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E L Travis

Publications and source records attributed to E L Travis.

At least 19 recordsLinked to original sources
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↗
PubMed1989

The influence of bone marrow depletion on intestinal radiation damage.

These experiments were designed to test the hypothesis that bone marrow damage contributes to lethality when the endpoint used is LD50 for gastrointestinal damage. Specific pathogen-free mice were irradiated to the total body, total abdomen, or to the total body followed by rescue with syngeneic bone marrow cells. The relationship between animal survival and jejunal crypt survival was also examined under these three experimental conditions. The LD50/10 after total abdominal irradiation (15.6 Gy) was higher than that for total body irradiation (11.4 Gy). Rescue with syngeneic bone marrow cells after total body irradiation also increased the LD50 10 days to 14.6 Gy. The proportion of animals surviving after total body irradiation depended on the number of bone marrow cells injected as a rescue inoculum. Hence gastrointestinal death after total body irradiation is influenced by bone marrow depletion. Crypt survival, however, was similar following all three experimental procedures. These data, therefore, demonstrate a dissociation between a clonogenic and lethality assay of intestinal damage. Furthermore, a comparison of crypt survival at the LD50 under the different conditions showed that a factor of 10 times more crypts were needed to rescue a mouse from gut lethality when the total body was irradiated than when only the total abdomen was treated. Hence, the concept of the intestinal "tissue rescuing unit" as a precise and constant number of crypts is inappropriate and will vary with the experimental conditions.

Abdomen↗
PubMed1989

A comparison of thermal enhancement of cis-diamminedichloroplatinum (II) induced renal and intestinal toxicities by whole body hyperthermia in the rat.

Thermal enhancement of cis-diamminedichloroplatinum (II) (DDP) induced renal and intestinal toxicities by whole body hyperthermia (WBH) were compared using a F344 rat model. Thermal enhancement ratios (TER) for DDP-induced nephrotoxicity were calculated using renal functional assays and morphological techniques. TER values for gastrointestinal (G.I.) toxicity were calculated using "severity of diarrhea" and jejunal crypt cell survival as assays. TER's for renal damage varied between 3 and 3.4, whereas the TER measured for G.I.-toxicity was 1.8. Physiological changes caused by WBH or intrinsic differences in the sensitivities of normal tissues to DDP +/- WBH may be responsible for the differences in thermal enhancement of DDP-induced renal and intestinal toxicities.

Animals↗
PubMed1989

Direct estimation of latent time for radiation injury in late-responding normal tissues: gut, lung, and spinal cord.

Mixture models are proposed for simultaneous analysis of the latency and fractionation characteristics of radiation injury in late-responding normal tissues. The method is an extension of the direct analysis for quantal response data. Conceptually, the application of the mixture model is based on the biological observation that over a wide range of doses a proportion of the irradiated subjects will never express damage. Mixture models allow the time of occurrence to be utilized in the analysis. Furthermore, this type of model takes time-censored observations into account in a natural way and provides an adequate framework for modelling and analysis of effect-dependent latency. Mixture models with complete and incomplete repair are applied to dose-incidence data for four late endpoints in rodents: death from radiation-induced pneumonitis, leg paralysis after spinal-cord irradiation, and radiation-induced rectal stenosis and anal discharge. Radiation-induced pneumonitis had an effect-dependent latency. The modelling of this phenomenon correlates well with the results of histologic studies. Interestingly, the ratio of hazard rates was not constant for this endpoint. The dominating feature in the latency of radiation injury to the spinal cord was a strong dependency on dose per fraction. After correction for this effect a tendency towards a longer latent time for lower effect levels was observed. For the rectal complications, there was no difference between latency with radiation only vs. radiation combined with cis-platin.

Animals↗
PubMed1989

Time course of loss of residual radiation damage in murine skin assessed by retreatment.

The amount of radiation damage remaining in mouse foot skin has been assessed by retreatment from 10 days to 6 months after a range of first doses. The acute skin reaction was used as the endpoint. Mice hind feet were first irradiated with a range of single doses (15-37.5 Gy) covering zero to near full effect. Feet were retreated with a full range of single doses together with groups of non-previously treated age-matched control mice. No age-related changes in radiation sensitivity were observed. Dose-response curves were constructed for all retreatment times for each priming dose, and isoeffect doses were calculated for both peak and average skin reactions. If 2-6 months were allowed to elapse before retreatment, the skin could be reirradiated as if it were previously untreated. However, if only 1 month was allowed to pass before retreatment, damage was 'remembered' after all first doses. The amount of damage 'remembered' in terms of dose was 11 Gy after a first dose of 37.5 Gy, and was less after the lower first doses.

