Biological basis of radiation therapy for cancer.
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Cell Division↗
Biomedical subjects
H R Withers
Publications and source records attributed to H R Withers.
The EORTC hyperfractionation trial.
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Clinical Trials as Topic↗
Dose-time factors in head and neck data.
This paper discusses two points regarding the interpretation of dose-time effects on tumor control in head and neck data. It is shown that the sample size in many clinical series will be too small to be able to statistically detect a dose-response relationship. The results from a non-parametric regression technique applied to control rate data from a large number of institutions suggest an influence of both dose and time on the control rate and qualitatively agree with a previous analysis of these data.
Algorithms↗
Alteration in myelin-associated proteins following spinal cord irradiation in guinea pigs.
The aim of this study was to investigate the pathological and cellular basis for radiation-induced myelopathy in guinea pigs by monitoring biochemical alterations in levels of myelin basic protein and 2',3'-cyclic nucleotide phosphohydrolase. Guinea pigs were irradiated to the lumbar region with various doses of neutrons or cobalt gamma irradiation. The ED50s for paralysis were 17.2 Gy and 67.5 Gy for neutron and cobalt irradiation, respectively, and was histologically associated with demyelination. In spinal cords taken from animals at the onset of paralysis myelin basic protein levels were decreased in direct relationship to the radiation dose. The lowest doses to cause paralysis led to a 25% decrease in MBP levels. In a separate experiment, alterations in MBP were measured in the spinal cords over the time period leading up to paralysis. Surprisingly, decreases in MBP were found immediately after the end of the 4 week irradiation period. These early changes in MBP were not markedly dose dependent and occurred with nonparalyzing doses. Dose-dependent decreases were found only just before the onset of paralysis. CNPase activity measured in the same specimens showed changes that were essentially similar to those for MBP. In the CSF, MBP levels were essentially constant until onset of paralysis. This study showed that demyelination, as assessed by the levels of the myelin-associated proteins MBP and CNPase, can occur soon after spinal cord irradiation but that profound dose-dependent changes are seen only immediately preceding the onset of paralysis. Although increases in MBP in the CSF were associated with the onset of radiation-induced myelopathy, its assay is unlikely to predict this complication of irradiation.
2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗
Adriamycin-induced recall of radiation pneumonitis and epilation in lung and hair follicles of mouse.
The influence of Adriamycin and Actinomycin D on the expression of residual damage following irradiation of mouse thorax was evaluated. Drugs were given i.v. at various times starting on the same day, up to 3 months after irradiation, and the mortality from lung damage up to 160 days or epilation up to 98 days after irradiation were noted. Adriamycin (1.2 mg/kg in two equal doses), which on its own did not cause pneumonitic deaths, did so when combined with doses of local thoracic radiation as small as 6 Gy. The dose effect factor was greater if Adriamycin was given at 1 or 2 months (1.68) rather than on the same day (1.49). A reduction in the latent period to death was also observed with a minimum period of 50-60 days after irradiation rather than the normal 80-160 days. Adriamycin enhanced the epilation response to radiation, but only at or above threshold radiation doses. There was no reduction in the latency. Actinomycin D had no dose-modifying effects on the radiation response of both lung and hair follicles. The interaction between irradiation and Adriamycin seen when the interval between the two modalities is long, as it was in this study, may be mechanistically similar to the "radiation recall" phenomenon described in the clinic.
Animals↗
The effect of single doses of radiation on mouse spinal cord.
We have used a mouse model to study spinal cord injury following single doses (12 to 75 Gy) of radiation. The spinal cord (T9,10-L4,5) of C3Hf/Sed//Kam mice was irradiated and response graded using four levels of neurological change. Findings were: (a) the doses required to paralyze 50% of animals (ED50) were 19.79, 20.77, and 21.85 Gy for mild, partial, and complete paralysis, respectively, as measured 200-360 days after radiation. (b) Most damage was progressive but it was not necessarily so; after doses up to 28 Gy recovery was occasionally seen. (c) Latency depended on the dose and the level of damage. Following doses around the ED50, paralysis occurred between 180 to 300 days. (d) There were significant fluctuations in the dose-latency relationship at doses less than 35 Gy. Latency may be not a reliable endpoint to compare biological effects of radiation in this dose range. (e) The radiosensitivity of mouse spinal cord was similar to that reported for rats. (f) Histologically, demyelination was the dominant lesion in the paralyzed animals. We conclude that the mouse is a good animal model to study radiation damage to the spinal cord, at least when a 2.2 cm length is irradiated.
