Kinetics of repair: its influence in low dose rate irradiations.
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Cell Survival↗
Biomedical subjects
W Landuyt
Publications and source records attributed to W Landuyt.
Effect of continuous infusion of bleomycin on the time for completion of repair of sublethal radiation damage in mouse lip mucosa during fractionated irradiation.
The influence of a simultaneous continuous infusion of bleomycin on the time necessary for repair of sublethal radiation damage during fractionated irradiation of mouse lip mucosa was studied. Although there are strong indications that bleomycin interferes with the accumulation and repair of sublethal radiation damage, no significant change in the time course of these repair processes could be demonstrated following various analyses of the experimental results. An interval of at most 4 h between successive irradiations was sufficient to allow for a similar amount of repair of sublethal damage as compared with either 24 h (2 fractions) or 6 h (10 fractions), whether or not radiation was combined with bleomycin infusion.
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Combined effects of bromovinyldeoxyuridine and fractionated or continuous administration of 5-fluorouracil in P388 leukemia-bearing mice.
The combined effects of fractionated administration of the antiviral agent (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and fractionated (4 injections at a 48-h interval) administration or continuous (7-day) infusion of 5-fluorouracil (FU) have been investigated in P388 leukemia-bearing mice. The LD50 of continuous FU infusion in normal mice was approximately 330 mg/kg, while that for the fractionated treatment was 160 mg/kg. When combined with BVDU (200 mumol/kg, 90 min before each FU injection; 4 injections at a 48-h interval), the LD50 of FU was decreased from 330 to 115 mg/kg and from 160 to 30 mg/kg, respectively. The 7-day continuous infusion of FU (up to a dose of 210 mg/kg) did not exert a therapeutic effect in P388-leukemic mice, and, similarly, combination of continuous FU infusion (at lower doses) with BVDU failed to increase the survival of the leukemic mice. If, however, FU was administered in fractionated doses, there was a dose-dependent increase in survival time of P388-leukemic mice, and simultaneous fractionated BVDU treatment allowed a 4-6-fold lower dose of FU to achieve the same increase in survival time, indicating that BVDU effectively increased the antitumor activity of FU in the leukemic mice.
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Unilateral kidney irradiation and late retreatment with cis-dichlorodiammineplatinum (II): functional measurements with 99mtechnetium-dimercaptosuccinic acid.
A rat model was used to study renal function after unilateral kidney irradiations. The left kidney was irradiated with a single dose (6-14 Gy), 2 equal sized fractions (10-16 Gy total dose) or 4 equal sized fractions (12 to 21 Gy total dose). At regular time intervals after treatment, the left kidney function was assessed with the use of 99mTc-Dimercaptosuccinic acid for a period of about 1 year. It was found that renal function declined in a dose- and time-dependent manner. The threshold dose for detecting functional impairment was 8 Gy for 1 fraction, 12 Gy for 2 fraction and 15 Gy for 4 fraction irradiations, demonstrating the sensitivity of the isotope tracer test used in these experiments. Retreatment of the rats with a single i.p. dose of 5 mg/kg cis-Dichlorodiammineplatinum (II) (cis-DDP) given at about 1 year after X ray exposure revealed an important relative decrease in the function of the irradiated compared to the unirradiated kidney. Reductions in function of 11 to 70% (depending on radiation dose and schedule) compared with control values were observed at 11 weeks after drug injection. These results demonstrate that a previously irradiated kidney is more sensitive to a subsequent treatment with cis-DDP than the contralateral hypertrophied kidney in the same animal.
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Effect of simultaneous administration of bleomycin on the acute skin reactions of mice after single and fractionated doses of radiation.
The effect of bleomycin on the acute mouse foot skin reactions, occurring after irradiation, was investigated. Bleomycin was delivered simultaneously with the irradiation treatment, either by intraperitoneal injection or by subcutaneous continuous infusion. Experiments were carried out to investigate (a) the modification by bleomycin of the response to single doses of radiation (b) the effect of total drug dose on this modification (c) the influence of the drug on repair of sublethal radiation damage and (d) the interference by the drug with compensatory repopulation after irradiation. In none of the experiments could any influence of the drug on these radiation induced reactions and recovery processes be demonstrated. These results are in direct contrast to what we have observed previously for similar types of experiments in another epithelial system, the mouse lip mucosa.