Animals↗
PubMed1988

Effect of cis-diamminedichloroplatinum(II) combined with whole body hyperthermia on renal injury.

The effect of whole body hyperthermia (WBH) on cis-diamminedichloroplatinum (II) (DDP) induced renal toxicity and antitumor effect was studied using a F344 rat model. Renal injury at 5 and 14 days after treatment was evaluated using animal mortality, renal functional assays (blood urea nitrogen, creatinine), and histopathological methods. WBH (120 min at 41.5 degrees C) enhanced both antitumor effects and toxic side effects. The latter included increased mortality, increased blood urea nitrogen and creatinine levels, and increased renal damage. After simultaneous treatment with WBH and DDP, thermal enhancement ratios (TER) for renal damage between 2.5 and 3.0 were calculated. The histopathological changes observed in the kidney after DDP alone or combined with WBH were primarily found in the proximal pars recta tubules (S3 segment) in the outer stripe of the outer medulla. There was no qualitative difference in tubular damage between rats treated with DDP alone or those treated with DDP combined with WBH. However, at a fixed DDP dose, damage in the combined treatment modality group was significantly greater than in the DDP-only treated group.

Animals↗
PubMed1988

Residual radiation damage in murine lung assessed by pneumonitis.

The amount of radiation damage remaining in mouse lung has been assessed by retreatment from 1 to 6 months after a range of first doses. Pneumonitis at 196 days after retreatment was used as the endpoint. Lungs were first irradiated with a range of single doses (6-10 Gy). Ten Gy was the highest dose that, on its own, produced no changes in breathing rate or deaths due to pneumonitis. One to 6 months later lungs were retreated with a full range of single doses. Isoeffect doses were calculated for lethality for all retreatment times after each priming dose. The amount of residual damage remaining in the lung has been calculated as both a proportion of first doses and as the effect equivalent of remembered dose. Following a 10 Gy first dose, there was evidence of remembered irradiation injury at all retreatment intervals. After a 6 Gy priming dose, the lungs could be retreated to tolerance. The amount of residual damage was proportional to the size of first dose and was highest at 1 month (27% after 6 Gy and 70% after 10 Gy) and lowest after 3 months (0% after 6 Gy and 46% after 10 Gy). This partial recovery of lung function between 1 and 3 months was followed by an increase in amount of damage "remembered"; that is, a reduction in the retreatment dose that could be delivered. The proportion of residual damage after 10 Gy was never less than 25%. The data suggest an early target cell depletion and regeneration in the lung (within 3 months), the extent of which is dependent on the size of initial injury.

Animals↗
PubMed1988

Protection of mouse bone marrow by WR-2721 after fractionated irradiation.

The ability of WR-2721 to protect mouse bone marrow after single or fractionated doses of radiation was assessed using both a clonogenic assay (survival of colony-forming units spleen (CFU) and a functional assay (lethality at 30 days) of stem cell survival. Cell survival curves and dose-response curves for radiation alone and drug with radiation were constructed over the dose range of .5 to 8 Gy and 1.5 to 15 Gy, respectively. The fractionated regimen consisted of four fractions ranging from 0.5 to 1.75 Gy given at 6-hr intervals for a total treatment time of 19.5 hr. WR-2721 was given 30 min before each fraction at a dose of 200 mg/kg. The protection factor was smaller after fractionated doses than after single doses for both assays, 1.3 (95% c.l., 1.0-1.6) vs. 2.3 (95% c.l., 2.0-2.6) for CFU survival and 1.34 vs. 1.8 for lethality at 30 days. No drug cytotoxicity could be demonstrated in the fractionated schedule. These data suggest that protection by WR-2721 is dependent on size of dose and will be less after clinically relevant, small dose fractions. However, some protection does remain even in the low dose range, where proportionally more damage is due to single-hit irreparable events.

Amifostine↗