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Biomedical subjects

S B Curtis

Publications and source records attributed to S B Curtis.

At least 55 records · Page 3Linked to original sources
PubMed1988

Basic radiobiology.

Experimental studies of the biological effects of radiation were started soon after the discoveries of x-rays in 1895, but there is still much that is not known. This article includes some research objectives that are essentially pragmatic in nature, intended to support and improve the current practice of radiotherapy, but the central thrust is the understanding of the mechanisms involved in the biological effects of radiation at the cellular and molecular levels. The article was written by a consortium of scientists and suffers inevitably from the drawback that writing styles are inconsistent, and coverage is not uniform. However, it benefits from the enormous advantage that it reflects the accumulated wisdom and judgment of more than a dozen scientists who, in their own areas of expertise, are recognized as being at the cutting edge of radiation research. The niceties of style and syntax are sacrificed in favor of the quality of the science and the maturity of judgment. The study of DNA damage as a mechanism for cell injury in early- and late-responding tissues, as well as a comparison of DNA damage that leads to lethality, as opposed to transformation and mutagenesis, are key items. The study of cell lethality with cells in culture led to the identification of repair, both sublethal and potentially lethal, as well as the dose-rate effect, and has had a considerable impact on radiotherapy. Future studies should focus on understanding the factors that determine radiosensitivity/radioresistance. A variety of approaches are available, including the study of genetically deficient cell lines from cancer-prone individuals. A parallel approach is the application of the techniques of molecular biology to clone the repair genes in mammalian cells, and to understand genetic defects that alter gene regulation, or to regulate biochemical factors in the cell. Substantial progress has been made in developing in vitro assays for mutagenesis, particularly using hybrids of rodent and human cells. Better methods are needed to study the effects of mutation on gene expression, and sensitive systems are needed that can detect low doses of radiation. Assays of oncogenic transformation, the in vitro counterpart of carcinogenesis, have been used to investigate the oncogenic potential of various types of radiation and chemotherapy agents. Key topics in future will include the investigation of supra-additivity between different agents, the identification and characterization of oncogenes that may be activated by radiation, the development of quantitative assays based on human cells, and further studies involving cell-to-cell communication.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Repair but not potentiation observed in mouse lung irradiated with neon ions.

The lungs of mice were irradiated with 1, 4, or 7 fractions of X rays or neon ions in a 4-cm spread Bragg peak. Lung function as a function of total radiation dose was tested at 7 and 12 months after irradiation by measuring the resting breathing rate in a whole-body plethysmograph. The isoeffect doses increased sequentially with X rays for 1 through 4 to 7 fractions, demonstrating repair of sublethal radiation injury as previously reported. There was also a significant increase of isoeffect dose with neon ions between 1 and 4 fractions but no further increase at 7 fractions. Thus repair instead of potentiation of radiation injury in lung clearly occurred after neon ion irradiation. The effectiveness of neon ions appeared to be closer to that of neutrons with a mean energy of 8 meV than those with a mean energy of 2.3 meV.

Animals↗
PubMed1986

Track structure in biological models.

High-energy heavy ions in the galactic cosmic radiation (HZE particles) may pose a special risk during long term manned space flights outside the sheltering confines of the earth's geomagnetic field. These particles are highly ionizing, and they and their nuclear secondaries can penetrate many centimeters of body tissue. The three dimensional patterns of ionizations they create as they lose energy are referred to as their track structure. Several models of biological action on mammalian cells attempt to treat track structure or related quantities in their formulation. The methods by which they do this are reviewed. The proximity function is introduced in connection with the theory of Dual Radiation Action (DRA). The ion-gamma kill (IGK) model introduces the radial energy-density distribution, which is a smooth function characterizing both the magnitude and extension of a charged particle track. The lethal, potentially lethal (LPL) model introduces lambda, the mean distance between relevant ion clusters or biochemical species along the track. Since very localized energy depositions (within approximately 10 nm) are emphasized, the proximity function as defined in the DRA model is not of utility in characterizing track structure in the LPL formulation.

Animals↗
PubMed1986

Radiation environments and absorbed dose estimations on manned space missions.

In order to make an assessment of radiation risk during manned missions in space, it is necessary first to have as accurate an estimation as possible of the radiation environment within the spacecraft to which the astronauts will be exposed. Then, with this knowledge and the inclusion of body self-shielding, estimations can be made of absorbed doses for various body organs (skin, eye, blood-forming organs, etc.). A review is presented of our present knowledge of the radiation environments and absorbed doses expected for several space mission scenarios selected for our development of the new radiation protection guidelines. The scenarios selected are a 90-day mission at an altitude (450 km) and orbital inclinations (28.5 degrees, 57 degrees and 90 degrees) appropriate for NASA's Space Station, a 15-day sortie to geosynchronous orbit and a 90-day lunar mission. All scenarios chosen yielded dose equivalents between five and ten rem to the blood forming organs if no large solar particle event were encountered. Such particle events could add considerable exposure particularly to the skin and eye for all scenarios except the one at 28.5 degrees orbital inclination.

