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E L Travis

Publications and source records attributed to E L Travis.

At least 37 records · Page 2Linked to original sources
PubMed1996

Fibroblast radiosensitivity in vitro and lung fibrosis in vivo: comparison between a fibrosis-prone and fibrosis-resistant mouse strain.

Radiation-induced pneumonitis and fibrosis in the lung after treatment to the thoracic cavity for malignant disease currently limit the maximum tolerated dose to that region. It has been suggested that heterogeneity in susceptibility to radiation-induced fibrosis exists in the population, implying that the lung tolerance dose is defined by a sensitive subset of the patient population. Studies of radiotherapy patients have indicated that the survival at 2 Gy (SF2) of cultured skin fibroblasts correlates with the incidence and severity of postirradiation damage in a number of tissues, suggesting that this assay may be a useful predictor of late tissue effects. The goal of the studies presented here was to determine if the radiosensitivity of fibroblasts in vitro isolated from mouse lungs was correlated with the severity of radiation-induced fibrosis in the lungs of two inbred strains of mice previously shown to differ markedly in their susceptibility to radiation-induced lung fibrosis: the C3Hf/Kam strain, classified as fibrosis-resistant, and the C57BL/6J strain, classified as fibrosis-prone. Quantitative measurements of lung fibrosis after irradiation were compared to SF2 values for fibroblasts of skin and lung cultured from each strain. Lung fibrosis was quantified, using computerized image analysis, as the percentage of fibrosis on Masson's Trichrome-stained lung sections from both strains after single doses of radiation to the thorax. For the measurements of SF2, fibroblasts plated at the second passage and grown to confluence were given single doses of radiation ranging from 0 to 6 Gy. Survival curves were constructed and SF2 values obtained from a linear-quadratic fit to the data. The radiosensitivity of fibroblasts from the lung and skin of SCID mice was determined and served as a positive control. The percentage of radiation-induced lung fibrosis was significantly different between the two strains, 5.1% and 0.2% in the C57 strain and C3H strain, respectively. Follow-up of long-term survivors (two mice) from the C3H strain did not change this conclusion. However, the lung fibroblast SF2 for the C57BL/6J strain (fibrosis-prone), 0.50 +/- 0.03, was not statistically different from the C3Hf/Kam strain (fibrosis-resistant), 0.55 +/- 0.07. These data indicate that in vitro radiosensitivity of lung fibroblasts as assayed by survival at 2 Gy does not correlate with the development of lung fibrosis in this mouse model. The SF2 for lung fibroblasts from SCID mice was 0.10. Similar SF2 values were obtained for both the C3Hf/Kam mouse lung and skin fibroblasts, 0.55 and 0.56, respectively, and C57BL/6J mouse lung and skin fibroblasts, 0.50 and 0.52, respectively, indicating that the radiosensitivity of fibroblasts isolated from lung and skin within a strain is the same.

Animals↗
PubMed1995

Damage and morbidity from pneumonitis after irradiation of partial volumes of mouse lung.

