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H D Thames

Publications and source records attributed to H D Thames.

At least 127 records · Page 7Linked to original sources
PubMed1987

Is the rate of repair of radiation-induced sublethal damage in rat spinal cord dependent on the size of dose per fraction?

In the present study the possible dependency of the kinetics of repair of sublethal damage in rat spinal cord on the fraction size has been further investigated. A wide range of sizes of dose per fraction (1.7-17.5 Gy) has been given with interfraction intervals varying from 0.5 to 24 hr. A direct method for analysis of quantal response and an incomplete-repair (IR) model for survival after fractionated exposures with short intervals were used to interpret the data. The half time of repair (T1/2) was found to be 1.6, 1.6 and 1.9 hrs for fraction sizes of approximately 4, 9, and 14 Gy respectively. There appears to be no significant effect of fraction size on the rate of repair. A clinically relevant feature observed from these experimental data is that in this tissue it takes more than 4 hrs for repair of sublethal damage, induced by a dose of approximately 4 Gy, to approach completion (i.e., sparing beyond the limit of the experimental resolution). This has to be taken into account when several fractions are to be given each day. Another feature noted from the analysis of these results is that the alpha/beta determined from the complete repair data is considerably smaller than that estimated from the incomplete repair data (interval less than or equal to 4 hrs). The nature of the inconsistency is discussed.

Animals↗
PubMed1987

The kinetics of repair in mouse lung after fractionated irradiation.

The kinetics of repair of sublethal damage in mouse lung was studied after fractionated doses of 137Cs gamma-rays. A wide range of doses per fraction (1.7-12 Gy) was given with interfraction intervals ranging from 0.5 to 24 h. The data were analysed by a direct method of analysis using the incomplete repair model. The half-time of repair (T1/2) was 0.76 h for the pneumonitis phase of damage (up to 8 months) and 0.65 h for the later phase of damage up to 12 months. The rate of repair was dependent on fraction size for both phases of lung damage and was faster after large dose fractions than after small fractions. The T1/2 was 0.6 h (95 per cent c.1. 0.53, 0.69) for doses per fraction greater than 5 Gy and 0.83 h (95 per cent c.1 0.76, 0.92) for doses per fraction of 2 Gy. Repair was nearly complete by 6 h, at least for the pneumonitis phase of damage. To the extent that extrapolation of these data to humans may be valid, these results imply that treatments with multiple fractions per day that involve the lung will not be limited by the necessity for interfraction intervals much longer than 6 h.

Animals↗
PubMed1986

Protection of mouse jejunal crypt cells by WR-2721 after small doses of radiation.

The ability of WR-2721 to protect jejunal crypt cells after single doses and multifractionated doses of radiation was studied. Effective dose survival curves for jejunal crypt cells were constructed over the dose range of 230 to 1600 cGy. WR-2721 was given 30 minutes before each fraction, in a regimen consisting of 200 mg/kg before the first radiation fraction, followed at 3 hr intervals by 100 mg/kg for a total of 12 drug doses for the largest number of fractions. Fractionation protocols were designed with common dose fractions in regimens with different fraction numbers, allowing a test of the hypothesis of equal effect per fraction and an estimate of the initial number of clonogens per crypt in both the drug treated and non-drug treated mice. The hypothesis of equal effect per fraction could not be rejected in either the drug or non-drug treated mice. An average number of 137 clonogens per crypt was estimated for the non-drug treated mice and 81 clonogens per crypt in the drug treated mice; the difference between these two values was not significant. The protection factor decreased with decreasing dose ranging from a high of 1.47 (95% C.L. = 1.44 to 1.50) after a single dose of 2000 cGy to a low of 1.21 (95% C.L. = 1.08 to 1.37) after 200 cGy. Analysis of the data using either the linear quadratic (LQ) or two-component (TC) model of cell survival showed that WR-2721 was not dose-modifying over the dose range tested. Analysis using the LQ model showed that both beta and alpha were modified by WR-2721, by 50% and 20% respectively. These data indicate that protection by WR-2721 can be expected to decrease with dose although there is some protection after clinically relevant doses.

Amifostine↗
PubMed1986

Tumor radioresponsiveness versus fractionation sensitivity.