Animals↗
Repopulation of mouse jejunal crypt cells.
The regenerative response to radiation of mouse jejunal crypt cells was investigated using a three fraction experiment. The time between the second and third fraction was varied between 5 and 60 h, and the dose in each of the three fractions was different. The data show that the onset of regeneration is within 14 h of the first dose and possibly earlier. The doubling time of the clonogenic cells during repopulation is estimated to be between 5 and 10 h, with the most likely value approximately 6 to 7 h. The data also show that the time course of repopulation in an acutely responding tissue depended in a complex way on the fractionation scheme. The implications of this for radiotherapy are that simple formulas are unlikely to be accurate predictors of acute effects in altered fractionation schemes. Detailed mathematical modelling of the data is undertaken using a model which consists of a single dose survival curve, a part to incorporate the regenerative response and a part to accommodate the delayed onset of regeneration. The model is shown to give a good, although not perfect, fit to the data. A mathematical derivation is given of the expected number of crypts following the 3 dose radiation schedule. This derivation takes into account the fact that any crypt could be denuded of cells prior to the final dose and hence not repopulate, and thus the formula given is necessarily more complex than previous formulas which were based on simpler models.
Animals↗
Efficacy of i.v. or i.p. injected cytotoxic drugs on proliferating and non-proliferating hair follicles of the mouse.
A range of drug doses of Adriamycin (ADR), Actinomycin-D (ACT-D), and Mitomycin-C (MMC) were given i.v. or i.p. to mice 1 day after a priming dose of radiation to elicit epilation response. The hair follicles were stimulated through plucking 11 days before irradiation or were unstimulated to represent proliferating and nonproliferating populations. The maximum epilation that appears at 8 days or at 8.5 weeks for proliferating and nonproliferating follicles was quantified using a subjective scale. In general, the i.v. route of administration was more effective than i.p. for all three drugs. Proliferating follicles were more susceptible than non-proliferating follicles to the action of drugs, especially ADR (p = .0001). Radiation doses which would give the same effect as ADR were calculated for proliferating follicles: 8 mg/kg given i.v. was equivalent to 4.6 (3.9, 5.2) Gy. For i.p. administration, 8 mg/kg was equivalent to only 0.6 (-0.1, 1.3) Gy. The in vivo assay of drug effect on hair follicles has advantages over LD10 as a model for toxicological investigation of new drugs: it can assess response of proliferating or non-proliferating cells of the same histotype and, in the case of proliferating follicles, it is quicker, thus enabling the use of doses higher than LD50 for bone marrow deaths.
Animals↗
Direct analyses of in vivo colony survival after single and fractionated doses of radiation.
Several methods are described for analysing the results of in vivo colony assays using the statistical procedure called maximum-likelihood analysis. The methods differ in the way in which they take into account possible sources of variability in the data. The methods described here for analysing microcolony data are direct methods, in that they use the observed colony counts rather than transformed (e.g. Poisson-corrected) data. Each method can be used to estimate the average number of surviving cells per tissue structure (e.g. per jejunal crypt) in a single dose group, together with 95% confidence intervals, or to fit cell-survival models to data from a range of dose groups (e.g. to obtain estimates of D0 or of the linear-quadratic parameters alpha and beta). Experimental microcolony data from murine jejunum, colon, and hair follicles irradiated in anagen (proliferative) or telogen (resting) phase have been analysed. Estimates of D0 have been derived from single-dose data and estimates of alpha, beta, and the initial number of clonogenic cells per structure have been derived from fractionation data. For hair follicles, the half-time of repair of sublethal radiation injury has also been derived from fractionation data.
Animals↗
Radiobiological aspects of electron beams.
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Animals↗
Effect of fibroblast implants on wound healing of irradiated skin: assay of wound strength and quantitative immunohistology of collagen.