PURPOSE: The aims of this study were to: (a) define the relationship of dose and volume irradiated to damage and morbidity in mouse lung, (b) determine the threshold volume for morbidity after partial lung irradiation; and (c) determine whether the response to radiation of mouse lung is independent of the region irradiated. METHODS AND MATERIALS: C3Hf/Kam female mice were used in this study. The fractional volume of the lung to be irradiated was determined by two methods, weights and computed tomography (CT) scanning. Two experiments were performed to define the volume effect and to determine whether the response of the mouse lung to radiation was homogeneous. In the first experiment, single doses of x-rays ranging from 12 to 20 Gy were given to partial volumes of 84%, 70%, and 40% including the base, 50%, 33%, and 17% including the apex, to 43% in the middle, and to the sum of 57% as 17% in the apex and 40% in the base. In the second experiment, the same volumes of 50% and 70-75% in the apex and base of the lung were irradiated with single doses ranging from 12-19.25 Gy. Morbidity from radiation pneumonitis was quantitated by two end points, breathing rate and lethality between 12 and 32 weeks after irradiation. Damage was assessed by histopathological evidence of pneumonitis. RESULTS: Clear well-defined dose-response curves were obtained for both breathing rate and lethality after all volumes irradiated. There was a clear volume-dependent shift of the dose-response curves for breathing rate and lethality at 28 weeks after irradiation, the end of the pneumonitis phase of damage, to higher doses compared with these data after whole-lung irradiation. In addition, the slopes of the dose-response curves for irradiation of partial lung volumes were more shallow compared to those after whole-lung irradiation. Increases in breathing rate correlated with lethality when the volume irradiated was equal to or greater than 50% of the reference volume. However, after irradiation of volumes smaller than 40%, breathing rate increases were not accompanied by death. A heterogeneous response of the mouse lung to radiation was observed in the first experiment and confirmed by the second experiment. For a given volume irradiated, the isoeffect dose was always less for the base than for the apex of the lung. The threshold volume for breathing rate changes was less than 17 and 40% when the irradiated volumes involved the apex and base, respectively. For lethality, the threshold volume was between 40 and 70% for the base and greater than 50% for the apex of the lung. Finally, damage as assessed by histological evidence of pneumonitis was observed in the irradiated area only. CONCLUSIONS: (a) The volume effect was resolvable in mice, (b) the volume effect in mouse lung exhibits a clear threshold for morbidity, (c) the threshold volume for morbidity is dependent on the end point, (d) the response of mouse lung is heterogeneous, dependent on the site irradiated, and is always greater for the same volumes irradiated in the base than the apex, and, (e) histopathological damage does not always produce observable morbidity.

Animals↗
PubMed1995

Acemannan-containing wound dressing gel reduces radiation-induced skin reactions in C3H mice.

PURPOSE: To determine (a) whether a wound dressing gel that contains acemannan extracted from aloe leaves affects the severity of radiation-induced acute skin reactions in C3H mice; (b) if so, whether other commercially available gels such as a personal lubricating jelly and a healing ointment have similar effects; and (c) when the wound dressing gel should be applied for maximum effect. METHODS AND MATERIALS: Male C3H mice received graded single doses of gamma radiation ranging from 30 to 47.5 Gy to the right leg. In most experiments, the gel was applied daily beginning immediately after irradiation. To determine timing of application for best effect, gel was applied beginning on day -7, 0, or +7 relative to the day of irradiation (day 0) and continuing for 1, 2, 3, 4, or 5 weeks. The right inner thigh of each mouse was scored on a scale of 0 to 3.5 for severity of radiation reaction from the seventh to the 35th day after irradiation. Dose-response curves were obtained by plotting the percentage of mice that reached or exceeded a given peak skin reaction as a function of dose. Curves were fitted by logit analysis and ED50 values, and 95% confidence limits were obtained. RESULTS: The average peak skin reactions of the wound dressing gel-treated mice were lower than those of the untreated mice at all radiation doses tested. The ED50 values for skin reactions of 2.0-2.75 were approximately 7 Gy higher in the wound dressing gel-treated mice. The average peak skin reactions and the ED50 values for mice treated with personal lubricating jelly or healing ointment were similar to irradiated control values. Reduction in the percentage of mice with skin reactions of 2.5 or more was greatest in the groups that received wound dressing gel for at least 2 weeks beginning immediately after irradiation. There was no effect if gel was applied only before irradiation or beginning 1 week after irradiation. CONCLUSION: Wound dressing gel, but not personal lubricating jelly or healing ointment, reduces acute radiation-induced skin reactions in C3H mice if applied daily for at least 2 weeks beginning immediately after irradiation.

Aloe↗
PubMed1995

Basic fibroblast growth factor does not protect against classical radiation pneumonitis in two strains of mice.

Basic fibroblast growth factor recently has been reported to confer significant protection against death from radiation pneumonitis in C3H/HeJ mice. Although the mechanism of this protection remains unknown, one hypothesis, based on in vitro data, is that basic fibroblast growth factor protects against radiation-induced apoptosis in pulmonary endothelial cells. Because of the potential clinical importance of these data, we repeated our experiments in two strains of mice with differing sensitivities to radiation pneumonitis. One mouse strain, C3Hf/Kam, originated from the same C3H/He strain as the C3H/HeJ mouse used by Fuks et al. in their 1994 study. The other strain, the NCR/Sed-nu/+ strain, is a white mouse heterozygous for the nude trait. In our laboratory, the LD50 for radiation pneumonitis between 12 and 28 weeks after irradiation, the standard assay time for this phase of radiation-induced lung damage, is 12.5 Gy in the C3Hf/Kam and 8.5 Gy in the NCR/Sed-nu/+ strain. Contrary to previous results in the literature, we found that basic fibroblast growth factor did not protect against radiation pneumonitis in either C3Hf/Kam or NCR/Sed-nu/+ mice. Quantitation of apoptosis after both doses to the lungs of the two strains showed that the incidence of apoptosis was less than 1% in C3Hf/Kam mice and 0.5% in NCR/Sed-nu/+ mice. These apoptotic bodies were scattered throughout the lung and were not located selectively in endothelial cells of any size blood vessels.

