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E L Travis

Publications and source records attributed to E L Travis.

At least 73 records · Page 4Linked to original sources
PubMed1985

Protection of mouse lung by WR-2721 after fractionated doses of irradiation.

The radioprotective effect of WR-2721 on mouse lung has been studied after single doses, 4 or 7 equal fractions of X rays. Using breathing rate and lethality to measure lung injury up to 1 year after radiation, significant protection against both pneumonitis at 7 months and fibrosis at 12 months was observed using 300 mg/kg of WR-2721. The degree of radioprotection was similar for pneumonitis and fibrosis and was not less after doses per fraction of 4.0 Gy. These data indicate that protection of mouse lung by WR-2721 will not be less in a multifractionated schedule of radiation, at least for doses per fraction greater than 4.0 Gy.

Amifostine↗
PubMed1985

The effect of breathing 100% oxygen on lung response to radiation in mice.

The response of the lung after single doses of radiation was measured in mice breathing air, or 100% oxygen, or in air-breathing mice given the hypoxic cell sensitizer misonidazole 30 min before irradiation. There was a clear enhancement of only the pneumonitis response in the mice breathing oxygen when breathing rate or lethality was used to assess injury. Less enhancement of the late fibrotic reaction was observed in these animals. No enhancement of either phase of lung response was observed in the misonidazole-treated mice. Dose reduction factors (DRF) were estimated from these data and used to calculate oxygen concentration in the lung, giving values ranging between 187 and 250 micron oxygen.

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

Late functional and biochemical changes in mouse lung after irradiation: differential effects of WR-2721.

The radioprotective effect of WR-2721 on late damage after whole thorax irradiation has been studied after split doses of radiation using the standard death and breathing rate assays at monthly intervals between 3 and 15 months after irradiation, as well as two biochemical measurements of injury at 15 months, hydroxyproline (HP), an indicator of tissue fibrosis, and DNA content, an indicator of tissue cellularity. A comparison of HP/lung and breaths per minute (BPM) in each dose group in the WR-2721 and non-WR-2721-treated mice 15 months after irradiation showed that the relationship between these two assays of late lung injury was not the same. There were large dose-related increases in breathing rate corresponding to relatively small changes in HP in the lungs of mice given radiation alone. In contrast, the mice given WR-2721 before irradiation showed large dose-related increases in HP/lung, but BPM remained relatively constant independent of dose. These data suggest then that changes in breathing rate and deaths later than 9 months after whole lung irradiation may not be due to collagen accumulation in the lung. WR-2721 did protect better against late lung functional changes (protection factors (PF) = 1.6) and late deaths (PF = 1.51) than against earlier changes in these same assays (PF = 1.4 and 1.28, respectively). Although the earlier-appearing injury after whole thoracic irradiation is most likely related to lung damage with deaths and increases in breathing rate resulting from pneumonitis, the cause of the late-appearing functional injury in the lung after radiation is not clear. Thus protection of late lung damage measured from either lethality or breathing rate is not related to the prevention of lung fibrosis.

Amifostine↗
PubMed1984

WR-2721 protection of pneumonitis and fibrosis in mouse lung after single doses of x rays.

The radioprotective effect of WR-2721 has been studied in mouse lung after single doses of radiation. Using the breathing rate assay and lethality, radioprotection was assessed at monthly intervals between 3 and 18 months after irradiation during both pneumonitis and chronic fibrosis. The degree of radioprotection was greater for fibrosis than for pneumonitis using both assays. In replicate experiments, dose modifying factors (DMF's) ranging from 1.2 to 1.4 were obtained for pneumonitis and 1.5 and 1.6 for fibrosis. The differences in DMF's for the two phases of lung damage were significant. A difference in the time course of expression of damage was seen in both the breathing rate and lethality assays between mice irradiated with and without WR-2721: the damage ended sooner in the drug-treated mice. This difference is best explained by protection of all damage after 5 months by WR-2721. No evidence of drug toxicity was found. We conclude that WR-2721 protects against chronic lung fibrosis caused by radiation at least as well as against the earlier appearing pneumonitis after single doses of radiation. Thus, if WR-2721 is dose modifying and if late tissue complications are dose limiting in clinical radiotherapy, then a therapeutic benefit would be obtained by the use of this drug in clinical radiotherapy, provided that the radioprotection of tumors did not exceed a factor of 1.5-1.6.

