799 or misonidazole at concentrations 30-fold higher. Although several earlier studies have indicated that RSU-1069 may be more efficient than misonidazole as an hypoxic cell sensitizer, the present findings suggest that it may also carry a higher risk of inducing tumors by itself at clinically relevant concentrations.

Animals↗
PubMed1985

Oncogenic transformation with radiation and chemicals.

Quantitative in vitro assay systems for oncogenic transformation are a powerful research tool. They may be based on short-term cultures of hamster embryo cells, or established cell lines of mouse origin. While X-ray-induced transformation of human cells has been demonstrated, it has proved difficult to develop quantitative assay systems based on cells of human origin. The presently available quantitative assays have two quite distinct basic uses. First, they may be useful to accumulate data which is essentially pragmatic in nature. For example, they may be used to compare and contrast the oncogenic potential of chemotherapeutic agents or hypoxic cell sensitizers used or proposed in the clinic. They may be used to identify compounds that inhibit or suppress the transformation incidence resulting from known oncogenic agents, or they may be used to demonstrate the interaction between two different agents, such as radiation and asbestos. Second, they may prove to be invaluable in the study of the basic mechanisms of carcinogenesis, inasmuch as they represent models of tumourigenesis in which the various steps can be manipulated and modified more readily and in a controlled way.

Animals↗
PubMed1985

Potentially lethal damage repair in cell lines of radioresistant human tumours and normal skin fibroblasts.

Radiation cell survival data were obtained in vitro for three cell lines isolated from human tumours traditionally considered to be radioresistant--two melanomas and one osteosarcoma--as well as from a diploid skin fibroblast cell line. One melanoma cell line was much more radioresistant than the other, while the osteosarcoma and fibroblast cell lines were more radiosensitive than either. For cells growing exponentially, little potentially lethal damage repair (PLDR) could be demonstrated by comparing survival data for cells in which subculture was delayed by 6 h with those sub-cultured immediately after treatment. For the malignant cells in plateau phase, which in these cells might be better termed 'slowed growth phase', since an appreciable fraction of the cells are still cycling, a small amount of PLDR was observed, but not as much as reported by other investigators in the literature. The normal fibroblasts, which achieved a truer plateau phase in terms of noncycling cells, showed a significantly larger amount of PLDR than the tumour cells.

Cell Cycle↗
PubMed1984

Depletion of intracellular GSH and NPSH by buthionine sulfoximine and diethyl maleate: factors that influence enhancement of aerobic radiation response.

Many investigators have observed aerobic sensitization of V79, CHO and A549 (human lung carcinoma) cells upon depletion of GSH using buthionine sulfoximine (BSO). Recently we discovered that this aerobic sensitization can be reversed if WR-2721 or N-acetylcysteine is added to the cells just prior to irradiation. Reversal requires that the exogenous thiols be present during the time of irradiation. One possible explanation was that these thiols entered the cells and either increased the pool of cellular nonprotein thiols or reversed the thiol-depleted state by stimulation of GSH synthesis. Cells treated with BSO do not readily regenerate intracellular GSH because this agent irreversibly inhibits gamma-glutamyl synthetase. For A549 monolayer cultures, there is approximately 50% regeneration 6 hr after removal of 0.01 mM BSO, 20% 6 hr after 0.1 mM BSO, and only 5% 6 hr after 0.5 mM BSO. We found that addition of WR-2721 or N-acetylcysteine to BSO-treated cells did not affect the rate of regeneration of intracellular GSH. Thus, reversal of the aerobic sensitization of A549 cells by BSO cannot be explained on the basis of intracellular thiol levels alone, or by rapid reversal of BSO inhibition. In addition, diethylmaleate (DEM)-treated cells are considerably different from BSO-treated cells with respect to the ability to regenerate GSH. After removal of DEM, A549 cells immediately begin GSH resynthesis, and return to control levels occurs within 2 hr. Exogenous 5 mM GSH increases the rate of resynthesis of GSH in DEM-treated cells, but not in BSO-treated cells.

Aerobiosis↗
PubMed1984

Effects of D,L-buthionine-S,R-sulfoximine on cellular thiol levels and the oxygen effect in Chinese hamster V79 cells.