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From 2 Gy to 1 Gy per fraction: sparing effect in rat spinal cord?
Recently published results, from this group, on rat cervical spinal cord, a late responding tissue, indicated no further sparing with lowering the fraction size from 2 to 1.8, 1.5, and 1.3 Gy. In the present experiments a small but probably significant rise in tolerance is suggested, when the dose per fraction was decreased from 2 Gy down to 1 Gy. This rise would however still be much less than what is predicted by the linear quadratic model, based on the experimental data obtained with fraction sizes larger than 2 Gy.
Animals↗
A simple graphical method for deriving kinetics of repair from fractionated and protracted irradiations.
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Animals↗
Effect of continuous infusion of bleomycin on repopulation in mouse lip mucosa during fractionated irradiation.
The effect of the administration of bleomycin on repopulation in mouse lip mucosa during fractionated irradiation was studied. Two equal-sized irradiation fractions were delivered with 1-, 7-, or 10-day intervals, with and without simultaneous administration of 40 mg bleomycin/kg in a continuous sc infusion, given over 7 days. In the experiments with irradiation only, the prolongation of the interval from 1 day to 7 days resulted in a net increase of the isoeffective dose due to compensatory proliferation. This effect was even more pronounced with the 10-day treatment interval. The addition of bleomycin, however, nearly completely suppressed this proliferative activity.
Animals↗
Evaluation of mouse lip mucosa reactions after combinations of cis-diammine-1,1-cyclobutanedicarboxylate platinum (II) (CBDCA) and irradiation: single and fractionated treatments.
The influence of CBDCA (JM8) on the radiation-induced mouse lip mucosal reactions has been tested. Both single and fractionated drug doses were used intraperitoneally at 60 mg/kg and 5 X 25 mg/kg respectively. A single injection of CBDCA did not alter the response to a single radiation dose, whether the drug was given at different time intervals from 24 hr prior, to 96 hr after irradiation. A concomitant treatment of daily CBDCA injections and irradiations for 5 consecutive days demonstrated no change of the capacity to repair sublethal radiation damage. When two equal sized radiation doses were separated by 10 days and CBDCA was administered daily from day 3 to 7, the ability to repopulate the lip mucosa epithelium during the radiation-free period was not influenced.
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The effect of small radiation doses per fraction on mouse lip mucosa assessed using the concept of partial tolerance.
The acute effect of small radiation doses per fraction on mouse lip mucosa was investigated in the present study. In order to minimize the amount of additional sparing by regeneration during fractionated irradiations in this rapidly proliferating tissue, the overall treatment time had to be limited to at most 4 days, so that the number of irradiations that could be delivered was limited. Therefore, the concept of partial tolerance, established in the rat spinal cord model, was applied. The present experimental data confirm the validity of using this concept for assessing the effect of small radiation doses on tissues. The results of experiments covering a wide range of fraction sizes show that the isoeffective dose for a given mucosal reaction increases when the dose per fraction is progressively decreased to about 2 Gy per fraction. Further reduction of the size of dose per fraction, however, does not result in a detectable extra increase in the total dose to produce the same level of biological effect. It seems that the dose limit of sparing by fractionation in this rapidly proliferating normal tissue might be situated at larger fraction sizes than 0.6 Gy as estimated on basis of the mathematical linear-quadratic model, using an alpha/beta ratio of 6 Gy measured from data with doses per fraction in the range of 2 to 10 Gy.
Animals↗
Irradiation of murine lip mucosa in combination with 5-fluorouracil, administered by single dose injection or continuous infusion.