The role of dermal fibroblasts in the expression of radiation-induced damage to the skin was studied. Fibroblasts from neonatal mice were cultured, harvested, and injected into full-depth surgical incisions in the dorsal area of mouse skin, which had been previously locally irradiated by 18 Gy X rays. As a control, cells irradiated with a dose of 20 Gy were also injected. The effect of radiation and fibroblast implants on the gain of skin wound strength was assayed. In an additional experiment freshly isolated cells were implanted. Two weeks following wounding the irradiated skin had reached only about a third of the strength of unirradiated skin. A significant increase of wound strength in irradiated skin was observed when 1.5-2 x 10(6) cultured fibroblasts or freshly isolated fibroblasts were injected into the 20-mm-long wound bed. Irradiated cells had significantly less effect. This suggests that implanting isolated syngeneic cells may "rescue" wounds from the effect of prior irradiation. Semiquantitative immunohistology of types I and III collagen was performed in parallel using a video image digitizing system. Levels of both types I and III collagen were altered in the dermis and the wound tissues in irradiated skin, but the implant of cultured fibroblasts did not affect notably the total levels and the disposition of the two collagen isotypes.
Animals↗
Dose-time considerations of head and neck squamous cell carcinomas treated with irradiation.
The dose-time factors in the external beam treatment of 473 patients with squamous cell carcinoma of the pharyngeal wall, vocal cord, pyriform sinus or supraglottic larynx were considered. The effect of overall treatment time on the tumor response was quantified by estimating the increment in dose per day needed to achieve a constant rate of local control, that is, the dose required to counterbalance the effect of growth of the tumor during irradiation. The estimated increment in isoeffect dose per day varies between sites, however, the increments, although estimated with considerable uncertainty, are in general larger than 1 Gy per day. These estimates are consistent with accelerated tumor clonogen repopulation during irradiation.
Carcinoma, Squamous Cell↗
Bone growth retardation induced by single and multifractionated irradiation.
The right hind legs of 12- to 14-week-old mice were exposed to single and multifractionated courses of gamma-ray irradiation. The recovery curves, time-dose relationships, and fraction number-dose relationships were analyzed using femoral growth retardation as an endpoint. The bones grew 2 mm, about a 10% increase over their original lengths, in 12 months; and 63% and 85% in volume in 6 and 12 months, respectively. The ratio of the volume increase of the irradiated right leg per unit time, the actual growth, to the volume increase of the non-irradiated left leg, the potential growth, was calculated for each mouse. The doses necessary to produce a given degree of bone growth retardation in 50% of the tested animals were calculated for each treatment schedule. The isoeffect doses for a given degree of bone growth retardation after 2 and 4 equal fractionation exposure increased (peak at one day-interval) and decreased (trough at 2-day interval), and later increased additionally with increasing time intervals between doses.
Animals↗
Dose fractionation and regeneration in radiotherapy for cancer of the oral cavity and oropharynx. Part 2. Normal tissue responses: acute and late effects.
The early responses of normal tissues of the oral cavity and oropharynx in 498 patients, and the slowly-developing responses in 268 patients who survived a minimum of 18 months after radiotherapy for squamous cell carcinoma were analyzed. The severity of acute responses correlated with dose intensity. The incidence of severe late responses increased with increase in dose per fraction and was characterized by a low alpha/beta ratio. Severe late responses were significantly associated with severe acute responses independently of dose per fraction and total dose, and were also ameliorated slightly by protraction of treatment time suggesting that some late effects were, at least partly, a consequence of acute injury. Probability of local tumor control correlated with severity of acute response, suggesting that excessive protraction of overall treatment time to minimize acute toxicity may compromise local control of the tumor. There was no demonstrable correlation between the volume of tissue irradiated and the severity of acute or late response.
Carcinoma, Squamous Cell↗
Radiation effect in mouse skin: dose fractionation and wound healing.
