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Biomedical subjects

E J Hall

Publications and source records attributed to E J Hall.

At least 109 records · Page 6Linked to original sources
PubMed1994

Taxol and ionizing radiation: interaction and mechanisms.

PURPOSE: Taxol has been shown to be clinically active against several types of human tumors. To assess the potential oncogenic effect of taxol, the in vitro cytotoxic and oncogenic transforming effects of taxol, either alone or in combination with gamma-irradiation, were examined. METHODS AND MATERIALS: Exponentially growing mouse C3H 10T1/2 cells were treated with taxol with or without concurrent gamma-irradiation. After treatment, cultures were replated for both clonogenic survival and transformation assays. To determine the effects of taxol on cell cycle kinetics, treated cells were concurrently labelled with bromodeoxyuridine coupled with fluorescein. Accumulated mitotic cells were isolated by the shake-off technique and their plating efficiency and radiosensitivity were determined. RESULTS: Taxol induced a dose dependent toxicity in 10T1/2 cells. In contrast to human tumor cells in culture, the mitotic block induced by a 100 nM dose of taxol in 10T1/2 cells was only partial. While taxol was ineffective in transformant induction, it enhanced the oncogenic transforming potential of gamma-rays in a supra-additive manner. The fact that approximately 15% of taxol-induced mitotic cells were clonogenically viable and at a cell cycle stage that was most radiosensitive suggests a mechanistic basis for the observed enhancement in transformation incidence by ionizing radiation. CONCLUSION: Taxol enhances the oncogenicity of radiation by partially blocking the 10T1/2 cells in G2/M phases of the cell cycle, phases that are most sensitive to radiation induced oncogenic transformation.

Animals↗
PubMed1994

Misoprostol-induced radioprotection of oncogenic transformation.

PURPOSE: Prostaglandins are associated with a variety of both pathologic and normal physiological effects in mammals. Among this broad array of effects, prostaglandins have been shown to provide protection to tissues from a variety of injurious agents including ionizing radiation. Of the prostaglandins tested to date, an analogue of prostaglandin E1, misoprostol (cytotec) was found to be a very effective radioprotector. The purpose of this study was to assess the ability of misoprostol to protect cells from the cytotoxic and oncogenic effects of ionizing radiation. METHODS AND MATERIALS: Pregnant Syrian hamsters were injected subcutaneously with 125 micrograms misoprostol/100 g body weight 2 h before being exposed to graded doses of X rays. Embryos were excised immediately after irradiation and cells were explanted into culture dishes. Following 14 days of incubation, cells were fixed in formalin and stained with giemsa for examination of cell clonogenicity and morphological transformation. RESULTS: First, misoprostol protected cells from some degree of radiation toxicity. A reduction in cell killing by a factor of 1.5 was seen at 10% cell survival. Second, based on transformation studies, a higher frequency of oncogenic transformation is seen for cells exposed in utero to graded doses of X rays alone than for cells exposed to the combination of misoprostol followed by radiation. In the presence of misoprostol, transformation is reduced by a factor of 20 at the level of 10(-3) transformants per surviving cell. CONCLUSION: Misoprostol may have clinical utility, not only in protecting selected normal tissues during cancer therapy, but it may also be useful in protecting cells from secondary tumors caused by ionizing radiation.

Animals↗
PubMed1994

Taxol in combination with acute and low dose rate irradiation.

Taxol is an investigational antineoplastic agent which acts by stabilizing microtubules, thereby preventing normal mitosis. It is believed to block cells in the G2/M phase of the cell cycle. The drug is a natural product isolated from the yew, Taxus brevifolia. We have used a cell line derived from human cervical carcinoma to investigate the combination of Taxol with high and low dose rate 137Cs irradiation. An additive effect for Taxol plus radiation was observed; supra-additivity or synergism is not suggested by our data. In the cell line studied, drug concentrations that accumulate cells to some degree in the G2/M phase of the cycle lead to cell lethality, so that no radiosensitizing effect is possible. We have also shown that the cytotoxic effect of Taxol is not limited to the G2/M phase of the cell cycle. In the clinic, Taxol shows promise both as a chemotherapeutic agent and as a possible adjunct to radiation. The present work demonstrates the need for further studies of Taxol plus radiation with a variety of human cell lines of normal and malignant origin.