Animals↗
PubMed1995

Differential expression of collagen types I and III in consequential and primary fibrosis in irradiated mouse colon.

These studies were undertaken to understand further the pathogenesis of consequential and primary fibrosis in mouse colon after irradiation. The distal 2.5 cm of colon of C3Hf/Kam mice was irradiated with either a single dose of 27 Gy or a split dose of 2 x 14.75 Gy separated by 10 days to induce a consequential or primary fibrotic lesion, respectively. The amount of total collagen in the two lesions was quantified by hydroxyproline, and tensile strength, an assay of tissue rigidity, was measured as a function of dose and time after irradiation. The relative distribution of collagen types I, III and IV in the colon was visualized by immunohistochemistry. Collagen types I, III and IV were quantified by immunoblot techniques, and in situ hybridization was used to identify and score the cells producing procollagen mRNA types I and III as a function of time after irradiation. The hydroxyproline and tensile strength measurements demonstrated that both lesions contained significantly increased amounts of collagen compared to controls. However, the ulcerated lesion of consequential fibrosis contained three times as much collagen and required a three- to fourfold increase in the peak force to rupture the colon as did the non-ulcerative lesion of primary fibrosis. The fibrosis accompanying the consequential lesion contained elevated levels of both collagen types I and III, but primary fibrosis contained only elevated levels of type I collagen compared to controls. The in situ hybridization studies showed cells producing increased amounts of procollagen mRNA 8 and 25 weeks before the elevated levels of collagen were detected for consequential and primary fibrosis, respectively. The cells producing the excess collagen mRNA were identified as fibroblasts. No distinction between the two lesions could be made based on the cell types producing the collagen. The distribution of labeled cells was localized to tissue areas showing specific immunofluorescence for the collagen types. These data show that the two histologically distinct lesions in irradiated colon, consequential and primary fibrosis, contain different collagen types and quantities of each type, suggesting that the underlying pathogenesis of these two lesions may be different.

Animals↗
PubMed1995

Repair rate in mouse lung after clinically relevant radiation doses per fraction.

Data published previously have shown that repair of sublethal damage in mouse lung proceeds with two significantly different repair half-times of 0.4 h and 4.0 h and that the fast component has approximately four times more weight than the slow component. None of these data, however, were obtained after small dose fractions similar to those used in clinical radiotherapy. The purpose of the experiments presented here was to determine the half-time of the fast component only of repair in mouse lung after doses per fraction of 2.0 Gy. We irradiated the whole thoraces of mice with six equal doses of 2.09 Gy given at intervals ranging from 0 to 45 min. The dose was topped up 24 h later by a range of single doses designed to bring the response, i.e. breathing rate and death from pneumonitis, into the observable range. Data on breathing rate were converted into quantal response data. All data were analyzed by the linear-quadratic model that contains two rates of repair (H.D. Thames et al., Radiother, Oncol. 15, 49-53, 1989). The data showed that the repair rate is very rapid, giving a t1/2 ranging from 0.25 to 0.75 h for breathing rate and mortality, in agreement with our data published previously for higher dose fractions. There were no differences between the t1/2's obtained from the two assays of damage. These data indicate that the half-time of the fast component of repair in mouse lung is approximately 0.4 h after clinically relevant dose fractions.

Animals↗
PubMed1994

Unilateral nephrectomy 24 hours after bilateral kidney irradiation reduces damage to the function and structure of the remaining kidney.