Cosmic Radiation↗
PubMed1986

Lethal and potentially lethal lesions induced by radiation--a unified repair model.

A model of radiation action is described which unifies several of the major existing concepts which have been applied to cell killing. Called the lethal and potentially lethal (LPL) model, it combines the ideas of lesion interaction, irreparable lesions caused by single tracks, linear lesion fixation, lesion repair via first-order kinetics, and binary misrepair. Two different kinds of lesions are hypothesized: irreparable (lethal) and repairable (potentially lethal) lesions. They are tentatively being identified with DNA double-strand breaks of different severity. Two processes compete for depletion of the potentially lethal lesions: correct repair following first-order kinetics, and misrepair following second-order kinetics. Fixation of these lesions can also occur. The model applies presently only to plateau (stationary)-phase cells. Radiobiological phenomena described include effects of low dose rate, high LET, and repair kinetics as measured with repair inhibitors such as hypertonic solution and beta-arabinofuranosyladenine (beta-araA). One consequence of the model is that repair of sublethal damage and the slow component of the repair of potentially lethal damage are two manifestations of the same repair process. Hypertonic treatment fixes a completely new class of lesions which normally repair correctly. Another consequence of the model is that the initial slope of the survival curve depends on the amount of time available for repair after irradiation. The "dose-rate factor" occurring in several linear-quadratic formulations is shown to emerge when appropriate low-dose and long-repair-time approximations are made.

Animals↗
PubMed1986

PLD repair in rat rhabdomyosarcoma tumor cells irradiated in vivo and in vitro with high-LET and low-LET radiation.

Results are reported of studies to measure the extent of recovery of potentially lethal damage (PLD) in rat rhabdomyosarcoma tumor cells after irradiation both in vivo and in vitro with either high-LET or low-LET radiation. Stationary-phase cultures were found to exhibit repair of PLD following irradiation in vitro either with low-LET X rays or with high-LET neon ions in the extended-peak ionization region. Following a 9-Gy dose of 225-kVp X rays or a 3.5-Gy dose of peak neon ions, both of which reduced the initial cell survival to 6-8%, the maximum PLD recovery factors were 3.4 and 1.6, respectively. In contrast, the standard tumor excision assay procedure failed to reveal any recovery from PLD in tumors irradiated in situ with either X rays or peak neon ions. PLD repair by the in vivo tumor cells could be observed, however, when the excision assay procedure was altered by the addition of a known PLD repair inhibitor beta-arabinofuranosyladenine (beta-ara-A). When a noncytotoxic 50 microM concentration of beta-ara-A was added to the excised tumor cells immediately following a 14.5-Gy in situ dose of X rays, cell survival in the inhibitor-treated cells was lower than in the untreated cells (0.018 compared to 0.056), resulting in a PLD repair inhibition factor of 3.1. Delaying the addition of beta-ara-A for 1, 2, or 3 h following tumor excision reduced the PLD repair inhibition factor to 1.6, 1.5, and 0.9, respectively. Following tumor irradiation in situ with neon ions in the extended-peak ionization region (median LET = 145 keV/micron), less PLD repair was observed than after X irradiation. For 5.8 Gy of peak neon ions, the PLD repair inhibition factors were 2.1, 1.5, 1.3, and 1.1 at 0, 1, 2, and 3 h, respectively. We interpret the absence of measurable PLD repair using the standard tumor excision assay procedure as resulting from undetectable repair occurring during the long interval (about 2 h) required for the cell dissociation and plating procedures. We conclude that at least for our tumor system, PLD repair does occur after irradiation of tumors in situ, even though it is not detectable using the standard tumor excision assay procedure. Thus a failure to measure such repair by this assay in a given tumor system does not necessarily mean the cells are incapable of PLD repair.

Animals↗
PubMed1984

Hypoxic cell sensitizers and heavy charged particle beams may play complementary roles in killing hypoxic tumor cells.

The analysis of growth delay data of a rat rhabdomyosarcoma tumor system with and without misonidazole and irradiated with spread-peak heavy-ion radiation yields two conclusions that bear on the relative efficacy of the two modes of treatment and imply a complementary role of the two modes which enhances the effects of either given separately. 1. For both carbon and neon ion peak radiation given in four fractions, RBE values for tumor growth delay are significantly greater than the enhancement ratio for an X ray plus misonidazole fractionation scheme [2.0-2.3 (carbon) and 2.6-2.8 (neon) vs. 1.2-1.5 (X rays plus misonidazole)]. This implies that high LET killing is considerably more effective in this tumor system (hypoxic fraction of about 35%) than the hypoxic cell sensitization caused by misonidazole. 2. When misonidazole is given in conjunction with the heavy ion beam irradiations, an increased growth delay is seen, greater than when either heavy ions or misonidazole plus X rays are given separately. The product of the sensitizer enhancement ratio for heavy ions and the RBE for no sensitizer yields a measure of the overall enhancement of effect relative to an X ray treatment. The values of this product for the carbon beam (2.4-2.5) and neon beam (3.4) show high effectiveness for either beam plus misonidazole. The interpretation is that heavy ion beams reach and kill hypoxic cells not penetrated by the misonidazole, and some hypoxic cells not killed by the high LET component receive low LET damage which is made lethal by the drug. Thus, the net hypoxic cell killing is enhanced by the high LET beams and in a complementary way by the combination of the drug and the low LET portion of the radiation.

