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Biomedical subjects

J Denekamp

Publications and source records attributed to J Denekamp.

At least 127 records · Page 7Linked to original sources
PubMed1984

The interaction between X-rays and 3 MeV neutrons in the skin of the mouse foot.

Mouse feet were irradiated with mixtures of 3 MeV neutrons and 140 kVp X-rays given simultaneously or within 24 hours of each other. The effects of different treatments were contrasted by comparing the doses required to give equal skin reactions. Irradiation was given as 1, 2, 4 or 8 equal fractions, in order to assess r.b.e. and the shapes of the underlying dose-response curves for mixed beams over a wide range of dose per fraction. All dose-effect curves were well fitted by a linear-quadratic (alpha, beta) model. For X-rays and neutrons given simultaneously, the linear coefficient (alpha) decreased by a factor of 4.80 while the quadratic coefficient (beta) increased by a factor of only 1.44 when the proton contamination in the beam increased from 11 to 100 per cent, with alpha/beta changing from 95.0 to 13.8. The data from simultaneous X-ray and neutron irradiation were consistent with full interaction of those effects from the two radiations which give rise to the total quadratic component of effect. When the two radiations are separated by up to 24 h, this interaction decreases but does not entirely disappear.

Animals↗
PubMed1984

RBE values and repair characteristics for colo-rectal injury after caesium 137 gamma-ray and neutron irradiation. II. Fractionation up to ten doses.

Early and late colo-rectal damage in mice have been assessed after 137Cs gamma irradiation and 3 MeV neutrons given as 1,2,5 or 10 fractions. Damage was measured by early changes in body weight, the late production of short faecal pellets and the pattern of lethality after irradiation. The data have been analysed in terms of the time course of expression of damage, fractionation effects and the RBE for neutrons over a wide range of doses per fraction (0.5-12.5 Gy neutrons, 3.5-33.5 Gy gamma rays). An initial epithelial denudation led to an early loss of weight, maximal at 11-17 days after irradiation. A dose-dependent weight reduction persisted over the animals' life-time. Deaths after localised pelvic gamma irradiation were progressive with no sharp demarcation between early or late phases of injury. The time course for lethality was qualitatively similar after neutrons. Beyond six months the rectum became constricted by fibrosis and a higher proportion of small faecal pellets was observed. At 6-15 months relatively shallow dose-response curves were obtained for this change. The sparing effect of fractionation was marked for the gamma-irradiated mice and almost absent after neutrons. A very high repair increment (11 Gy) was seen with two gamma-ray fractions of 20 Gy. At lower doses per fraction the proportion of each gamma-ray fraction recovered was 50-69% for all assays, i.e., similar to that for other normal tissues. There was a slight enhancement in the sparing effect for the late compared with the early assays over the lower dose range. The RBE was strongly dependent on dose per fraction because of the lack of reparable damage after neutrons. The RBE for both early and late effects was 5.0 at a neutron dose per fraction of 1 Gy. Extrapolation of the RBE data to lower doses, using the linear quadratic model, predicts a higher RBE for late (7.4-12.7) than for early damage (5.7-8.5) if gamma-ray doses below 5 Gy are used.

Animals↗
PubMed1984

The RBE for renal damage after irradiation with 3 MeV neutrons.

Mouse kidneys were locally irradiated with single doses or up to 8 fractions of 240 kV X rays or 3 MeV neutrons. Damage was assessed from measurements of urine output, isotope clearance or haematocrit levels. All three assays gave steep dose-response curves by 4-5 months after irradiation. The repair capacity of the kidney was considerable after X-irradiation but was very small after irradiation with neutrons. Thus the RBE increased sharply with increasing fractionation. After large doses, an RBE of 2.3-2.5 was measured, rising to 4.5-5.1 after 8 fractions of 4 to 5 Gy X rays. Linear-quadratic analysis of these data has allowed RBE's to be calculated outside the measured dose range. The limiting RBE predicted at very low doses per fraction is 20 to 26, whereas at extremely high doses it would be as low as 1.2 to 1.4. This indicates that high RBE values may be seen in a slow turnover tissue after low doses per fraction (within the clinically relevant range) although this may not be evident after larger doses. Such high RBE's arise because of the shape of the underlying X-ray dose-response curve rather than the shape of the neutron curve.