The effect of unilateral nephrectomy 24 h after irradiation on renal function and death with renal insufficiency as well as histopathological changes in the kidney was assessed. Single doses totaling 8-18 Gy were given bilaterally to unanesthetized female and male C3Hf/Kam mice. Renal function damage was assayed by blood urea nitrogen (BUN) and hematocrit.(Hct). Histological damage was quantified by two parameters: kidney area and number of surviving tubule cells along the renal capsule. The number of glomeruli was scored as an indication of the number of nephrons. Changes in the two functional parameters did not appear sooner after irradiation in the nephrectomized mice than in the non-nephrectomized mice. Rather, less impairment of function was measured by both parameters in the nephrectomized mice but only after radiation doses greater than 12 Gy. The LD50 at 424 days after irradiation was also higher in the nephrectomized mice than that in the mice receiving only irradiation, 13.98 Gy (95% confidence limits = 12.03, 15.93) and 11.71 Gy (95% confidence limits = 10.4, 13.1), respectively, in agreement with the data on function. Unilateral nephrectomy alone induced a 10% increase in size of the contralateral kidney. The dose-response curve for the kidney area from nephrectomized mice was parallel to and displaced above that for non-nephrectomized mice, indicating that the increase in renal mass occurred independent of and was not compromised by radiation. Unilateral nephrectomy alone induced no increase in the number of proximal tubules in the contralateral kidney. However, tubule survival was higher in nephrectomized mice given doses greater than 12 Gy compared with mice receiving only radiation. Fitting the tubule survival data by maximum likelihood analysis gave D0's of 6.7 Gv (95% confidence limits = 6.3, 7.1 Gy) and 3.7 Gy (95% confidence limits = 3.5, 3.8 Gy) for the irradiated nephrectomized mice and irradiated mice, respectively. However, the number of glomeruli was the same for both groups, suggesting that the number of the nephrons did not change. These data suggest that the improvement in renal function in mice nephrectomized 24 h after irradiation of both kidneys compared to those receiving only irradiation was due to tubule hyperplasia and not renal hypertrophy.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Histological changes in mouse colon after single- and split-dose irradiation.

These studies were undertaken to determine the relationship between acute mucosal damage and late obstructions in the colorectal region in the mouse after exposure to radiation. Radiation doses that either permanently depleted the mucosal epithelial cells or spared the mucosal lining by allowing epithelial regeneration were used. The distal 2.5 cm of colon and rectum of male C3Hf/Kam mice was irradiated with either a range of single doses (15-35 Gy) or two equal doses ranging from 9.75 to 14.75 Gy separated by 10 days. The time of onset and the incidence of obstructions and strictures in the bowel were recorded as a function of dose and time after irradiation. Acute damage in the mucosa and subsequent histological changes in the bowel were documented by sequential histological studies. Doses greater than 20 Gy caused acute crypt depletion followed by nonproductive attempts at regeneration and repopulation that culminated in persistent epithelial denudation. In these mice, obstructions appeared as early as 4 weeks and were characterized histologically by a mucosal ulceration extending deep into the muscularis. Single doses of less than 20 Gy and the split doses produced acute crypt cell depletion followed by successful regeneration, repopulation, and restoration of the colonic mucosa. In these mice, obstructions did not appear until at least 40 weeks after irradiation and were characterized by an intact mucosa with a thickened and fibrotic submucosa. Animals given a single dose of 20 Gy developed obstructions throughout the duration of the experiment. Those obstructions that occurred before 6 months were characterized by ulcerations, whereas those that appeared after this time exhibited only fibrosis in the submucosa with no mucosal ulceration. Based on these data, we suggest that two types of late obstructions occur in the bowel, one that depends on persistent epithelial denudation, i.e., a "consequential" response, and the other in the absence of epithelial denudation, i.e., a true late effect.

Animals↗
PubMed1993

Interleukin-1 dose, mouse strain, and end point as they affect protection of mouse jejunum.

