Giovanni Silini

Influence of age on life shortening and tumor induction after x-ray and neutron irradiation

The main object of this study is to investigate the role of age on the susceptibility to radiation carcinogenesis and life shortening for different qualities of radiation. Over the last few years, a line of research at the Laboratory of Pathology, C.R.E. Casaccia, has been set up to study the effects of exposure to neutron irradiation, including observations on late effects (both neoplastic and nonneoplastic) as a function of radiation dose and of age at irradiation. Graded single doses of X rays or attenuated fission neutrons have been given to male BC3F1 mice 3 and 19 months old and to animals in utero at 17 days postcoitum. The analysis of data from over 3000 mice indicates that irradiation at 3 months of age causes life shortening which is associated with the incidence and rate of radiation-induced neoplasms. Prenatal irradiation or irradiation at 19 months of age does not show a clearly measurable life shortening for both X-ray and neutron exposures. However, significantly higher incidence and rate of solid tumors and reticulum cell sarcomas were observed. In general the data confirm the higher biological effectiveness of neutrons compared with X rays. The estimates of neutron relative biological effectiveness for different end points were found to be in the range of 3 to 18 and their variation was closely dose dependent.

Late Somatic Effects in Syngeneic Radiation Chimaeras: II. Mortality and Rate of Specific Diseases

SummaryShort- and long-term pathological and epidemiological observations were conducted on a group of control hybrid mice and several groups of animals irradiated with 900 rads and injected with various doses of normal isogeneic bone-marrow stem-cells.Bone-marrow transplantation was effective in enhancing the short-term survival of the treated animals. By comparison with the controls, the long-term survivors showed a shortened life-span, an increased incidence of degenerative and malignant neoplastic diseases and a reduced incidence of reticulum cell sarcoma.The quantitative analysis of the data in terms of age-specific death-rate from all causes and/or with specific diseases provides a description of the basic features of a model of late radiation action, which allows the control of cellular variables and may be of potential interest in studies on radiation carcinogenesis and leukaemogenesis.

RECUPERATION FROM LETHAL INJURY BY WHOLE-BODY IRRADIATION. I. KINETIC ASPECTS AND THE RELATIONSHIP WITH CONDITIONING DOSE IN C57BL MICE.

Many different experimental approaches have been used to investigate the problem of the recuperation4 of biological systems from radiation injury. Since its application to the study of lethality in whole-body irradiated rats by Hagen and Simmons (1), the two-fraction method has been applied widely. The subject has not been thoroughly surveyed since Sachers critical review in 1958 (2). Relevant findings based on this method may be summarized by several generalizations: (1) When the degree of recuperation is estimated from the lethal effects of second doses administered at widely spaced intervals after a range of conditioning doses of different sizes, the course of events appears, at least superficially, to be consistent with exponential decay of residual injury (2, 3). (2) The rate of recuperation depends on the magnitude of the conditioning dose-higher conditioning doses are followed by slower recuperation (4-6). (3) Different species of animals recuperate at characteristically different rates (2, 7). (4) Genetically different strains of the same animal species may show differences in recuperation rates (8). (5) The onset of recuperation, as determined by the sensitivity to a second dose, may be delayed until several hours after conditioning irradiation (9). (6) In the case of the mouse and with respect to the end point of the LD50(3o), those cells the inactivation of which is primarily responsible for survival or death are the primitive stem

Studies of the LSA Ascites Lymphoma of C57B1 Mice

SummaryRadiation dose-survival curves have been obtained for the LSA ascites lymphoma of C57B1/Ka mice after administration of the halogenated thymidine analogue BCDR, alone or in combination with FUDR. A 7 per cent thymine replacement by BU has been obtained with BCDR-treatment alone with a sensitization factor relative to the saline-treated control of 1·7. A 14 per cent thymine replacement was obtained with combined FUDR-and BCDR-treatment. The latter treatment was accompanied by a 9-fold increase in the TD50 and a 2·4 sensitization factor to x-irradiation relative to the controls.

