Search PubMed⌕ Search

Biomedical subjects

E L Travis

Publications and source records attributed to E L Travis.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1987

WR 2721 modification of type II cell and endothelial cell function in mouse lung after single doses of radiation.

The ability of WR 2721 to protect endothelial cells and Type II cells in mouse lung after single doses of X rays was studied using specific assays of cell function to assess damage. The whole thorax of mice was exposed to a range of single doses of X rays either alone or 30 minutes after an i.p. injection of 400 mg/kg of WR 2721. Endothelial cell function was assayed by angiotensin converting enzyme (ACE) and Type II cell function by phosphatidylcholine and total protein present in lavage fluid 28 days after radiation. Similar protection factors (PFs) were found for the functional activity of both cell types, 1.2 and 1.24 for ACE and phosphatidylcholine respectively. These values were somewhat less than the PF of 1.37 for lethality from pneumonitis 7 to 9 months after irradiation for this mouse strain. The lack of a clear difference between the PFs for the functional activity of these two cell types suggests that neither the endothelial cell nor the Type II cell can be accepted or excluded as the target cell for radiation pneumonitis in lung.

Amifostine↗
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↗
PubMed1987

Repair but not potentiation observed in mouse lung irradiated with neon ions.

The lungs of mice were irradiated with 1, 4, or 7 fractions of X rays or neon ions in a 4-cm spread Bragg peak. Lung function as a function of total radiation dose was tested at 7 and 12 months after irradiation by measuring the resting breathing rate in a whole-body plethysmograph. The isoeffect doses increased sequentially with X rays for 1 through 4 to 7 fractions, demonstrating repair of sublethal radiation injury as previously reported. There was also a significant increase of isoeffect dose with neon ions between 1 and 4 fractions but no further increase at 7 fractions. Thus repair instead of potentiation of radiation injury in lung clearly occurred after neon ion irradiation. The effectiveness of neon ions appeared to be closer to that of neutrons with a mean energy of 8 meV than those with a mean energy of 2.3 meV.

Animals↗
PubMed1986

Enzymatic defense against radiation damage in mice. Effect of selenium and vitamin E depletion.

Radiation effects are mediated in part by the generation of oxygen-derived free radicals and hydrogen peroxide. Membrane polyunsaturated fatty acids are important biological targets of these toxic molecules which cause lipid peroxidation. Radiation damage to DNA is also known to result in base hydroperoxides, especially thymidine hydroperoxide. Glutathione (GSH) is known to inhibit lipid peroxidation both chemically and through its interaction with the selenium-dependent glutathione peroxidase (GSH-Px). Although cytosolic GSH-Px can metabolize organic lipid peroxides in solution, it cannot metabolize phospholipid peroxides in micelles. This may be due to the interference of phase differences between the aqueous cytosol and the membrane, or the result of steric hindrance. Recent studies have suggested the presence of a membrane-bound GSH-dependent peroxidase system. We examined the cytosolic versus membrane-associated GSH-Px, in various tissues of mice on a selenium and vitamin E deficient diet, and found significant differences among organs in the distribution of enzyme activity in these two subcellular fractions. The effect of single high-dose whole body irradiation did not appear to be related to the activity of these enzymes.

Animals↗
PubMed1986

A comparison in rodents of renal and intestinal toxicity of cisplatin and a new water-soluble antitumor platinum complex: N-methyl-iminodiacetato-diaminocyclohexane platinum (II).

A new third-generation water-soluble platinum complex, N-methyliminodiacetato-1,2-diaminocyclohexane platinum (II) (MIDP) has been reported to have remarkable antitumor activity against several murine tumor model systems. In the present study, the renal and intestinal toxicity of MIDP was compared directly with that of cis-diamminedichloroplatinum (cisplatin). Measurement of renal physiologic parameters in Fischer 344 rats 3 and 5 days after receiving equitherapeutic doses of either cisplatin or MIDP (6.0 and 25 mg/kg, respectively) revealed that, whereas cisplatin significantly reduced glomerular filtration rates (GFR) and increased blood urea nitrogen (BUN) and serum creatinine values, MIDP produced no alteration in either GFR or BUN levels and only a slight rise (Day 5) in serum creatinine value. Histopathologic analyses by light and electron microscopy showed severe renal proximal tubular necrosis in cisplatin-treated rats yet no detectable lesions were produced by MIDP. Determination of elemental platinum content revealed that less platinum was retained in the kidneys of MIDP-treated rats than in cisplatin-treated animals. The degree of drug-mediated intestinal injury was determined for each drug by measurement of jejunal crypt cell regeneration in mice. Cisplatin reduced crypt survival by 1 log whereas no killing of crypt cells was seen even at MIDP doses exceeding the median lethal dose. Our data demonstrate that far less renal and intestinal toxicity results from administration of MIDP than from administration of cisplatin.

Animals↗
PubMed1986

Actinomycin D and radiation: effects on mouse lung.

The effect of actinomycin D (0.4 mg/kg) on radiation-induced lung damage in the mouse was investigated. The drug was administered either 4 weeks before, immediately after, or 16 weeks after single doses of 240 kV X-rays applied to the thorax of CBA mice. Lung damage was assessed by measuring respiration rate, with a whole body plethysmograph. Dose-response curves were obtained at 2-week intervals from 12 to 40 weeks after irradiation. Actinomycin D had no significant effect on respiration rate in this study. A summary of other experimental studies is included which shows conflicting results.

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

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↗