Interleukin 1 (IL-1) has been shown to protect a number of normal tissues against radiation injury. In mouse jejunum, modest protection against radiation injury has been reported using only the in vivo crypt survival assay in one mouse strain. The major goal of this study was to determine the protective effect of IL-1 on mouse jejunum using two assays of damage, crypt cell survival and lethality from radiation-induced crypt cell depletion, in two mouse strains, C3Hf/Kam and BALB/c nu/+, which were bred and maintained in a specific-pathogen-free barrier colony. In addition, the dependence of protection on the IL-1 dose in both assays was determined. Our findings showed that IL-1 protection of crypt cell depletion and subsequent death of the animals from loss of these cells was dependent on the IL-1 dose. We found that the amount of protection by IL-1 was related to the criterion used to assess the protection. For example, if protection was determined as a ratio of D10's or LD50/10, a bigger DMF was obtained for BALB/c mice than C3H mice with the same IL-1 dose, suggesting that C3H mice were not as well protected. However, if protection was determined by the increase in crypt cell number after IL-1, there was an identical 2.4-fold increase in crypt cells after the same IL-1 dose in both strains. On the basis of this criterion, then, protection of crypt cells by IL-1 did not depend on the mouse strain. Although the effect of IL-1 on animal survival at 10 days was strain dependent, the difference was related to differences in the slopes of the respective crypt cell survival curves for the two strains and not to different effects of IL-1 in the two strains tested.

Abdomen↗
PubMed1993

Recovery from radiation damage in mouse lung: interpretation in terms of two rates of repair.

A reanalysis was performed of the extensive data set obtained with fractionated irradiations of mouse lung reported by Travis et al. (Int. J. Radiat. Biol. 52, 903-919, 1987). The possibility was investigated that the poor fit of these data to the linear-quadratic model might have been the result of the presence of two rates of repair of sublethal damage instead of one. Therefore, the incomplete-repair linear-quadratic model was adapted to incorporate two independent rates of repair and the data were analyzed using this two-component incomplete-repair model. The results which are subjected to certain qualifications with respect to the assessment of the validity of the confidence limits indicated the presence of two significantly different repair rates, corresponding to a fast-repair half-time (t1/2) of 0.40 h (0.28, 0.53) and a slow t1/2 of 4.01 h (1.55, 6.57). A weight factor determined simultaneously indicated that the fast component has approximately four times more weight than the slow component. The alpha/beta value calculated for the entire data set using the same model was 3.8 Gy (3.0, 4.6), which is not significantly different from the alpha/beta of 3.6 Gy (2.8, 4.5) calculated for the 8- and 12-h data only, using the complete-repair linear-quadratic model. An experiment specifically designed to test the significance of the fast-repair component was performed in which mouse lungs were irradiated with two equal dose fractions, separated by intervals ranging from 10 min to 6 h. Data obtained from this experiment allowed only one repair rate to be determined, corresponding to a t1/2 of only 0.4 h. This finding confirms the presence of a very fast repair rate in mouse lung.

Animals↗
PubMed1992

No change in repair capacity of mouse lung irradiated three months after a single dose of cyclophosphamide.

The repair capacity of mouse lung was determined at 3 months after a single i.p. injection of cyclophosphamide (Cy) at a maximally tolerated dose of 275 mg/kg. Mice were irradiated to the whole thorax only with 1, 2, 9, or 15 fractions of X-rays using doses/fraction ranging from 1.2 to 11 Gy. Breathing rate (breaths per minute), histology and pulmonary mortality were used to assess lung damage. Raw breathing rate data were converted to quantal response data by scoring the number of mice in each dose group in each fractionation schedule with a breathing rate 1.3 times the breathing rate of control mice. Dose-response curves of mortality and the converted breathing rate data were constructed at 15 weeks after irradiation (approximately 28 weeks after drug treatment) fitted by logit analysis and 50% effective doses with 95% confidence limits obtained. Values of alpha/beta were obtained by using the direct analysis method of H. D. Thames et al. (Int. J. Radiat. Biol., 49:999-1009, 1986). The alpha/beta for mice given Cy 3 months before radiation was 3.69 Gy (95% confidence limits, 2.83, 4.69 Gy) and 3.06 Gy (95% confidence limits, 2.31, 3.99 Gy) for the lethality data and breathing rate data, respectively. These alpha/beta values are in good agreement with the previously published ranges of alpha/beta of 3 to 4 Gy for mouse lung not given Cy previously. Because the repair capacity of the target cells of a tissue govern the fractionation response and choice of fractionation regimen in clinical radiotherapy, these data indicate that the fractionation regimen used can remain the same as that used in non-drug-treated lungs when the lung is irradiated 3 months after exposure to Cy.