Amifostine↗
PubMed1984

The oxygen dependence of protection by aminothiols: implications for normal tissues and solid tumors.

This paper reviews the role of oxygen in the protection of both normal tissues and tumors in vivo by WR-2721. Although the presence of hypoxic cells in tumors is well accepted, data are presented that suggest there is a range of oxygen concentrations and thus OERs in normal tissues in vivo, too, and that some may, in fact, be radiobiologically hypoxic. Thus, the range of protection factors in normal tissues (which appears unrelated to tissue drug levels), as well as tumors can perhaps be explained by the range of OERs in these same tissues. The question of whether protection decreases with radiation dose per fraction is related to the distribution of oxygen in both normal tissues and tumors, i.e., whether oxygen is homogeneously or heterogeneously distributed among the cells. It is hypothesized that sulphydryl compounds may equalize the OER differential between tumors and normal tissues and thus remove the natural advantage (radioresistance) of the tumor when treated with radiation. Thus, no loss of therapeutic benefit would occur when sulphydryl compounds were given with radiation if the normal tissue were better oxygenated than the tumor.

Amifostine↗
PubMed1984

Late effects of irradiation in mouse jejunum.

The response of mouse jejunum at intervals up to 1 year after single 'priming' doses of X-rays has been assessed by crypt survival after retreatment with single doses of X-rays and morphometric analysis of changes in the intestinal submucosa. The first 'priming' dose was given as a single dose to the whole abdomen. To assess crypt survival, groups of mice were retreated to the whole body with a range of test doses 2, 6 or 12 months later, while other groups of mice were given only the priming doses. These data were compared to crypt survival in mice not previously irradiated. The crypt dose-survival curves in mice re-irradiated at all three intervals after priming irradiation were displaced to higher doses in pre-treated than in non-pre-treated mice and were characterized by higher D0 values. Misonidazole given before the test exposure reversed this effect so that the dose survival curve for crypts in pre-treated mice were superimposed on that for mice not previously irradiated, suggesting that the increase in isoeffect dose and the change in the D0 in previously exposed mice was due to crypt hypoxia. Quantification of the area of the submucosa showed that its area was increased at all three times after the priming doses and was a result of collagen deposition and oedema. Thus, the hypoxia in the crypts was probably secondary to these changes. Deaths began at 6-7 months after priming irradiation and were due to intestinal obstruction and stenosis. Thus, as in other tissues, two phases of injury can be assayed in the intestine of experimental animals.

Animals↗
PubMed1983

Effects of intraoperative electron irradiation in the dog on cell turnover in intact and surgically-anastomosed aorta and intestine.

Adult dogs were subjected to laparotomy and intraoperative electron irradiation after division and reanastomosis of aorta or after construction of a blind loop of small intestine having a transverse suture line and an end-to-side anastomosis. Dogs received intraoperative irradiation of both intact and anastomosed aorta or intestine in doses of 0, 2000, 3000, or 4500 rad. Animals were sacrificed at seven days or three months following treatment. At 24 hours prior to sacrifice, dogs received 5 mCi tritiated thymidine intravenously. Irradiated and non-irradiated segments of aorta and small intestine, including intact and anastomotic regions, were analyzed for tritiated thymidine incorporation and were subjected to autoradiography. Incorporation studies showed diminution in tritiated thymidine uptake by irradiated portions of aorta and small intestine, in both intact and anastomotic regions. Autoradiograms revealed that irradiated areas of intact or anastomotic aorta or intestine had diminished labeling of stromal cells, suggesting a lowered cell proliferative capacity of irradiated tissue compared to non-irradiated portions. Inflammatory cells showed similar labeling indices in irradiated and non-irradiated tissues, both intact and surgically-manipulated, suggesting that irradiation does not significantly affect a subsequent local inflammatory response. Radiation-induced decreases in tritiated thymidine incorporation in irradiated aorta and small intestine were generally more marked at seven days than at three months following irradiation, suggesting that radiation-induced depression of cell turnover rates decreases with time. The presence of tritiated thymidine uptake after irradiation demonstrates the ability of intact and surgically-manipulated aorta and intestine to recover from radiation-induced damage.