Animals↗
PubMed1982

Molecular and cellular radiobiology of heavy ions.

Quantitative studies at the BEVALAC have demonstrated some of the physical and radiobiological factors that promise to make accelerated heavy ions important for the therapy of cancer. The measured physical dose-biological effect relationships allow the safe and effective delivery of therapeutic schedules of heavy ions. Among the charged particle beams available, carbon, neon and helium ions in the "extended Bragg peak mode" have optimal physical and biological effectiveness for delivery of therapy to deep seated tumors. The depth-dose profiles of these beams protect intervening and adjacent tissues as well as tissues beyond the range of the particles. For the treatment of hypoxic tumors, silicon and argon beams are being considered because they significantly depress the radiobiological oxygen effect in the region of the extended Bragg ionization peak. The depth-effectiveness of the argon beam is somewhat limited, however, because of primary particle fragmentation. Silicon beams have a depth-dose profile which is intermediate between that of neon and argon, and are candidates to become the particle of choice for maximizing high LET particle effects. Heavy accelerated ions depress enzymatic repair mechanisms, decrease variations of radiosensitivity during the cell division cycle, cause greater than expected delays in cell division, and decrease the protective effects of neighboring cells in organized systems. Near the Bragg peak, enhancement of heavy particle effects are observed in split dose schedules. Late and carcinogenic effects are being studied. With the newly developed Repair-Misrepair theory we can quantitatively model most observations.

Animals↗
PubMed1981

Comparative effects of 60Co gamma-rays and neon and helium ions on cycle duration and division probability of EMT 6 cells. A time-lapse cinematography study.

Exponentially growing cultures of EMT 6 cells were irradiated in vitro with neon ions, helium ions or 60Co gamma-rays. Time-lapse cinematography allowed the determination, for individual cells, of cycle duration, success of the mitotic division and the age of the cell at the moment of irradiation. Irradiation induced a significant mitotic delay increasing proportionally with the delivered dose. Using mitotic delay as an endpoint, the r.b.e. for neon ions with respect to 60Co gamma-rays was 3.3 +/- 0.2 while for helium ions it was 1.2 +/- 0.1. Mitotic delay was greatest in those cells that had progressed furthest in their cycle at the time of irradiation. No significant mitotic delay was observed in the post-irradiation generation. Division probability was significantly reduced by irradiation both in the irradiated and in the post-irradiated generation. The reduction in division probability obtained with 3 Gy of neon ions was similar to that obtained after irradiation with 6 Gy of helium ions or 60Co gamma-rays.

Cell Cycle↗
PubMed1981

Misonidazole enhancement of radiation-induced growth delay in rat rhabdomyosarcoma tumours exposed to accelerated carbon and neon ions.

The response of a rat rhabdomyosarcoma tumour was assessed by measurements of radiation-induced growth delay resulting from administration of the hypoxic cell sensitizer misonidazole in combination with single and fractionated doses of X-rays and charged-particle radiation. Enhancement ratios of 1.8--2.1 were obtained following single doses of misonidazole (500 mg/kg i.p.) and 225 kV X-rays. Single doses of misonidazole with either carbon-ion or neon-ion radiation in the 4 cm extended-peak ionization region led to enhancement ratios of 1.2--1.3. When combined misonidazole (300 mg/kg i.p.) and X-ray treatments were given in four daily fractions, the enhancement ratios decreased to 1.2--1.5. However, a four-fraction schedule using either carbon-ion or neon-ion radiation in combination with misonidazole gave enhancement ratios of 1.1--1.3, which are similar to the values obtained for single-dose schedules with the sensitizer and charged-particle radiation.

Animals↗
PubMed1980

Assessment of tumour response in a rat rhabdomyosarcoma.

A rhabdomyosarcoma in a WAG/Rij rat with capacity for colony growth after tumour excision and enzymatic dissociation has been used to study response to high and low LET radiation. End points are tumor volume response, TCD50/180, clonogenic capability after tumour irradiation in situ, and in vitro cell survival after irradiation in both the well-oxygenated and the hypoxic conditions. Experience has shown that sublines with different growth rates, radiosensitivity and plating efficiency can arise from the same frozen stock. The conclusions that can be drawn from an analysis of the data obtained to date are as follows: 1. There is no correlation between the doubling times of our two cell lines growing in culture and in the animal. 2. RBE values obtained from growth delay and from TCD50 end points are in fair agreement. 3. Cell survival curves obtained after in situ irradiation show the cells to be more radioresistant than cells irradiated in suspension in vitro. 4. RBE values for cell survival after in situ irradiation compare favourably with those obtained both for tumour growth delay and in vitro cell survival. 5. Not enough is known at present about radiation-altered cell kinetics to develop a self-consistent model of tumour response after irradiation.

Animals↗