The role of glutathione (GSH) and total non-protein thiols (NPSH) in repairing radiation-induced free radical damage incurred under aerated and hypoxic conditions was investigated using Chinese hamster V79 cells cultured in vitro. GSH and NPSH levels were depleted in V79 cells of varying cell densities using the gamma-glutamyl-cysteine-synthetase inhibitor, D,L-Buthionine-S,R-sulfoximine (BSO). A small change in hypoxic cell radiosensitivity could be attributed to the loss of GSH while depletion of thiols to lower levels affected both aerated and hypoxic cell radiosensitivity, resulting in no change in the OER. Only a long term incubation with BSO produced a large change in the OER, by which time many other biochemical pathways using GSH and amino acids are likely to be affected.

Animals↗
PubMed1984

Effects of cellular non-protein sulfhydryl depletion in radiation induced oncogenic transformation and genotoxicity in mouse C3H 10T1/2 cells.

A study was made of the effects of cellular non-protein sulfhydryl (NPSH) depletion on cytotoxicity, cell cycle kinetics, oncogenic transformation and sister chromatid exchange (SCE) in C3H 10T1/2 cells. Using DL-Buthionine S-R-Sulfoximine (BSO) at a concentration of 0.05 mM to deplete thiols, it was found spectrophotometrically that less than 5% of control NPSH level remained in the cells after 24-hour treatment under aerated conditions. Such NPSH depleted cells, when subject to a 3 Gy gamma-ray treatment, were found to have no radiosensitizing response either in terms of cell survival or oncogenic transformation. In addition, decreased levels of NPSH had no effect on spontaneous or radiation-induced SCE nor were cell cycle kinetics additionally altered. Therefore, the inability of NPSH depletion to alter gamma-ray induced cellular transformation was unrelated to any possible effect of BSO on the cell cycle. These results suggest that, while endogenous NPSH depletion has been considered to play an important role for most radiosensitizers in clinical or preclinical use, such depletion may result in little or no additional oncogenic or genotoxic effects on aerated normal tissues.

Aerobiosis↗
PubMed1984

Chemosensitization: do thiols matter?

It is well known that endogenous sulfhydryls are radioprotective in mammalian cells. Their comparable role in chemotherapeutic drug toxicity has been known for almost as long but less well defined. Thiol depletion as a mechanism responsible for enhanced cytotoxicity of melphalan was assayed by pretreatment of cells in vitro with misonidazole and buthionine sulfoximine (BSO). Hypoxic cell sensitizers, such as MISO, deplete endogenous thiols by metabolic activation under hypoxic conditions to thiol reactive intermediates, whereas BSO specifically inhibits a key enzyme in the synthesis of glutathione. For a given level of thiol reduction, sensitization to melphalan was far greater by preincubation with MISO than it was for BSO. This indicated that thiol reduction itself was not the sole factor involved in chemosensitization by MISO. As evidence that the method of thiol depletion predisposes to the expression of biological damage, it was shown that cells preincubated with MISO were appreciably more vulnerable to oxidative stress than those exposed to BSO. BSO was shown to totally inhibit the repair of damage from a preincubation treatment with MISO, demonstrating that recovery is dependent upon thiol regeneration. Thiol depletion "per se" is a good qualitative but not necessarily a quantitative indicator of chemosensitization--the biological and biochemical function of the thiol depleting agents used influences further drug interactions. The results of the study with these two agents suggest that thiols may play a potentially more critical role in the repair rather than the initiation of drug-induced damage.

Animals↗
PubMed1984

Misonidazole as a chemosensitizer in the treatment of the Dunning prostate cancer model.

Utilizing a Dunning prostate tumor model, we investigated the ability of misonidazole, a compound with known radiosensitizing properties, to act as a chemosensitizer when administered in combination with the alkylating agent cyclophosphamide. This combination caused a decrease in tumor growth rate when compared to the growth of the tumor in animals receiving cyclophosphamide alone. However, only at toxic levels was this decrease statistically significant (p less than 0.01).

Animals↗