Since the introduction of mammalian cell survival curves, the parameters D0 and N have been used as quantitative measures of inherent radiation sensitivity, as was the shoulder width Dq. These parameters are more generally applicable at high doses. We propose to introduce a measure of tumor radioresponsitivity that is more applicable to the clinical treatment schedules that employ small fractional doses (1-2 Gy), the ratio alpha/E, derived from the linear quadratic model for cell inactivation as the intercept on the reciprocal-dose plot. For tumor-control experiments this ratio is the reciprocal of the TCD50 when radiation is given in very small fractions or at low dose rates (assuming negligible clonogen proliferation). The rationales for this choice are: alpha is a measure of the steepness of the initial linear segment of the dose-survival curve. Accordingly, at doses per fraction of 1-2 Gy the observed effect increases with alpha. E is by definition a positive measure of the clonogen kill required for a specified tumor response, e.g., E = -log (surviving fraction of clonogens at the 50% control level). Therefore it is also a measure of the number of clonogens present at the time of inception of treatment, which for a given dose is a prime determinant of the probability of tumor control. This measure of radioresponsitivity is to be distinguished from the ratio alpha/beta, which is a measure of fractionation sensitivity. A survey of the literature indicates that these do not correlate, except in highly hypoxic tumors (e.g., clamped); such tumors are characterized by low radioresponsitivity as well as low fractionation sensitivity (high alpha/beta ratio). There are at present only limited data for determination of this ratio, however, since reciprocal-dose analysis requires tumor control doses for several different sizes of dose per fraction.

Animals↗
PubMed1986

Protection of acute and late radiation damage of the gastrointestinal tract by WR-2721.

WR-2721 was investigated for its protective effect against acute and late damage produced by irradiation of the esophagus, small intestine, and colon of mice. The microcolony assay was used to measure the acute response of the small intestine and the colon, and an LD50 assay (within the 28- to 42-day time range) was used to measure acute esophageal damage. A dose of WR-2721 at 400 mg/kg, injected 30 min prior to irradiation, resulted in a protection factor (PF) of 1.6 against radiation damage in these three regions of the gastrointestinal tract. Lethality and histology scores were applied to determine late radiation damage to the rectum, at times ranging from 3 to 15 months after irradiation. Deaths occurred after doses of 20 Gy and above throughout the postirradiation period. WR-2721 increased the survival of mice; the PF calculated from the LD50 values was 1.5. PFs of animal survival did not vary during the observation period. Histological studies showed evidence of ulceration, fibrosis, and vascular changes as late radiation damage. WR-2721 protected against radiation-induced histological damage with a PF of 1.3. There was no qualitative difference between the types of histological damage observed in the group undergoing only irradiation and the group treated with WR-2721. Biochemical measurements of fibrosis by hydroxyproline determination of collagen 16 months after irradiation showed an increase in collagen per milligram wet weight of rectal tissue in all irradiated groups, but no increase in the amount of collagen per 5 mm segment of the rectum. Thus it appears that the apparent fibrosis is a result of atrophy rather than collagen accumulation. We conclude that WR-2721 is indeed effective at protection against late damage from large single doses of radiation to the rectum as measured histologically and also improves the long-term survival of the mice, although the target cells for this damage are not known.

Animals↗
PubMed1986

Effect of latency on calculated complication rates.

Late complications of radiation therapy and other cancer therapies may not always be expressed because of the shortened survival of cancer patients. Methods for estimating the true complication rate must account for censoring of the data. Actuarial methods give the time-dependent probability of remaining free of the injury. However, these methods fail when the last surviving patient develops a complication. This study describes a different method for calculating the corrected complication rate. One advantage is that the method does not produce estimates of 100% for the complication rate that occur using the actuarial method when the last survivor suffers a complication. To use the method presented here, the distribution of latent periods of the injury and the survival function for the patients at risk must be identified.

Actuarial Analysis↗
PubMed1986

Direct analysis of quantal radiation response data.