Animals↗
PubMed1984

Vascular endothelium as the vulnerable element in tumours.

The difference between blood vessels in tumours and normal tissues has been recognised for a long time, but little has been done to exploit this in cancer therapy. An overview is presented of the possible contribution of vascular mediated injury with several existing forms of treatment. Interventive radiology and, to some extent, hyperthermia are most obviously mediated through ischaemic cell death. The successful cure of many tumours with radiation, and the complete regressions seen with systemic chemotherapy may also be partially due to a vascular component of damage. The proliferation characteristics of endothelial cells in normal and tumour blood vessels are summarised. These have been derived from single injections or repeated administration of tritiated thymidine. A very large and consistent difference exists between the turnover times. The tumour endothelium is proliferating 20 to 2 000 times faster than any normal tissue endothelium in the adult. The single exception is the placenta which has even more rapid proliferation than the tumour endothelium. The large difference in proliferation rates, coupled with the poor wall structure, lack of innervation and lack of collateral supply, make the blood vessels an attractive target for tumour therapy. Possible means of utilizing this are outlined.

Animals↗
PubMed1984

Neutron RBEs for mouse skin at low doses per fraction.

The effect of low doses of 240 kVp X rays or of 3 MeV neutrons has been investigated using skin reactions on mouse feet as the biological system. Eight or nine repeated small doses of radiation were used, followed by graded "top-up" doses to bring the reactions into a detectable range. By comparing dose-response curves, the RBE has been determined for neutron doses per fraction ranging from 0.25-1.0 Gy. The data are consistent with a limiting RBE of between 7 and 10 at very low doses. A review of other published RBE values for low doses per fraction shows a wide range of RBEs . Very few studies show a plateau value for the RBE. These findings are more consistent with dose-response data that fit a linear-quadratic model than with a multitarget single-hit model.

Animals↗
PubMed1984

Radiation-induced renal damage: the effects of hyperfractionation.

The response of mouse kidneys to multifraction irradiation was assessed using three nondestructive functional end points. A series of schedules was investigated giving 1, 2, 4, 8, 16, 32, or 64 equal X-ray doses, using doses per fraction in the range of 0.9 to 16 Gy. The overall treatment time was kept constant at 3 weeks. Kidney function was assessed from 19 to 48 weeks after irradiation by measuring changes in isotope clearance, urine output, and hematocrit. The degree of anemia (assessed from the hematocrit measurements) is a newly developed assay which is an early indicator of the extent of renal damage after irradiation. All three assays yielded steep dose-effect curves from which the repair capacity of kidney could be estimated by comparing the isoeffective doses in different schedules. There was a marked influence of fractionation, with increasing dose being required to achieve the same level of damage for increasing fraction number, even between 32 and 64 fractions. The data are well fitted by a linear quadratic dose-response equation, and analysis of the data in this way yields low values (approximately 3.0 Gy) for the ratio alpha/beta. This would suggest that hyperfractionation , using extremely small X-ray doses per fraction, would spare kidneys relative to tumors and acutely responding tissues.

Animals↗
PubMed1984

Increased collagen and fluid content of mouse kidneys at 9 months after single or fractionated X irradiation.

