[Organisms and radiation - effects of radiation on the genetic mechanism].
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A number of powerful chemical compounds that modify radiation effects have been discovered and tested both in the laboratory and clinically over the past 25 years. There are four major classes of compounds: aminothiol radio-protectors which act on well vascularized euoxic cells and concentrate in tissues such as skin, gut and marrow; nitromidazole radiosensitizers which act on hypoxic tumor cells; pyrimidine analogues which are incorporated into the DNA of cycling cells and cause radiosensitization; and cancer themotherapy agents which, in addition to their ability to kill tumor cells directly, also may sensitize tumor and normal cells to radiation. The mechanism of action, experimental activity, and clinical results or the potential for each of these agents are reviewed.
In five previous papers, the concept of the Cumulative Radiation Effect (CRE) has been presented as a scale of accumulative sub-tolerance radiation damage. The biological effect generated in normal connective tissue by fractionated or continuous radiation therapy given in any temporal arrangement is described by the CRE on a unified scale of assessment, so that a unique value of the CRE describes a specific level of radiation effect. The basic methods of evaluating CREs were shown in the papers to facilitate a full understanding of the fundamental aspects of the CRE-system, but these methods can be time-consuming and tedious for complex situations. In the previous papers in this series, one way of overcoming the difficulties in evaluating CRE problems was presented in simple nomographic and tabular methods for the solution of practical problems. An alternative way of overcoming the difficulties in the evaluation of CRE problems is to use computers and it is the purpose of this paper to outline computer calculations and applications in clinical practice in connection with the CRE-system. In a general appraisal of the applications of computers to the CRE-system, the various problems encountered in clinical radiotherapy are categorised into those involving the evaluation of a CRE at a point in tissue and those involving the calculation of CRE distributions. As a general guide, the computer techniques adopted at the Glasgow Institute of Radiotherapeutics for the solution of CRE problems are presented, and consist basically of a package of three interactive programs for point CRE calculations and a Fortan program which calculates CRE distributions for iso-effect treatment planning. Many examples are given to demonstrate the applications of these programs, and special emphasis has been laid on the problem of treating a point in tissue with different doses per fraction on alternate treatment days. The wide range of possible clinical applications of the CRE-system has been outlined and described under the categories of routine clinical applicatons, retrospective and prospective surveys of patient treatment, and experimental and theoretical research. Some of these applications such as the results of surveys and studies of time optimisation of treatment schedules could have far-reaching consequences and lead to significant improvements in treatment and cure rates with the minimum damage to normal tissue.
In five previous papers, the concept of the Cumulative Radiation Effect (CRE) has been presented as a scale of accumulative sub-tolerance radiation damage. The biological effect generated in normal connective tissue by fractionated or continuous radiation therapy given in any temporal arrangement is described by the CRE on a unified scale of assessment, so that a unique value of the CRE describes a specific level of radiation effect. The basic methods of evaluating CREs were shown in these papers to facilitate a full understanding of the fundamental aspects of the CRE-system, but these methods can be time-consuming and tediuous for complex situations. In this paper, simple nomographic and tabular methods for the solution of practical problems are presented. An essential feature of solving a CRE problem is firstly to present it in a concise and readily appreciated form, and, to do this, nomenclature is introduced to describe schedules and regimes as compactly as possible. Simple algebraic equations are derived to describe the CRE achieved by multi-schedule regimes. In these equations, the equivalence conditions existing at the junctions between schedules are not explicit and the equations are based on the CREs of the constituent schedules assessed individually without reference to their context in the regime as a whole. This independent evaluations of CREs for each schedule results in a considerable simplification in the calculation of complex problems. The calculations are further simplified by the use of suitable tables and nomograms, so that the mathematics involved is reduced to simple arithmetical operations which require at the most the use of a slide rule but can be done by hand. The order of procedure in the presentation and calculation of CRE problems can be summarised in an evaluation procedure sheet. The resulting simple methods for solving practical problems of any complexity on the CRE-system are demonstrated by a number of examples.
An equation is proposed to link the Cumulative Radiation Effect (CRE) scale of radiation damage with the fraction of basal cells surviving after irradiation of skin epithelium. The model assumes an expression for the basal cell survival curve which fits the various hit-target models over the range of doses found in clinical practice. The model is consistent with CRE in the dependence on total treatment dose and fractionation number. A 'first order' analysis using a Gompertzian re-growth of cells also yields reasonable agreement with the CRE equation in time dependence during treatment and during a gap. This model is suitable for acute skin reactions but not necessarily for late effects in connective tissue.
The CRE formula was used for calculation of biologically equivalent radiation doses with different fractionation schedules. The early radiation effects, skin erythema and pigmentation were measured with a reflectance spectrophotometer at wavelengths 578 and 660 nm. The course and maximum for both erythema and pigmentation agreed well with the two types of fractionation. The results seem to justify further use of this simple formula.