A direct analysis is proposed for quantal (all-or-nothing) responses to fractionated radiation and endpoint-dilution assays of cell survival. As opposed to two-step methods such as the reciprocal-dose technique, in which ED50 values are first estimated for different fractionation schemes and then fit (as reciprocals) against dose per fraction, all raw data are included in a single maximum-likelihood treatment. The method accommodates variations such as short-interval fractionation regimens designed to determine tissue repair kinetics, tissue response to continuous exposures, and data obtained using endpoint-dilution assays of cell survival after fractionated doses. Monte-Carlo techniques were used to compare the direct and reciprocal-dose methods for analysis of small-scale and large-scale studies of response to fractionated doses. Both methods tended toward biased estimates in the analysis of the small-scale (3 fraction numbers) studies. The alpha/beta ratios showed less scatter when estimated by the direct method. Most important, the 95 per cent confidence intervals determined by the direct method were more appropriate than those determined by reciprocal-dose analysis, for which 18 per cent (small-scale study) or 8 per cent (large-scale study) of the confidence intervals did not include the 'true' value of alpha/beta.

Animals↗
PubMed1986

Late radiation response of kidney assayed by tubule-cell survival.

An assay for the survival of renal tubule cells was developed using mice. It is analogous to other in-situ clonogenic cell survival assays. One kidney was irradiated using a 137Cs irradiator and removed 60-68 weeks later for histological examination. In unirradiated animals there were about 370 tubules in contact with the capsule in a coronal cross section at the middle of the kidney. After irradiation, extensive tubular damage was the dominant lesion. The number of epithelialized tubules in contact with the capsule showed a dose-dependent logarithmic decline. The dose-survival relationship for the clonogenic cells responsible for the regeneration of tubule epithelium was described by a D0 value of 1.5 Gy over the dose range 11-16 Gy. This radiosensitivity resembles that of stem cells in acutely responding tissues. The lack of histological evidence of damage to the arterial vasculature at the time the tubules are initially denuded of epithelium, and the similarity of renal tubule cell radiosensitivity to that of other mammalian cells, support the hypothesis that "late" radiation injury results primarily from depletion of parenchymal cells, not indirectly from injury to blood vessels, as has been the prevailing belief.

Animals↗
PubMed1985

Effect of dose-rate on total body irradiation: lethality and pathologic findings.

The effect of low dose-rate total body irradation (TBI) on hemopoietic and nonhemopoietic lethality has been studied in BALB/c mice using dose-rates ranging from 25 to 1 cGy/min. Deaths were scored at 10 days, 30 days, and one year after irradiation, and dose-response curves were constructed to determine the dose-rate dependence of deaths from the gastrointestinal syndrome, hemopoietic syndrome, and late lethal syndrome(s), respectively. A plot of the LD50S for each of these lethal syndromes versus dose-rate showed the dose-rate dependence for late lethality to be somewhat greater than that for gut death, but both of these endpoints were markedly more dose-rate dependent than was hemopoietic lethality, particularly at dose rates less than 5 cGy/min. To determine which late responding normal tissues might be critical for low dose-rate TBI, complete necropsies were performed on all mice dying later than 60 days after irradiation and on all mice surviving at one year; all tissues were examined histologically. Morphologic evidence of radiation injury was present in only three tissues, lung (fibrosis and scarring) kidney (tubule depletion), and liver (presence of mitoses). Subjectively, the lung changes were most severe up to 9 months while kidney changes became more prominent after this time, suggesting that late death after low dose-rate TBI may not be entirely attributable to lung injury. However, regardless of which late responding normal tissue is dose-limiting, it is clear that low dose-rate TBI preferentially spares these tissues compared with hemopoietic stem cells.

Animals↗
PubMed1985

An 'incomplete-repair' model for survival after fractionated and continuous irradiations.

An incomplete-repair (IR) model of survival after fractionated or continuous irradiation is derived from the concept of 'dose-equivalent' of incomplete repair. The model gives reasonably good predictions of the effect of interfraction interval, dose per fraction, and dose rate on cell survival in vivo and on tissue responses. This model is compared to the 'lethal, potentially lethal' (LPL) model after the latter has been generalized to an arbitrary number of fractions and to low dose-rate, continuous exposures. It is shown that the two models are equivalent, given certain constraints on the size of dose per fraction and dose rate. For example, in a particular cell line the equivalence of fractionation models breaks down if dose per fraction is well in excess of 4 Gy (the IR model employs the linear-quadratic survival model). The equivalence of low dose rate models breaks down for dose rates well in excess of 20 cGy/min. The assumptions on which the generalized LPL model is based are used to give a radiobiological interpretation to the incomplete-repair model. The larger beta/alpha ratio characteristic of late-responding normal tissues is interpreted in terms of the relatively faster fixation of potentially reparable lesions in the target cells of acutely responding tissues, on account of progression in the cell cycle. According to this interpretation the beta/alpha ratios estimated from isoeffective fractionation regimens are directly related to the parameters of clonogenic cell killing.