Mouse kidneys have been analyzed at sacrifice, 9 months after single-dose and fractionated irradiation, using wet and dry weight, a biochemical determination of hydroxyproline, and quantitation of dilated renal tubules in histological preparations. Dose-response curves have been constructed to determine the sensitivity and precision of the assays and to study the influence of dose fractionation on a variety of radiation responses of the kidney. There was a marked loss of kidney weight, measured either wet or dry, with maximum changes from control values by factors of 3 and 5, respectively. The wet:dry weight ratio increased with X-ray dose, indicating that relative fluid content was increased even 9 months after irradiation. This could be partly attributed to dilated renal tubules. Total collagen content per kidney, determined by a hydroxyproline assay, showed a less marked dose dependence, with a maximum increase of a factor of 1.4. However, hydroxyproline per dry weight increased by a factor of 7, and this ratio proved to be the most sensitive and precise measure of radiation damage. The "fibrosis" that is detected in histological sections appears to be more a relative than an absolute alteration in connective tissue. The loss of parenchymal cell mass, particularly in the proximal tubules, is the predominant factor; the increase in the absolute amount of collagen per kidney contributes to a lesser degree. The influence of radiation dose fractionation was analyzed using a linear-quadratic response model. The alpha/beta ratios were between 0.9 and 2.9 Gy.

Animals↗
PubMed1983

Vascular occlusion and tumour cell death.

Vascular occlusion has been tested as a means of inducing regrowth delay, local control, reduced cell viability and prolonged alteration of blood flow in mouse tumours. The occlusion has been achieved by applying D-shaped metal clamps across the base of subcutaneously implanted tumours. The period of clamping has been varied from 30 min to 24 hr. Marked tumour regression, delayed growth and long-term tumour control were seen, with the magnitude of the response being proportional to the duration of clamping. Vessel occlusion for at least 15 hr is necessary to achieve local cure of the tumour. The overall effect results partly from an immediate loss of cell viability and partly from a failure of the capillary network to recover its normal perfusion pattern after the clamp has been removed. The implications of this for anti-proliferative endothelial therapy is discussed.

Animals↗
PubMed1983

Radioprotection of two mouse tumors by WR-2721 in single and fractionated treatments.

The radioprotective effect of WR-2721 has been studied in two murine tumors using single doses or five daily fractions. Single dose irradiations of the SA FA resulted in a highly variable radio-protective response. In one experiment large protection factors (1.2-2.5) were obtained, with the greatest protection at low X ray doses. In later experiments with the same tumor, there was little or no radioprotection. The Ca MT was significantly protected against single dose irradiation with both 250 mg/kg and 400 mg/kg of the drug. In a five fraction schedule the extent of radioprotection for CA MT was greater than with single X ray doses for the same drug dose per fraction. Tumor protection factors from the present work and from the literature are compared with published protection factors for normal tissues. Significant tumor radioprotection is seen in most studies. The data indicate more variability in the extent of tumor protection for a given drug dose than is seen in normal tissues. Tumor protection is often greatest at low X ray doses which may be a result of preferential protection of the better-oxygenated tumor cells.

Amifostine↗
PubMed1983

Modification of the radiation response of the mouse kidney by misonidazole and WR-2721.

The radiation response of the mouse kidney has been assayed after a range of X ray doses given with or without the nitroimidazole misonidazole or the aminothiol WR-2721. Sensitization and protection of the kidney were investigated by comparing the X ray dose needed to achieve a particular level of injury in the presence or absence of the drug. Two functional assays and kidney weight at sacrifice were used to obtain dose response curves. Urine output and 51Chromium EDTA excretion were used as functional assays at 25 and 49 weeks after irradiation. They demonstrated no radio-sensitization by misonidazole with 1, 2 or 5 fractions of X rays. Significant radioprotection was seen when 400 mg kg 1 WR-2721 was given before single X ray doses (PF = 1.34). Similar radioprotection was observed when renal weight at 1 year after irradiation was used as the third assay of damage. These results confirm that the kidney responds as a well-oxygenated normal tissue with only a small protection being afforded against radiation injury by WR-2721.

Amifostine↗
PubMed1983

Interaction of misonidazole and WR-2721--II. Modification of tumour radiosensitization.