Animals↗
PubMed1994

Effects of increased expression of protein kinase C on radiation-induced cell transformation.

The in vitro oncogenic transformation of C3H 10T1/2 cells by ionizing radiation is known to be enhanced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). It is also known that the activation of protein kinase C (PKC) by TPA is an important step in its tumor-promoting effect. In the present study, we examined the effects of overexpression of a specific isoform of PKC, PKC beta 1 on gamma-ray-induced transformation of 10T1/2 cells. In addition, the effects of overexpression of PKC beta 1 on the malignant phenotype of a previously transformed 10T1/2 cell line were also evaluated. Derivatives of 10T1/2 cells that stably overexpress PKC beta 1 were obtained by transduction with the retroviral expression vector pMV7 carrying the rat PKC beta 1 cDNA sequence. We found that the parental 10T1/2 cells and a control cell line 10T1/2 MV7, which carried only the pMV7 vector without the cDNA insert, expressed dose-dependent transformation frequencies when exposed to gamma-rays. On the other hand, concurrently treated PKC-overexpressing cells that had an 11-fold increase in enzyme activity (PKC-4 cells) failed to yield any morphologically identifiable foci. Cell lines that expressed lower levels of PKC beta 1 were partially resistant to transformation by gamma-rays. Clonogenic survival data indicated that this observation was not due to radioresistance per se. Thus, overexpression of PKC beta 1 did not appear to function as an endogenous substitute for TPA in promoting radiation-induced transformation. Furthermore, overexpression of PKC did not reverse the transformation phenotypes in tumorigenic 10T1/2 cells once it was established. These findings are discussed with respect to the specific roles of individual isoforms of PKC in growth control.

Animals↗
PubMed1994

Malignant transformation of human bronchial epithelial cells by radon-simulated alpha-particles.

Epidemiological studies have shown that inhalation of radon is associated with an increased risk for bronchogenic carcinoma in uranium miners. These alpha-emitting radon daughters also represent the largest component of background radiation to the general public. In the present study, the oncogenic transforming effects of single versus multiple doses of radon-simulated alpha-particles were examined using human papillomavirus-immortalized human bronchial epithelial cells. Endpoints such as growth kinetics, resistance to serum and 12-O-tetradecanoylphorbol-13-acetate-induced terminal differentiation, anchorage-independent growth and tumorigenicity in nude mice were used to assess the various stages of transformation in the bronchial epithelial cells. We show here, for the first time, that immortalized human cells in culture can be malignantly transformed by a single 30 cGy dose of alpha-particles. Transformed cells produced progressively growing subcutaneous tumors upon inoculation into athymic nude mice. Immunofluorescent staining of keratin and isozyme analysis of the cell lines subsequently generated from these tumors indicated that the cells were of human epithelial origin. Analysis of genomic DNA from the tumorigenic cell lines using PCR amplification and restriction enzyme analysis demonstrated no point mutation at either codon 12/13 or 61 in any of the ras oncogenes examined (K-, N- and H-ras). This system provides an opportunity to study the cellular and molecular changes at the various stages in radiation carcinogenesis involving human cells.

Animals↗
PubMed1994

Oncogenic transformation through the cell cycle and the LET dependent inverse dose rate effect.

Synchronised populations of mouse C3H/10T-1/2 cells were obtained by a stringent mitotic dislodgment procedure. Mitotic cells rapidly attach and progress sequentially through the cell cycle. Irradiation (3 Gy of X rays) was carried out at intervals from 0 to 18 h after initiating cell cycle progression of the mitotic cells. Oncogenic transformation was enhanced 10-fold over cells irradiated soon after replating (G1 and S phases) for cells in a near 2 h period corresponding to cells in G2 phase but not in mitosis. The cell surviving fraction had a 2-1/2-fold variation with resistant peaks corresponding to the late G1 and late S phases. These findings provide experimental support for the hypothesis initiated by Rossi and Kellerer and developed by Brenner and Hall to explain the LET dependent inverse dose rate effect for oncogenic transformation.