Animals↗
PubMed1992

Time course for the hazard of radiation-induced pneumonitis death in mice.

The form of the hazard function for radiation-induced pneumonitis death in mice was investigated. 'Hazard' refers to the instantaneous failure rate at a specified time, conditional upon non-failure to that time. Thus, the hazard function describes the time profile for the risk of pneumonitis death among still-surviving subjects. Single-dose lethality data from nine previously published studies involving irradiation of the lung were combined. Sufficient data were then available to estimate the hazard for eight different dose groups (dose range 12-15 Gy). The results of this study suggest that there are multiple distinct peaks in the hazard function for radiation pneumonitis, corresponding to distinct waves of death separated by an average interval of 33 days. The times of the peak hazards are dose dependent, with the peak hazards occurring earlier after larger doses, and the values of the hazards at the peaks are also dose dependent, with larger doses corresponding to a greater risk of death. The implications of a multiply-peaked hazard function for the possible mechanisms of response to whole-lung irradiation are discussed.

Animals↗
PubMed1991

Cyclophosphamide 24 hours before or after total body irradiation: effects on lung and bone marrow.

Preparative regimens for bone marrow transplantation (BMT) use a sequence of drugs, such as cyclophosphamide, in combination with radiation. However, the optimum sequencing of the two agents that will maximize tumor cell kill and minimize normal tissue damage is unknown and controversial. The studies presented here were done in order to determine the effect of cyclophosphamide on bone marrow and lung damage in mice when given 24 h before or after total body irradiation (TBI). A range of single doses of TBI was given before or after a single sublethal dose of 180 mg/kg of cyclophosphamide. The bone marrow of all mice intended for lung damage assessment was reconstituted with 5 x 10(6) syngeneic bone marrow cells. Lung damage was assessed by breathing rate and lethality; bone marrow damage by lethality at 30 days. LD50 values for pneumonitis were obtained between 30 and 84 days after cyclophosphamide and radiation and between 80 and 180 days after radiation alone. Dose modifying factors were obtained as the ratio of LD50s for mice given only TBI compared to those for mice given cyclophosphamide and TBI. Cyclophosphamide enhanced radiation pneumonitis when given before or after TBI, giving DMFs of 1.4 and 1.2 (1.1-1.4, 95% c.l.) respectively. The effect of cyclophosphamide on radiation pneumonitis was drug dose-dependent. The LD50 for death from bone marrow damage was reduced when cyclophosphamide was given either before or after TBI but the effect was greater, i.e. the LD50 was lower when cyclophosphamide was given after TBI. These data show that cyclophosphamide given 24 h after TBI causes less lung damage but more bone marrow damage in this mouse model.

Animals↗
PubMed1990

Residual damage in mouse lungs at long intervals after cyclophosphamide treatment.

The purpose of these studies was to quantify the effects of radiation given to mouse lungs at intervals up to 6 months after injection of the maximally tolerated dose of cyclophosphamide. In one set of experiments a single i.p. injection of 300 mg/kg of cyclophosphamide was followed at either 1, 3, or 6 months by a range of single doses of gamma-rays delivered to the whole thorax only. In a second set of experiments mice were given five daily i.p. injections of cyclophosphamide, 100 mg/kg, followed at 1, 3, and 6 months by a range of fractionated doses of X-rays. Breathing rate, histology, and mortality were used to assess lung damage. These data were compared with age-matched animals given either the drug alone or single doses of radiation alone. Dose-response curves of lethality were constructed and fitted by a logit program, and 50% lethal doses with 95% confidence limits were determined at monthly intervals after irradiation. Dose enhancement factors were then calculated at this isoeffect for the mice given the drug and radiation. Deaths from radiation pneumonitis occurred as early as 6 weeks in mice given cyclophosphamide before irradiation; few deaths occurred after 26 weeks. However, in the mice given radiation alone, deaths from pneumonitis did not occur before 12 weeks. Cyclophosphamide given as either single doses or fractionated doses at all three times before irradiation enhanced radiation pneumonitis in mouse lung. Dose enhancement factors of 1.2, 1.4, and 1.3 were obtained when single doses of radiation followed single doses of cyclophosphamide at 1, 3, and 6 months, respectively. The dose enhancement factor for radiation pneumonitis after the fractionated exposures was less, 1.1, and was independent of time between the two treatments. An enhancement factor of 1.2 was observed for the later wave of lung damage in those few studies available for analysis at this time. These data clearly show that prior treatment of the animal with cyclophosphamide significantly reduces the radiation dose that can be given to the lung for as long as 6 months after drug treatment. In addition, lung damage occurred sooner when the drug was given prior to irradiation. These data indicate that the lung will be sensitive to retreatment with radiation when a full tolerance dose of cyclophosphamide precedes radiation.