Two types of mouse tumour have been used to study the radiomodifying actions of Misonidazole (MISO) and WR-2721 when used alone and in combination with each other. Single dose studies were performed in both of the tumours and fractionated studies were performed on the anaplastic carcinoma, CA MT. Radioprotection with WR-2721 was seen in both tumours, being most marked at low X-ray doses. The protection was more obvious and the sensitization by MISO less in the fractionated experiment. The combination of MISO and WR-2721 gave an intermediate response compared with either drug used alone, resulting in some sensitization with single doses and an overall protection with repeated small doses. An interactive toxicity of the 2 drugs was also observed, suggesting an additive effect when assessed in terms of lethality. These studies indicate that the effects of both MISO and WR-2721 are dependent upon the oxygen status of the cells in the tumour, and that MISO can act in an oxygen-mimetic manner to modify the radioprotection observed with WR-2721.

Amifostine↗
PubMed1983

Radiosensitization of a mouse tumour by Ro 03-8799: acute and protracted administration.

The nitroimidazole Ro 03-8799 has been tested as a sensitizer of hypoxic tumour cells, using regrowth delay of a mouse mammary carcinoma. This drug has a short biological half-life and has previously proved to be less promising in tumour experiments than was predicted from in vitro studies and from artificially hypoxic skin. The postulate that this might result from the delay in penetrating to poorly vascularized tumour regions has been tested by maintaining constant blood and tumour levels for 2 hours before irradiation, using an infusion pump. For equivalent gross tumour concentrations at the time of irradiation there was no significant difference in the radiosensitization achieved with a single dose or with prolonged administration. This indicates that slow penetration of the drug is not a problem.

Animals↗
PubMed1983

RBE values for colo-rectal injury after caesium 137 gamma-ray and neutron irradiation. I. Single doses.

Colo-rectal damage in mice has been assessed after caesium gamma irradiation and 3 MeV neutrons given as single doses. Several assays were used, including body weight changes, faecal deformity and lethality. Dose response curves have been constructed for each assay at different times after irradiation, ranging from 10 days to 16 months. The data have been analysed in terms of the time course of expression of damage and the RBE for neutrons. An initial loss of weight at 10-20 days was presumably related to epithelial denudation, but a dose-dependent weight reduction (compared with controls) persisted over the animal's life span. Mice died progressively after localised pelvic gamma irradiation; there was no sharp demarcation between an early and late phase of lethal injury. Death resulted from intestinal stricture or stenosis. The time course for lethality was qualitatively different after neutrons, with little progression of damage between 5 and 11 months. Faecal deformity was detectable as a higher proportion of small pellets when the rectum became constricted by fibrosis. No significant faecal deformity was observed before 6 months after which time dose response curves could be obtained. The RBE for early damage (assessed at 1-3 months) was 2.2-2.7. This fell to 1.7-1.9 for late damage (determined at 10-15 months) over the range of neutron doses of 7.5-12 Gy. The need for sublethal assays allowing for sequential evaluation of radiation damage within the same animal is stressed, as is the need to compare RBE values from early and late endpoints at equivalent neutron doses.

Animals↗
PubMed1983

Sequential functional testing of radiation-induced renal damage in the mouse.

Two nondestructive assays of functional impairment were developed to measure renal damage in mice after local irradiation of both kidneys with 240-kV X rays. Daily urine output after irradiation was measured indirectly by determining urination frequency. A dose-related response began 17 weeks after treatment and then progressed; dose-response curves with a threshold of 12 Gy were established by 22 weeks. The time of onset of damage was dose related and there was some recovery of kidney function between 25 and 38 weeks. The rate of excretion of 51Cr-EDTA was measured as an estimate of glomerular filtration either by sequential external counting over 20 min or from the activity remaining in a single blood sample at 60 min. Both methods gave dose-response curves, but the results from the blood sample were more precise. These assays are suitable for sequential testing of individual mice and have been used to establish a dose-related latent period of approximately 17 weeks after bilateral renal irradiation.

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