The capillary networks of normal and irradiated abdominal organs of mouse were investigated by a resin cast technique. The structure of the capillary system had characteristic appearances. Radiation effects on the fine vascular structures were demonstrated from one appearances. Radiation effects on the fine vascular structures were demonstrated from one to 30 days after a single dose of 5 to 30 Gy whole body irradiation. Prominent morphologic abnormalities of the shape and distribution of the capillaries were identified, especially in the small intestine.
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Acid phosphatase is present in the nucleus and cytoplasm of cells in the seminiferous tubules and the interstitium of rat testes. The effect of irradiation on acid phosphatase is dependent on the environmental temperature and the dose of irradiation. It appears that initial rise in the enzyme at a low radiation dose and a high environmental temperature or at a high dose and low temperature is associated with a lysosomal breakdown of the germinal cells of the testes. A decrease in acid phosphatase in the advanced stages of radiation injury is a secondary radiation effect which may lead to decreased metabolic synthesis of phosphate esters owing to the unavailability of orthophosphate in the testicular tubules. The reduced acid phosphatase activity can be detected in the seminiferous tubules, suggesting that the enzyme activity is related to the state of the germ cell population. An initial increase in acid phosphatase is matched by an initial rise in acid DNAse within hours of irradiation, further suggesting that there is radiation interaction with the cells of the germinal epithelium. The enhanced activity of DNAse following a 2nd week of irradiation at 2000 R confirms the phagocytic activity of the non-germinal cells.
Using nuclear medical techniques, especially that of functional scintigraphy with the gamma camera after injection of 99mTc-pertechnetate, it is possible to objectify dose-dependent radiation effects on the salivary glands: Radiation doses from 500 to 1200 rd lead to a temporary reduction of the capacity to accumulate the 99mTc-pertechnetate. This functional restriction is reversible. With radiation doses of more than 2000 rd there appear irreversible functional disorders being proportional to dosage. Focal doses of about 6000 rd produce a complete loss of the capacity for 99mTc accumulation of the salivary glands. The chronological course of radiation response is characterized by a) an activation of the radionuclide accumulation following ca. 3000 rd in about three weeks, b) a following decrease of the capacity for accumulation of 99mTc, c) a renewed activation after the end of irradiation, and d)the progressive and irreversible loss of function of the salivary glands.
In three previous papers, a scale of accumulated sub-tolerance radiation damage, the Cumulative Radiation Effect (CRE), was described for fractionated treatment regimes and continuous radiation therapy from both long-lived and short-lived sources. This scale provides a means of assessing and comparing the biological effects of various treatments. In this paper, it is intended to further the scope of application of the CRE-system by describing in detail the normalisation between the assessments of fractionated and continuous therapy. To do this, it is necessary to consider area and volume correction factors, whose roles are to modify the values of uncorrected CREs so that a specific biological effect, regardless of the area or volume treated, is described by a unique value of the corrected CRE. The problem arising when the CRE achieved by a treatment regime is not constant over a volume is briefly discussed and a simple hypothesis is proposed which may stimulate interest in this problem. The establishment of a normalisation procedure between fractionated treatment regimes and continuous radiation therapy, which is the primary aim of this paper, serves to integrate the concept of the CRE into a unified system of assessment of biological damage, so that a unique value of the CRE describes a specific level of biological damage regardless of the area or volume treated, or the time course of administration of the radiation employed.
The effects on pig skin from radiations producing different densities of ionization have been determined. For the qualities of radiation employed, erythema was produced at a dose range from 1,240 to 3,440 rads and ulceration at 1,250 to 5,000 rads. In no instance did a radiation-induced neoplasm develop. In determining dose response, two of the most important physical parameters, associated with time of appearance and extent of lesions, were found to be the size of the area irradiated and the density of ionization of the radiations used. These data, on normal tissue tolerance, should be a value in future programs initiated in experimental radiation therapy of both animal and human neoplasia utilizing protons, alpha particles, and carbon ions.
Three groups of rats were studied. Group 1 rats received 6,000 R of irradiation, group 2 rats received 4,000 R, and group 3 rats acted as a control. Four weeks following irradiation, the femoral artery of each rat was cut and reapproximated using microvascular surgical techniques. Four weeks after surgery, the same femoral artery was evaluated for patency. There was no notable effect of irradiation on the patency of subsequently performed anastomosis of these small (1 mm in diameter) muscular arteries. Radiation effects were obvious on histological examination, but the anatomical and physiological alterations apparently were not severe enough to cause early thrombosis after microsurgical manipulation of these vessels.
Colloidal forms of radioactive isotopes are being used for the treatment of some articular diseases. The radiation effects of intra-articular injection of 0.25 mCi of 32P in the form of colloidal chromic phosphate were investigated in one of the knee joints of adult Wistar rats. The contralateral knee was used as a control. The animals were sacrificed one, 7, 14, 28 and 56 days later. Destructive changes were found after 56 days. The articular cartilage was atrophied and covered by a fibrous pannus. The growth cartilage was severely disorganized and there were deleterious effects on both cells and matrix.