The possible interaction of 5-fluorouracil (5-FU) and irradiation on mouse lip mucosa was studied, with special interest for the influence of the route of administration of the drug, either by single intraperitoneal (i.p.) injection or by 7 days continuous subcutaneous infusion. Apart from the possible modification by the drug of radiation-induced damage to the lip mucosa assessment was made of the systemic toxicity. No modification of the radiosensitivity of mouse lip mucosa nor of its repair capacity was observed with the use of 5-FU given either by i.p. injection or by continuous infusion. However, the combination of 5-FU and irradiation resulted in an increased systemic toxicity which was only seen when 5-FU was administered by an i.p. injection in close timing with irradiation. It is suggested that this increased systemic toxicity is caused by the combined effects of irradiation and 5-FU on the alimentary tract, although we could not demonstrate the mechanism of it.
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Effect of decreasing the dose rate of irradiation on the mouse lip mucosa. Comparison with fractionated irradiations.
The effect of continuous irradiation, delivered at five different dose rates (642, 76.8, 14.1, 2.9 and 1.5 Gy.h-1), has been investigated using the mouse lip mucosa. There was a striking dose rate effect (DRE) below 14.1 Gy.h-1 while above this dose rate the DRE was relatively small. No DRE was observed between irradiations delivered at 642 and 76.8 Gy.h-1. A comparison was made with the previously published results of high dose rate (84 Gy.h-1) fractionated irradiation (2, 4, 10 and 20 fractions). For both types of irradiation treatment an alpha/beta value of 7.4 Gy and a half-time for repair of 47 min was derived.
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[Effects of irradiation on the lip mucosa in the mice as a function of rate. Comparison with the effect of fractionation].
We have investigated the effect of single doses delivered at various dose rates on the mouse lip mucosa biological system. The dose rates were: 642, 76.8, 14.1, 2.9 and 1.5 Gy/h. The incidence of desquamation in the different groups of mice was used for constructing dose effect curves. The dose leading to desquamation in 50% of the animals (ED50) was obtained by probit analysis. These ED50 were 16.5, 16.7, 19, 30.2 and 33.5 Gy for the respective dose rates. Fractionated irradiations have also been performed in the same biological system (separately published), and we have therefore been able to compare the fractionated and low dose rate irradiations. The recently published model of Dale was used for this comparison. With that mathematical approach a alpha/beta value of 7.4 Gy and a half time of repair of sublethal damage of 47 minutes have been derived. These results compare well with others from the literature on biological systems with similar characteristics (rapidly proliferating systems).
Animals↗
The combined effect of bleomycin and irradiation on mouse lip mucosa. 1. Influence of timing, sequence and mode of drug administration with single dose irradiation.
The effect of the combination of single dose irradiation and bleomycin on the mucosa of the mouse lip was investigated. Bleomycin was administered either by IP injection or by subcutaneous continuous infusion. With the combined treatment an increased effect was observed compared to irradiation alone. The effect was drug-dose dependent in the range of doses used (5-80 mg/kg) and was similar for both ways of drug administration. There was only a limited influence of timing and sequence of the two agents within a period of 4 days. Since the dose-response curves were shifted in a parallel way, a constant cell killing effect by bleomycin is suggested for all irradiation doses used. This could be due to independent cell kill by the drug, although some mechanism of interaction, such as interference with accumulation of sublethal radiation damage or a true dose modification can not be excluded.
Animals↗
The combined effect of bleomycin and irradiation on mouse lip mucosa. 2. Influence on the accumulation and repair of sublethal damage during fractionated irradiation.
The effect on the mouse lip mucosa of different fractionated irradiation schedules (with respectively 1, 2, 4 10 and 20 equal fractions) with and without a simultaneous constant drug regimen (bleomycin 40 mg/kg in a continuous subcutaneous infusion over seven days) was investigated. Lowering the fraction size resulted in a progressive increase of both the dose modification factors (DMF) and the absolute dose reduction (ADR), i.e. from 1.19 and 2.8 Gy respectively for single doses to 1.86 and 21.5 Gy respectively for 20 fractions (at isoeffect level 3.5). The mechanisms involved are most probably a direct cell kill by bleomycin, together with a reduced capacity to accumulate and/or to repair sublethal damage, although the influence of redistribution in the cell cycle during bleomycin infusion can not be excluded. Such large differences in the interaction between chemotherapy and irradiation as a function of the fractionation schedule could lead to a significant underestimate of response if data from single dose or 2-fraction experiments are extrapolated to regimens used in clinical practice.