Radiation induced dermal injury was measured by the gain in the physical strength of healing wounds in mouse skin. A sigmoid dose response for the inhibition of wound healing 14 days after surgery was found for single doses of X rays. The sparing of dermal damage from fractionation of the X-ray dose was quantified in terms of the alpha/beta ratio in the linear-quadratic (LQ) model, at a wide range of doses per fraction reaching as low as about 1 Gy. The fit and the appropriateness of the LQ model for the skin wound healing assay was examined with the use of the Fe-plot in which inverse total dose is plotted versus dose per fraction for wound strength isoeffects. The alpha/beta ratio of the skin was about 2.5 Gy (95% confidence of less than +/- 1 Gy) and was appropriate over a dose range of 1 Gy to about 8 Gy. The low alpha/beta value is typical for a late responding tissue. This assay, therefore, has the advantage of measuring and forecasting late radiation responses of the dermis within a short time after irradiation.
Animals↗
Effect of interleukin 1, inflammation, and surgery on the incidence of adhesion formation and death after abdominal irradiation in mice.
There is clinical evidence that prior surgery and inflammation can increase the risk of the chronic complications of radiotherapy delivered to the pelvic/abdominal region. We have established a murine model to study this interaction using as end points mortality and late gut-associated peritoneal adhesion formation. A single dose of 16 Gy of total abdominal irradiation (TAI) was used. This gave no early deaths (less than 1 mo) and a relatively low mortality over the period 1 to 6 mo after TAI. The incidence of adhesions, which is the most serious complication 2 to 6 mo after TAI, was also low. Injection of lipopolysaccharide (50 micrograms, i.p.) or human recombinant interleukin 1 (IL-1) in doses as low as 100 units prior to TAI greatly enhanced both radiation-induced adhesion formation and death. Prior surgery also increased radiation-induced mortality, so much so that adhesions could not be accurately quantified. The timing of administration of lipopolysaccharide and IL-1 and of surgery relative to TAI was important in determining the outcome. For example, IL-1 enhanced adhesion formation and death if given from 3 days before to 1 day after, but not 4 days or 4 wk after, TAI. If given 20 h or less before TAI, there was a dramatic increase in early mortality 1 to 3 wk later, which was not seen if IL-1 was given at other times. These early deaths were not caused by bone marrow or gut stem cell depletion and may be a result of fluid leakage. We propose that surgery, bacterial invasion, or other inflammatory signals might act through a common mechanism of stimulating IL-1 production to enhance radiation-induced adhesion formation and the early and late morbidity and mortality associated with abdominal irradiation. If this is the case, blocking IL-1 production might inhibit the development of these late complications.
Abdomen↗
Radiosensitivity of pre-irradiated mouse skin to second courses of single and multi-fractionated irradiation--skin shrinkage.
The hind legs of mice were re-irradiated with various gamma-ray doses in single or multi-fractionated exposures 6 or 12 months after conditioning irradiation was administered using a variety of treatment schedules. Dose-response relationships were evaluated to ascertain "residual injuries", permissible doses during the second treatments. Fifty to 60 days after the second treatments, the degrees of shrinkage of the skin on the dorsal aspects of the hind legs were measured and used as endpoints. The residual injuries were affected by the biologically effective doses, or by the treatment schedules of not only the first, but also the second exposure. The higher the biologically effective doses, the greater were the residual injuries. Compared to the previously untreated skin, the pre-irradiated skin was relatively radioresistant to the second course of treatments, regardless of the treatment schedule used. The response of the pre-treated skin to a given test dose (25 or 40 Gy) lessened with increasing dose for each treatment schedule used during the first treatment course.
Animals↗
Repair kinetics of mouse lung.
Pathological manifestations of lung damage after irradiation support the use of death between 11 weeks (80 days) and 23 weeks (160 days) as an assay for pneumonitis in the C3Hf strain of mice. The proportion of deaths and the time to reach a specific percent of lethality were found to be dose and dose per fraction-related. The median survival time and the latency period for the time of occurrence of pneumonitis, were dependent on total biological dose over a narrow range, equivalent to "normalized" doses of 36-41 Gy in 2 Gy fractions. All these criteria entered into the analysis of data. The linear-quadratic isoeffect model gives a good fit for the results over a range of doses from 1.6 to 8 Gy per fraction, that is, with the exclusion of the single dose data. The value of alpha/beta was always approximately 4.0 Gy from three kinds of analyses. The half-time for repair from sublethal injury was approximately 0.75 h. Both of these values are in agreement with the results from other investigators.
Animals↗