Animals↗
PubMed1993

The Janeway Lecture 1992. Nine decades of radiobiology: is radiation therapy any the better for it?

Nine decades have elapsed since Pierre Curie performed the first radiobiologic experiment when he used a radium tube to produce an ulcer on his arm and charted its progress and ultimate healing. A wide range of topics have been investigated in experimental radiation biology from chromosomal aberrations to fractionation effects in normal tissues to the use of neutrons and bioreductive drugs. Many of the strategies used in clinical radiation therapy, including hyperfractionation and accelerated treatment, are firmly based on laboratory experiments conducted in the past. Much current research is focused on understanding the molecular genetics of cancer to identify the genes that are activated or deleted in cells exposed to radiation. Radiobiology has played a key role in shaping radiation therapy into the vigorous, scientifically based, and highly quantitative branch of medicine that it is currently. In addition, research is preparing the field for the future when treatment protocols must be based on molecular rather than cellular biology.

Animals↗
PubMed1993

Complex patterns of sequence variation and multiple 5' and 3' ends are found among transcripts of the erythroid ankyrin gene.

The structural protein ankyrin functions in red blood cells to link the spectrin-based membrane skeleton to the plasma membrane. Ankyrin proteins are now known to occur in most cell types, and two distinct ankyrin genes have been identified (erythroid (Ank-1) and brain (Ank-2)). We have characterized transcripts of the mouse erythroid ankyrin gene by cDNA cloning and DNA sequencing. Ank-1 transcripts of 7.5 and 9.0 kilobases are found in erythroid tissues, and a 9.0-kilobase transcript is found in cerebellum. RNA hybridization blot analysis of 13 additional mouse tissues has detected four novel Ank-1 transcripts (5.0, 3.5, 2.0, and 1.6 kilobases in size). Sequencing of Ank-1 cDNA clones isolated from mouse reticulocyte, spleen, and cerebellar libraries has identified (i) multiple 5' ends that indicate possible multiple promoters; (ii) alternative polyadenylation sites that probably account for the 7.5- and 9.0-kilobase size difference; (iii) a variety of small insertions and deletions that could produce transcripts (and ultimately proteins) of nearly identical size, but different functions; and (iv) clones with large deletions of coding sequence that account for the smaller transcripts seen in spleen, skeletal muscle, and heart.

Amino Acid Sequence↗
PubMed1993

Taxol, radiation, and oncogenic transformation.

The novel antineoplastic drug taxol has been shown to be active clinically against several types of human tumors. With improvement in treatment strategy and the number of long-term survivors increasing, a question that needs to be addressed is the potential carcinogenic effect of the treatment in the induction of second malignancies. We show here that when tested using an in vitro assay for oncogenic transforming potential, taxol is ineffective in focus induction at doses significantly higher than those used in the clinic. However, taxol enhances the oncogenic potential of gamma-rays in a synergistic fashion. The fact that taxol blocks cells at the G2/M phases of the cell cycle may account for this interaction since G2/M are relatively radiosensitive phases of the cell cycle.

Animals↗
PubMed1993

The radiobiology of radiosurgery: rationale for different treatment regimes for AVMs and malignancies.

Based on basic radiobiological principles, we suggest that the radiosurgery technique of delivering a radiation dose in a single fraction, whilst appropriate for benign brain lesions such as arteriovenous malformations (AVM), is not optimal for treating malignant tumors. Radiosurgery was originally developed to treat benign lesions in the brain, such as AVMs, and has been successfully used for this purpose for over four decades. Recently, the technique has been adopted for treating small primary malignant brain tumors or single metastases. We argue, and derive radio-biological data to support the view that, treating malignant tumors with a single fraction will result in a suboptimal therapeutic ratio between tumor control and late effects, even for small tumors; and that improved therapeutic ratios would be expected if the treatment were fractionated into a small number of fractions. On the other hand, no therapeutic gain is to be expected from fractionating treatment of AVMs. A new generation of noninvasive relocatable stereotactic head frames makes feasible the use of fractionated stereotactic external-beam radiotherapy, and may allow significant benefits over single, radiosurgical, treatments for malignant brain tumors. As stereotactic fractionation/protraction regimes become more widespread, a uniform approach for determining equivalent fractionation schemes becomes important for intercomparing clinical results, and such calculations can be reliably carried out using the linear-quadratic formalism.