Animals↗
PubMed1983

Is there a loss of repair capacity in mouse lungs with increasing numbers of dose fractions?

The capability of mouse lung to repair sublethal damage after up to 10 fractions of X rays was assessed by an in situ breathing rate assay and lethality. The whole thorax of mice was irradiated "daily" with 4, 7 or 10 fractions of 2.75 or 3.0 Gy of X rays followed at 24 hours by graded "test" doses of X rays or neutrons. Repair capability was measured by determining the difference in test dose between 4 and 7 fractions or 7 and 10 fractions at a given isoeffect. Damage was assessed monthly up to 76 weeks after irradiation, during pneumonitis and chronic fibrosis. The data from both assays for the pneumonitis phase suggested that there may be some loss of repair between 7 and 10 fractions, although it was not large enough in only 10 fractions to be clearly demonstrated. In contrast, there was no suggestion of loss of repair for late damage after up to 10 fractions of X rays using either assay.

Animals↗
PubMed1983

Tolerance of canine anastomoses to intraoperative radiation therapy.

Radiation has been given intraoperatively to various abdominal structures in dogs, using a fixed horizontal 11 MeV electron beam at the Armed Forces Radiobiologic Research Institute. Animals were irradiated with single doses of 2000, 3000 and 4500 rad to a field which extended from the bifurcation of the aorta to the rib cage. All animals were irradiated during laparotomy under general anesthesia. Because the clinical use of intraoperative radiotherapy in cancer treatment will occasionally require irradiation of anastomosed large vessels and blind loops of bowel, the tolerance of aortic anastomoses and the suture lines of blind loops of jejunum to irradiation were studied. Responses in these experiments were scored at times up to one year after irradiation. In separate experiments both aortic and intestinal anastomoses were performed on each animal for evaluation of short term response. Response was graded by arteriography, gastrointestinal roentgenography, blind loop bursting pressure, and pathologic findings at autopsy and microscopic evaluation. The dogs with aortic anastomoses showed adequate healing at all doses with no evidence of suture line weakening. On long-term follow-up one animal (2000 rad) had stenosis at the anastomosis and one animal (4500 rad) developed an arteriovenous fistula. Three of the animals that had an intestinal blind loop irradiated subsequently developed intussusception, with the irradiated loop acting as the lead point. One week after irradiation, bursting pressure of an intestinal blind loop was normal at 3000 rad, but markedly decreased at 4500 rad. No late complications were noted after the irradiation of the intestinal anastomosis. Thus, it appears that adequate healing can take place with minimal risk of suture line breakdown even after a high single dose of irradiation (up to 3000 rad) to an anastomotic site. No late complications were observed after irradiation of intestinal anastomoses, but one needs to be cautious with regards to possible late stenosis at the site of an irradiated vascular anastomosis.

Animals↗
PubMed1983

Experimental and clinical studies with intraoperative radiotherapy.