Radiation-Induced Tumors in Transplanted Ovaries

was similar in the two cases, showing a steeply rising branch at doses up to 0.75 Gy followed by a maximum and an elevated plateau up to 4.00 Gy. A higher incidence of tumors in transplanted organs was apparent for doses up to the maximum, which was attributed to castration-induced hormonal imbalance. Specific death rate analysis of mice dying with ovarian tumors showed that in this system radiation acts essentially by decreasing tumor latency. Ovarian tumors were classified in various histological types and their development in time was followed by serial sacrifice. Separate analysis of death rate of animals carrying different tumor classes allowed further resolution of the various components of the tumor induction phenomenon. It was thus possible to show that the overall death rate analysis masks a true effect of induction of granulosa cell tumors in whole-body-irradiated animals. The transplantation technique offers little advantage for the study of radiation induction of ovarian tumor.

SOME OBSERVATIONS AND AN HYPOTHESIS CONCERNING THE EARLY STAGES OF RADIATION RECOVERY

Data are presented relating to the fluctuations in radiosensitivity, as determined by the acute LD/sub 50/, of two inbred strains of mice within the four days following conditioning whole-body irradiation. The kinetics of this recuperative process are typified by an initial minimum in radiosensitivity, succeeded by a rise to a maximum, terminating in a progressive return to the preirradiation level. A review of the relevant literature reveals the same kind of kinetics in other systems. It is therefore suggested that this is a general phenomenon applicable to the effects of divided doses of radiation on mammalian cell reproductive integrity. An hypothesis is proposed to account for these recuperation kinetics, based largely upon the evidence for generation phase- dependent radiosensitivity differences in division delay and survival of cell reproductive integrity. (auth)

Late somatic effects in syngeneic radiation chimaeras. III. Observations on animals repopulated with irradiated marrow.

Lethally-irradiated mice received a graft of bone-marrow cells obtained from intact syngeneic animals or from donors pre-irradiated with 200 or 400 rad. The numbers of haemopoietic cells injected were sufficient to give a high percentage of recipients which survived short-term bone-marrow failure. Epidemiological and pathological observations on long-term surviving animals showed an increased incidence of nephrosclerosis and of systemic or solid tumours following different relationships with the radiation dose given to the cells. These data are discussed within the framework of an experimental model system which might allow estimates of incidence of some neoplastic diseases according to cellular hypotheses of tumour induction.

A THEORETICAL MODEL FOR THE STUDY OF NEUTRON EFFECTS ON TUMORS

Aspects of neutron radiotherapy for tumnors are presented fromn an entirely theoretical point of view. A model is proposed assuming: loss of reproductive integrity is some portion of the tumor mass; limitation of the effects to a specific tumor mass; exhibition by the tumor cells of a multibit survival curve; continuation past the survival curve shoulder in an indefinite exponential trend; interpretation of recovery as damage recuperation at the cellular level; application of observed irradiated phenomena in free cells to tumor masses; time intervals between radiation doses sufficient for maximumn possible recovery; and a recovery rate independent of linear energy transfer. From a purely theoretical analysis and in the absence of experimental data on the subject, it was impossible to make predictions of immediate practical value. It seemed possible to anticipate, however, that necrotic tumors with an insufficient blood supply would be particularly responsive to neutron treatment. In special cases, when the state of oxygenation of the cells may be thought to improve during fractionated therapy, a mixed treatment could also be considered. (H.M.G.)

[A THEORETICAL MODEL FOR THE STUDY OF THE EFFECTS OF NEUTRONS AND X-RAYS ON TUMOR CELL POPULATIONS].

This work deals with the mathematical formulation of a model for studying the effects of X-ray and fast-neutron irradiation on tumor cell populations, the end-effect being the inhibition of reproductive integrity. The variables considered in such a model are largely based on original work performed on trasplantable tumors and obtained in part from other published data; they regard: a) The sensitivity of the tumor cell population with respect both to the extrapolation number and to the slope of the exponential part of the survival curve. b) The type of radiation used, allowing for different RBE values under oxygenated or anoxic conditions. c) The oxygen-enhancement ratios of the radiations considered. d) Different modalities of irradiation (single and multiple doses), allowing for cell recovery in the latter case. e) Different modalities of fractionation with respect to the magnitude of the dose delivered at each fraction. f) The degree of anoxia and the percentage of anoxic cells in the tumor population. g) Possible variations in the percentage of anoxic cells at various points along the course of the radiation treatment. The results of this theoretical analysis are presented, both with regard to the shape of the survival curve of the total cell population and to dose-cure-rate tables, under each of the above-mentioned conditions. Finally, the possible advantages and limitations of the use of neutrons in clinical radiotherapy are briefly discussed.