Animals↗
Combinations of single doses and fractionated treatments of cis-dichlorodiammineplatinum (II) and irradiation: effect on mouse lip mucosa.
Tolerance of the lip mucosa of NMRI mice to single and fractionated irradiation combined with cis-diamminedichloroplatinum (II) (cis-DDP) was investigated. For the various combination schedules total drug doses varying from 6 mg kg-1 to 13 mg kg-1 were injected i.p. It was found that cis-DDP did not alter the radiation sensitivity of this tissue at any of the time intervals tested (ranging from 24 h before to 72 h after single dose irradiations). When 5 daily drug injections were given concomitantly with 5 daily radiation treatments, a slight reduction of the lip mucosal reactions occurred, possibly due to partial synchronisation during treatment. No effect was seen when a single injection of cis-DDP preceded two irradiations given with increasing intervals up to 4 h. Both these combined fractionated treatment data suggest no inhibitory effect on repair of sublethal radiation damage. When repeated daily injections of cis-DDP were given in between 2 radiation doses separated by 10 days, no interference with repopulation could be detected. The present study also demonstrated an increase in systemic drug toxicity when cis-DDP was combined with irradiation, compared with that seen with either agent alone.
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The kinetics and capacity of repair of sublethal damage in mouse lip mucosa during fractionated irradiations.
The kinetics and capacity of repair of sublethal damage in mouse lip mucosa have been investigated. To assess the rate of repair 2 and 5 irradiations have been given with intervals ranging from 1 to 24 hours. It was found that the sublethal damage induced by a dose of approximately 10 Gy was fully recovered in approximately 4 hr. After a dose of 5-6 Gy, cellular repair was completed within 3 hr. The half time of repair (T1/2) was estimated to be approximately 72 min for 10 Gy and approximately 54 min for 5-6 Gy. Although these results suggest that the rate of repair is dependent on the fraction size, the possible influence of the amount of repair of sublethal radiation damage with the various fraction sizes used can not be ruled out. To evaluate the capacity of repair, a single dose, 2, 4 and 10 fractions have been given in a maximal overall time of 3 days in order to minimize the influence of repopulation. The slope of the isoeffective curve was 0.32 and the alpha/beta ratio was 8.5 Gy. This indicates that the capacity of cellular repair of lip mucosa is similar to those of other rapidly proliferating tissues but smaller than those of late responding tissues. The results of the present and other studies demonstrate that there are considerable differences in the repair characteristics between acutely and late responding tissues. These features have to be dealt with when fractionation schedules are markedly altered.
Animals↗
The effect of actinomycin D on radiation induced reactions of the lip mucosa of mice.
The interaction of intraperitoneally injected Actinomycin D and irradiation was investigated in the lip mucosa of NMRI mice. In this rapidly proliferating tissue, a semiquantitative assessment of possible modifications of the radiation response by a drug can be done without using lethality as an endpoint. It was shown that a single dose of 0.5 mg/kg drug given at different times between 24 hr prior to and 24 hr after single radiation doses did not effect the rate of development nor the intensity of mucosal radiation damage. With extended time intervals of 2, 3, or 7 days between both single agents, a slight increase of the lip mucosal reaction was measured. Similar results were obtained when 5 daily drug injections of 0.15 mg/kg were administered starting at day 5 after a single radiation exposure. No differences in response could be demonstrated when fractionated irradiations with intervals ranging from 1 to 24 hr were closely combined with either single or repeated drug treatments (0.5 mg/kg in total) as compared to irradiation alone. However, a slight modification of the iso-effect dose was measured when 0.5 mg/kg Actinomycin D was administered at various periods in between 2 radiation doses separated by 10 days. A maximal effect was measured with 5 daily injections of 0.15 mg/kg drug each and given at a time when proliferative capacity was high. With 0.1 mg/kg Actinomycin D per daily injection, no enhancement of the radiation injury was found. Thus, in these circumstances no influence of Actinomycin D on radiosensitivity nor on repair of sublethal damage could be demonstrated. A clear inhibitory effect on lip mucosal repopulation by the drug is evident, but only at high drug doses close to toxic concentrations.
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