Studies of normal tissue tolerance to intraoperative radiotherapy were done upon 65 dogs subjected to laparotomy and 11 million electron volt electron irradiation in doses ranging from zero to 5,000 rads. Results of studies indicated that intact aorta and vena cava tolerate up to 5,000 rads without loss of structural integrity. Ureteral fibrosis and stenosis develop at doses of 3,000 rads or more. Arterial anastomoses heal after doses of 4,500 rads, but fibrosis can lead to occlusion. Intestinal suture lines heal after doses of 4,500 rads. Bile duct fibrosis and stenosis develop at doses of 2,000 rads or more. Biliary-enteric anastomoses fail to heal at any dose level. A clinical trial of intraoperative radiotherapy combined with radical surgery was performed upon 20 patients with advanced malignant tumors which were considered unlikely to be cured by conventional therapies and which included carcinomas of the stomach, carcinomas of the pancreas, carcinomas involving the hilus of the liver, retroperitoneal sarcomas and osteosarcomas of the pelvis. All patients underwent resection of gross tumor, followed by intraoperative irradiation of the tumor bed and regional nodal basins. Some patients received additional postoperative external beam radiotherapy. Treatment mortality for combined operation and radiotherapy occurred in four of 20 patients. Postoperative complications occurred in four of the 16 surviving patients. Local tumor control was achieved in 11 of the 16 surviving patients, with an over-all median follow-up period of 18 months. The clinical trial suggested that intraoperative radiotherapy is a feasible adjunct to resection in locally advanced tumors, that the resulting mortality and morbidity is similar to that expected from operation alone and that local tumor control may be improved.

Abdominal Neoplasms↗
PubMed1983

Repair in mouse lung between multiple small doses of X rays.

Multiple fraction experiments have been carried out to determine the response of mouse lung to repeated small doses of 240 kV X rays down to 150 rad/fraction using breathing rate and lethality to assess damage. Two experimental approaches were used to measure the effect of small doses in vivo: (1) multiple equal doses and (2) multiple priming doses followed by a large test dose. Analysis was performed using the multitarget two-component model and the linear quadratic model of cell survival. The amount of repair was calculated as a function of either dose per fraction (FR) or total dose (Frec). Both FR and Frec increased with decreasing dose per fraction but the change in FR was small. The advantage of Frec was that it varied more rapidly with dose per fraction than FR, so that possible differences between tissue repair capabilities are more visible on plots of repair as a function of dose per fraction. FR and Frec both decreased with the level of single-dose isoeffect injury; thus neither parameter is acceptable for comparing repair capability of different normal tissues with widely differing single-dose end point levels. Beta/alpha values were calculated and found to be a more acceptable index of repair capability than either FR or Frec because unlike those two parameters, beta/alpha varied little with level of damage. Beta/alpha values of 1.7 to 4.2 krad-1 were obtained for both lung death and increased breathing rate and are clearly intermediate between the lower beta/alpha ratios for acute reactions, i.e., skin and intestine, and the higher values for late reactions in kidney and spinal cord.

Animals↗
PubMed1982

The time course of radioprotection by WR 2721 in mouse skin.

The radioprotective effect of 400 mg/kg of WR 2721 on mouse skin has been investigated over a series of times from 5 to 60 minutes after intravenous or intraperitoneal injection of the drug. The acute desquamation reaction on the hind leg of white mice was studied. Dose response curves were obtained for the average reaction over 15 to 25 days after single-dose irradiation. A high dose-rate electron beam (13--17 Gy/min) was used to minimize the irradiation time. Single doses of 20 to 60 grays were given. Dose modifying factors (DMFs) of 1.7--2.1 were obtained at 30 to 60 minutes, but only 1.1 to 1.3 at 5 minutes and intermediate values at 10 and 15 minutes. DMFs rose slightly faster and to slightly higher values after i.v. than after i.p. injection of WR 2721. We conclude that 30 minutes is the shortest interval which should be used between injection of Wr 2721 and irradiation with this normal tissue.

Amifostine↗
PubMed1982

Early and late effects in mouse lung and rectum.

No higher RBE's were found for late than for early damage in mouse rectum up to 70 weeks or mouse lungs up to 48 weeks after irradiation with 3.0 MeV neutrons (4 MeV deuterons on Be). The smallest neutron doses per fraction were 1.5 and 0.6 Gy for rectal and lung irradiation, respectively. There was a suggestion of higher late RBE's for small doses per fraction in the lung. Slow repair after 2 neutron doses split by 31 days was unequivocally demonstrated in the lung, of magnitude about 1 Gy, possibly decreasing after about 40 weeks.

Animals↗