Brain Neoplasms↗
PubMed1993

The inverse dose-rate effect for oncogenic transformation by charged particles is dependent on linear energy transfer.

Mouse C3H 10T1/2 cells were exposed to single or fractionated doses of charged particles of defined linear energy transfer (LET) from 25 to 200 keV/microns. Dose fractionation with prolonged time intervals enhanced the yield of transformed foci compared with a single acute dose for a range of LET values between 40 and 120 keV/microns. Radiations of lower or higher LET did not show the enhancement that is commonly referred to as the inverse dose-rate effect. The fractionation scheme that was used consisted of three dose fractions; the maximum enhancement of transformation occurred with an interval of 150 min between dose fractions. This inverse dose-rate effect, demonstrated for cycling cells in log phase, was not seen for cells in plateau phase.

Animals↗
PubMed1993

Mechanistic considerations on the dose-rate/LET dependence of oncogenic transformation by ionizing radiations.

When exposure to densely ionizing radiation is protracted, the resulting biological effect is sometimes, but not always, enhanced for transformational end points, relative to acute exposure. A pattern has emerged as to the dependence of this effect on dose, dose rate, and radiation quality. Previous calculations indicated that the dose and dose-rate trends can be predicted by a model in which there is a period within the cell cycle of very high sensitivity to oncogenesis. Recent experiments indicate that the inverse dose-rate effect is significant over a very limited range of LETs--from about 30 to 130 keV/microns. We discuss such LET effects in the context of cell cycle-dependent models, and suggest that the effects are understandable on the basis of such models. In essence, the inverse dose-rate effect disappears at high LET because of a reduction in the number of cells being hit, and disappears at LETs below about 30 keV/microns because most of the dose is deposited at low specific energies, insufficient to produce the saturation effect which is central to the phenomenon. At even lower LETs, damage repair yields the familiar sparing associated with protraction of X- or gamma-ray doses.

Cell Survival↗
PubMed1992

Taxol sensitizes human astrocytoma cells to radiation.

Taxol is a chemotherapeutic drug which acts by stabilizing microtubules, preventing normal mitosis and resulting in a block of the cell cycle at G2 and M. The drug is isolated from the yew, Taxus sp. L., and is currently being evaluated in a series of Phase II and Phase III clinical trials. Taxol blocks cells in the most radiosensitive phases of the cell cycle and thus could act as a cell cycle-specific radiosensitizer. We report the results of combined taxol-radiation exposures in the human Grade III astrocytoma cell line, G18. Taxol is a potent inhibitor of G18 cell division; a concentration of 10 nM is cytostatic for a cell population observed for at least two doubling times. Cell survival curves for G18 cells showed a significant concentration-dependent interaction between taxol and radiation. Treatment of G18 cells with a fixed taxol concentration and radiation dose showed the interaction to be dependent on the duration of taxol exposure and consequently the fraction of cells in the G2 or M phase of the cell cycle. The sensitizer enhancement ratio for 10 nM taxol at 10% survival is 1.8 and, for 1 nM taxol, it is 1.2. These results suggest that appropriate combinations of taxol have a more than additive interaction in human tissue culture and may have a role in clinical protocols.

Alkaloids↗
PubMed1992

Use of lithium for treatment of estrogen-induced bone marrow hypoplasia in a dog.

Marrow hypoplasia and consequent pancytopenia caused by simultaneous administration of estradiol cyclopentylpropionate and diethylstilbestrol were diagnosed in a 6-year-old Old English Sheep-dog. The dog was treated with lithium carbonate (11 mg/kg of body weight, PO, q 12 h) for 6 weeks. Despite the generally grave prognosis associated with estrogen toxicosis, lithium treatment was apparently successful in inducing regeneration of the bone marrow. Side effects of lithium treatment were not noticed.

Amoxicillin↗