Cell Survival↗
PubMed1985

Multifraction radiation response of mouse lung.

The response of mouse lung to repeated doses of 60Co gamma-rays of as low as 115 cGy per fraction was measured using death from pneumonitis between 80 and 120 days after irradiation as the endpoint. A fractionation interval of 3 h was maintained for most regimens but in the longer experiments some 12 h intervals were introduced for logistic reasons. The longest overall duration (for a 43 fraction regimen) was 8 days. The total doses required to produce 50 per cent mortality increased continuously as dose/fraction was decreased, even from 160 to 115 cGy per fraction. Of clinical relevance, the steepness of the isoeffect curve over the dose range 115-500 cGy indicates that the lung shows greater sparing from dose fractionation than is characteristic of more rapidly-responding normal tissues, resembling, in this respect, other more slowly-responding tissues such as spinal cord. The plot of the reciprocal of the LD50 values as a function of dose per fraction was non-linear, suggesting that a linear quadratic dose response model may not be appropriate or that repair of cellular injury in lung is not complete in 3 h, or both.

Animals↗
PubMed1984

Tumor sensitizing effect by misonidazole in a clinically relevant radiation dose range.

The survival of cells from two murine fibrosarcoma (FSa) subpopulations after exposure to radiation only or radiation in combination with misonidazole (0.2 mg/g/fraction) was determined using a lung colony assay. FSa tumors grown in the hind legs of C3Hf/Kam pathogen-free mice were irradiated in situ when the tumors were 8 to 10 mm in diameter. Single cell suspensions prepared from excised tumors were separated on linear density gradients of Renografin, and the clonogenicity of predominantly oxic Band 2 (density 1.08 g/cm3) and predominantly hypoxic Band 4 (density 1.14 g/cm3) cells were measured. The surviving fraction of cells after doses of 1, 2, and 3 Gy, alone or preceded 30 minutes earlier with an i.p. injection of misonidazole (0.2 mg/g) was estimated from that measured after total radiation doses of 5 Gy = 5 X 1 Gy, 10 Gy = 5 X 2 Gy, and 15 Gy = 5 X 3 Gy, with the misonidazole-treated groups receiving a total drug dose of 1 mg/g, under the assumption of an equal effect per fraction. Under these conditions the initial slopes of Band 2 cells following irradiation only or irradiation plus misonidazole were 1D0 = 3.6 Gy and 2.74 Gy, respectively, giving rise to a sensitizer enhancement ratio of 1.3. Band 4 cells exhibited a 1D0 of 5.15 Gy to radiation only and 2.75 Gy to radiation plus misonidazole (SER of 1.9). In addition, misonidazole when administered alone in a single dose or up to 5 fractions of 0.2 mg/g each separated by 4-hour intervals, was effective in killing 50% of the Band 4 cells. The target population at risk appeared to remain constant regardless of the number of dose fractions administered. In contrast, Band 2 cells were not affected by the cytotoxic action of misonidazole. These data suggest that misonidazole is effective in sensitizing hypoxic cells in the clinical dose range, and that it is directly cytotoxic to hypoxic tumor cells.

Animals↗
PubMed1984

Twice-daily fractionation schemes for advanced head and neck cancer.

Eighty-five patients with advanced squamous cell carcinoma of the head and neck were treated with twice-a-day fractionation schedules between April 1972 and December 1980. Two types of treatment were distinguished: hyperfractionation, by which 65 patients (Group I) were treated at a weekly dose rate of 1100 to 1200 rad (10 fractions of 110 to 120 rad) in 5 to 6 1/2 weeks for either advanced primary disease (Group 1A) and/or advanced neck metastases (Group IB); and accelerated treatment, used to treat 20 patients (Group 2) who had fast-growing and usually massive neck nodes, at a weekly dose rate of 1300 to 1500 rad in 7 to 10 fractions, to a total dose of 6100 to 8000 rad in 4 to 6 weeks. The radiation portals for patients in Group 2 excluded the mucosa of mouth and throat for part of the treatment. The local control rate at 1 year in Groups 1A and 1B was 41 and 54%, respectively; the incidence of complications was 17%, 5% of them fatal. The local control rate in Group 2 was 80%. Seven patients in this group underwent a neck dissection 6 to 8 weeks following irradiation. Four specimens were negative for tumor. In two, only necrotic tumor cells were identified, and in one specimen morphologically intact tumor cells were seen. There were no fatal complications.