Animals↗
PubMed1990

Assessment of pulmonary and hematologic toxicities of liblomycin, a novel bleomycin analog.

The antitumor efficacy as well as hematologic and pulmonary toxicity of Liblomycin, a new lipophilic analog of bleomycin, was evaluated in BDF1 mice. In comparison to bleomycin which was without any antitumor efficacy against P388 leukemia, a dose of 10 mg/kg Liblomycin administered on a daily schedule for 10 consecutive days resulted in a significant increase in animal survival (% T/C of 190). This therapeutic dose and schedule of drug administration did not produce any evidence of pulmonary histopathologic injury; at a similar dose and schedule bleomycin resulted in greater than 40% consolidation of alveolar lung space. Mouse lung collagen synthesis measured as rate of [3H]hydroxyproline formation was increased almost 4-fold by bleomycin 7 days following a single maximally tolerated i.v. injection (133 mg/kg); in contrast, Liblomycin (60 mg/kg) did not significantly alter the rate of lung collagen synthesis compared to saline injected control animals. Lung function was assessed by whole body plethysmography. Bleomycin produced an increase in breathing rates above control values by day 15 following administration of drug at 10 mg/kg (d1-10). Mice treated with Liblomycin did not exhibit an increased rate of breathing. Liblomycin, in contrast to bleomycin, produced mild and transient leukopenia and thrombocytopenia suggesting that this toxicity will be a limiting one in future clinical trials. The only other toxicity noted in this study was the appearance after repeated intraperitoneal administration of Liblomycin of a hepatic collagenous fibrous capsule. The capsule formation resulted in an abnormal and grossly lobulated liver which was believed to have affected animal survival. Intravenous administration of Liblomycin, however, was not associated with any detectable hepatic injury.

Animals↗
PubMed1990

Comments on a time-dependent version of the linear-quadratic model.

The accuracy and interpretation of the "LQ + time" model (E = D(alpha + beta d) - gamma T) are discussed. Evidence is presented, based on data in the literature, that this model does not accurately describe the changes in isoeffect dose occurring with protraction of the overall treatment time during fractionated irradiation of the lung. This lack of fit of the model explains, in part, the surprisingly large values of gamma/alpha that have been derived from experimental lung data. The large apparent time factors for lung suggested by the model are also partly explained by the fact that gamma T/alpha, despite having units of dose, actually measures the influence of treatment time on the effect scale, not the dose scale, and is shown to consistently overestimate the change in total dose. The unusually high values of alpha/beta that have been derived for lung using the model (approximately 5 Gy) are shown to be influenced by the method by which the model was fitted to data. Reanalyses of the data using a more statistically valid regression procedure produce estimates of alpha/beta more typical of those usually cited for lung (approximately 3 Gy). Most importantly, published isoeffect data from lung indicate that the true deviation from the linear-quadratic (LQ) model is nonlinear in time, instead of linear, and also depends on other factors such as the effect level and the size of dose per fraction. Thus, we do not advocate the use of the "LQ + time" expression as a general isoeffect model.

Animals↗
PubMed1989

The high steepness of dose-response curves for late-responding normal tissues.

Values are calculated for the parameters alpha, beta, and the number of tissue-rescuing units (TRU), which together describe the location and the steepness of dose-incidence curves for functional injury in various normal tissues. The analysis is based on a Poisson model of the distribution of surviving TRUs. The steepness of the curves for early-responding tissues has been shown previously to be compatible with values of sensitivity for the target colony-forming cells in these tissues. We now show that the steepness of curves for late responses in spinal cord, lung, and kidney is higher by a factor of up to 3 than the steepness of curves for early responses in other tissues. Although the interpretation of this higher steepness is not fully understood, this observation is likely to be of importance for radiotherapy.

Animals↗