Cornelius A. Tobias

INACTIVATION OF HUMAN KIDNEY CELLS BY HIGH-ENERGY MONOENERGETIC HEAVY-ION BEAMS

Presented are fundamental data on the biological effects of monoenergetic beams of carbon (400 MeV/amu), neon (425 MeV/amu), and argon (570 MeV/amu). Cell survival of human kidney T-1 cells was measured under aerobic and hypoxic conditions over a range of mean LETinfinity from 10 to 600 keV/..mu..m. RBE and OER were measured under hypoxic and aerobic conditions with attention paid to dose, mean LETinfinity, and particle charge effects. (DS)

Neoplastic Cell Transformation by Heavy Charged Particles

With confluent cultures of the C3H10T1/2 mammalian cell line, we have investigated the effects of heavy-ion radiation on neoplastic cell transformation. Our quantitative data obtained with high-energy carbon, neon, silicon, argon, iron, and uranium particles show that RBE is both dose- and LET-dependent for malignant cell transformation. RBE is higher at lower doses. There is an increase of RBE with LET, up to about 100-200 keV/micron, and a decrease of RBE with beams of higher LET values. Transformation lesions induced by heavy particles with LET values greater than 100 keV/micron may not be repairable in nonproliferating cells. RBE for slow and nonproliferating cells may be much higher than for actively growing cells.

The Repair-Misrepair Model in Radiobiology: Comparison to Other Models

Biological phenomena related to the inactivation of eukaryotic cells by noxious agents have been formulated mathematically in the repair-misrepair (RMR) model by separately quantitating the initial submicroscopic production of molecular lesions and the later, macroscopic expression of effects in the course of cell progression and repair. This paper presents some conceptual and quantitative similarities and differences between the RMR and seven other models proposed for cellular radiobiology including: the linear-quadratic, three-lambda, cubic-survival, target theory, hit-size probability, cybernetic, and lethal-potentially lethal models. The comparison of the various approaches has shown that the RMR model can be generalized to show relationships with each.

Effects of ploidy and linear energy transfer on radiobiological survival curves.

Abstract The radiobiological influence of linear energy transfer (energy transferred per unit length of the track of an ionizing particle) was investigated with respect to inhibition of cell division in three microorganisms: a diploid strain of the yeast Saccharomyces cerevisiae; a haploid yeast derived form the diploid; and the unicellular green alga Stichococcus. Complete survival curves were obtained for each organism at each of nine different values of linear energy transfer (LET), ranging from 0.73 to 190 k.e.v. per micron of path in tissue. Most of these values of LET were obtained by using different portions of the paths of very speedy deuterons, accelerated helium nuclei, and natural α-particles in such fashion that, in any given exposure, the value of LET was essentially the same for all particles that traversed the cell sample. At all values of LET, the survival curves of the haploid yeast were exponential, while those of the diploid were strongly sigmoid and of a shape essentially independent of LET. The relative biological effectiveness (RBE) (a quantity inversely proportional to the 50 % survival dose) of the nine radiations for both yeasts was practically constant for LET values from 0.73 to 27 k.e.v./μ but increased by about a factor of four or five between 27 and 190 k.e.v./μ. The yeast survival curves are consistent with a theory that, in the haploid, cell division can be inhibited by inactivating any one of some tens of chromosomal sites by means of a single ionizing particle, whereas in the diploid it is necessary to inactivate both members of any one allelic pair of corresponding sites. The variation of RBE with LET is not consistent with simple target theory but is readily explained in terms of chemical intermediates which can diffuse from their places of origin in the ionization tracks to the chromosomal sites. The survival curve of Stichococcus was sigmoid, and the RBE increased by a factor of twelve as LET varied from 1.5 to 190 k.e.v./μ.