Carcinoma, Squamous Cell↗
PubMed1984

Effect-independent measures of tissue responses to fractionated irradiation.

Tissue repair factors measure the sparing that can be achieved from dose fractionation in the absence of proliferation. Four repair factors are analysed in these terms: FR, Frec, the ratio of linear-quadratic survival model parameters beta/alpha, and the half-time T1/2 for intracellular repair processes. A desirable feature of any repair factor is that it be independent of the level of injury induced in the tissue (or its single-dose equivalent, D1), since the comparison of tissues on the basis of the factor would not be meaningful, if they were characterized by differing D1S. Theoretically, FR and Frec are increasing functions of D1, and thus depend on level of effect. This is confirmed by analysis of skin reactions after multifractionated radiation. By contrast, beta/alpha is effect-independent as a measure of repair capacity in skin, gut, and bone marrow, tissues for which it is reasonable to assume that survival of identifiable target cells is the primary determinant of the endpoint. For a functional endpoint not clearly connected with the depletion of a specific target-cell population (late fibrotic reactions in the kidney), there was an increase in beta/alpha with increased levels of injury, but this was statistically insignificant. Effect-independence is defined for T1/2 as independence from size of dose per fraction. T1/2 is independent of fraction size in skin, gut, and spinal cord, and is longer (1.5 hours) in the late-reacting tissues (lung and spinal cord) than in those that react acutely (T1/2 less than 1 hour), with skin as the exception (T1/2 approximately 1.3 hours). Therefore, early and late-responding normal tissues may be distinguished in terms of both repair capacity and repair kinetics: repair is slower in late-responding tissues, which are also more sensitive to changes in dose fractionation. If generally true, these results imply that the potential for a therapeutic gain from hyperfractionation to spare late effects differentially would be limited by the number of daily doses that could be given, allowing sufficient time for repair between fractions in late-reacting tissues. In practice, dose fractions should be separated by 6 hours or more to permit repair to approach completion in late-responding tissues. Similar considerations lead to the conclusion that late effects would be more sensitive to changes in dose rate in low dose-rate brachytherapy.

Animals↗
PubMed1984

Tissue repair capacity and repair kinetics deduced from multifractionated or continuous irradiation regimens with incomplete repair.

A model is proposed to account for cell survival after multiple doses, when the interfraction interval is insufficient for complete Elkind repair. In the limit of ever-increasing numbers of ever-smaller fractional doses, the model transforms into the accumulation model (Roesch, 1978) of survival after continuous irradiation. When it is adapted to describe tissue responses to isoeffective multifractionated regimens, wherein repair is incomplete, a generalization of the usually linear plot of reciprocal total dose versus dose per fraction is obtained, in which downward curvature is evident. There is some advantage in studying tissue responses to multifractionated regimens with incomplete repair in the interfraction intervals, or continuous exposures at various dose rates since in addition to determination of repair capacity (defined by beta/alpha) there is an estimate of repair kinetics (defined by the halftime T1/2 for repair of sublethal injury). There is a saving in overall treatment time with either method, thereby reducing the influence of regeneration on the interpretation of the results. The results of analyses of previously published data are presented to illustrate the use of the models. Estimated from the response of three acutely responding normal tissues in the mouse (jejunum, colon and bone marrow), repair halftimes ranged from 0.3-0.9 h and values of beta/alpha were approximately 0.1 Gy-1. From the response of mouse lung (LD50 for pneumonitis) to multifractionated regimens with incomplete repair, the repair halftime was estimated at 1.5 h and beta/alpha was 0.27 Gy-1. In the rat spinal cord beta/alpha was 0.7 Gy-1 and T 1/2 was 1.5 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