Effects of Alpha Particle Radiation on the Rat Brain, Including Vascular Permeability and Glycogen Studies

Dorsal pants of rat cerebrum and cerebellum were exposed to alpha radiation (12 Mev per nucleon) from a 60-in. cyclotron at a brain surface dose of 6000 rad (a Bragg-peak dose of 30000 rad). The animals were sacrificed at time intervals from 5 min to 5 months and the brains were subjected to various techniques, including fluorescein-labeled serum protein (FLSP), sodium fluorescein (NaFl), and other procedures for assessment of vascuiar permeability. Histochemical methods were employed for evaluation of changes in brain tissue components, especially for demonstration of glycogen. The results suggest that alphaparticle energy exerts an injurious effect on cellular elements primarily according to its physical properties and distribution in the tissue and that the vascular permeability disturbances play a secondary role. Also from the appearance of glycogen in glial cells, the possibility is suggested that disruption of protein-bound tissue glycogen due to radiation injury may lead to its liberation and subsequent uptake by the glial cells, presumably by pinocytosis. (P.C.H.)

Heavy-Charged-Particle Radiosurgery of the Pituitary Gland: Clinical Results of 840 Patients

Since 1954, 840 patients have been treated at Lawrence Berkeley Laboratory with stereotactic charged-particle radiosurgery of the pituitary gland. The initial 30 patients were treated with proton beams; the subsequent 810 patients were treated with helium ion beams. In the great majority of the 475 patients treated for pituitary tumors, marked and sustained biochemical and clinical improvement was observed. Variable degrees of hypopituitarism developed in about one-third of patients treated solely with radiosurgery. In the earlier years of the program, 365 patients underwent radiosurgery to treat selected systemic diseases by inducing hypopituitarism. Focal temporal lobe necrosis and cranial nerve injury occurred in about 1% of patients who were treated with doses less than 230 Gy.

Impaired repair capacity of DNA breaks induced in mammalian cellular DNA by accelerated heavy ions.

The capacity of human kidney T-1 cells to rejoin DNA breaks induced by accelerated heavy-ion beams of C/sup 6 +/, Ne/sup 10 +/, and A/sup 18 +/ (308 to 500 MeV/amu) was studied. Cell monolayers were irradiated on ice with 2000 rad at various positions in the unmodified Bragg ionization curve. The data show that as the LET increases, the rate of rejoining becomes substantially slower than that normally found for x rays. The impaired rejoining capacity becomes maximal in the 100 to 200 keV/..mu..m range where 25% (+-6.8%) of the initial number of breaks per cell do not rejoin. In comparison, the induction of a maximal number of unrejoined breaks cell/sup -1/ rad/sup -1/ and cell-inactivation studies made under the same experimental conditions show a maximal biological effectiveness at about 100 keV/..mu..m. The data were evaluated both in terms of ionization densities expressed as LET (keV/..mu..m) and in terms of the factor (Z*)/sup 2//..beta../sup 2/, where Z* is the charge of the stripped nucleus and ..beta.. is the ratio of its velocity to the velocity of light.

Radial Cutoff LET and Radial Cutoff Dose Calculations for Heavy Charged Particles in Water

A model has been presented to calculate radial energy deposition around the trajectory of a heavy charged particle in water. The model originates from the basic concept of knock-on collisions and glancing collisions in stopping-power theory. Energy deposition by diffusive motion of low-energy electrons has been included in the calculation. Available experimental data agrees reasonably well with the results of the present model.

Heavy-Ion Effects on Mammalian Cells: Inactivation Measurements with Different Cell Lines

In track segment experiments, the inactivation of different mammalian cells by heavy charged particles between helium and uranium in the energy range between 1 and 1000 MeV/u has been measured at the heavy ion accelerator Unilac, Darmstadt, the Tandem Van de Graaf, Heidelberg, and the Bevalac, Berkeley. The inactivation cross sections calculated from the final slope of the dose-effect curves are given as a function of the particle energy and the linear energy transfer.

Sequential Exposures of Mammalian Cells to Low- and High-LET Radiations: I. Lethal Effects Following X-Ray and Neon-Ion Irradiation

Experiments have been designed to test the independent action hypothesis for cell killing between low- and high-LET radiations. Asynchronous Chinese hamster V79 cells were irradiated at the Berkele...