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Biomedical subjects

J Denekamp

Publications and source records attributed to J Denekamp.

At least 109 records · Page 6Linked to original sources
PubMed1985

The influence of overall treatment time on renal injury after multifraction irradiation.

The influence of overall treatment time on the radiation response of the mouse kidney was studied in an experiment in which 16 fractions were administered either evenly distributed over 20, 40 or 80 days, or as a split course (8 F/3 days; 74 days rest; 8 F/3 days). Urine output and an isotope assay of glomerular filtration were used to test the mice sequentially. The data were used both to obtain dose-response curves and also to determine the latent period before a chosen level of injury was expressed functionally. Prolonging the overall time from 20 to 80 days increased the isoeffect dose by 2-5 Gy (4-9%) for the isotope assay, and by 4-9 Gy (7-18%) for the urine output assay. This additional recovery as the interval between fractions was prolonged from 1 to 5 days is consistent with slow repair and can be expressed as a small "T" exponent of 0.02-0.12. (One analysis gave a result consistent with negative repair, but the errors on this result were unusually wide.) When the radiation was given as a split course, at the rate of 2 fractions per day, with a large gap of 10.5 weeks between courses, there was no additional sparing compared with 16 fractions over 20 days. This indicates that any sparing that might have resulted from slow repair or stimulated repopulation in the gap has been counterbalanced by having less time for repair of sublethal injury when intervals of 6-12 h are used instead of 24-48 h. Clearly no great increase in the tolerance dose for mouse kidney resulted from the split course.

Animals↗
PubMed1985

Factors influencing the chemosensitization of melphalan by misonidazole.

The effect of melphalan alone or combined with various schedules of misonidazole (MISO) has been tested on a murine fibrosarcoma. The tumoricidal effect has been determined using the growth delay assay. Large single doses (500-1000 mgkg-1) of MISO enhanced the anti-tumour effect of melphalan, especially at high melphalan doses. This was accompanied by a drop in body and tumour temperature and an increase in the melphalan half-life. The MISO-induced hypothermia was prevented in one experiment by keeping the mice in an ambient temperature of 35 degrees C for 3 h. This reduced the exposure to melphalan but did not diminish the cytotoxic effect of the drug combination. Chronic administration of MISO for an 8 h period gave no enhancement of melphalan damage, whether melphalan was given half-way through or at the end of the period of dosing. It seems that a threshold tumour concentration of MISO, in excess of 70 micrograms g-1, is needed for enhancement of melphalan cytotoxicity; prolonged exposures to very low doses are ineffective.

Animals↗
PubMed1985

The influence of pre-treatment temperature on the thermal sensitivity of a mouse tumour.

The response of tumours to hyperthermia was tested by giving graded heat treatments and assessing local control at 90 days. Mice were divided into three groups which were pre-treated for 3 days in ambient temperatures of 4, 21 or 35 degrees C. This enabled the mean tumour resting temperature to be varied by up to 11 degrees C, before subsequent heat treatment. For the heat treatments, the tumours were clamped in order to eliminate blood flow, resulting in uniform temperature distributions and hence more uniform thermal sensitivity. TCD50 values were used to construct Arrhenius plots. For all three pre-treatment temperatures, these plots demonstrated a factor of 1.6 increase in heating time per degree Celsius reduction in heating temperature. However, tumours kept in a 4 degrees C environment before treatment were more thermally sensitive than those kept in 21 degrees C conditions, while those in a 35 degrees C environment were more resistant. Pretreatment at 4 degrees C was equivalent to an increase of either 0.5 degree C in heating temperature or 28 per cent in heating time, compared with pre-treatment at 21 degrees C. Pre-treatment at 35 degrees C was equivalent to a reduction of either 0.6 degree C in heating temperature or 25 per cent in heating time. These data indicate that the pre-treatment tumour temperature is an important parameter, but the effect of heat treatment is more closely related to absolute heating temperature rather than to the increase in temperature above the normal resting level.

Acclimatization↗
PubMed1985

In vitro and in vivo studies of the TRIUMF pion therapy beam.

Patient treatments at TRIUMF (Tri-University Meson Facility, Vancouver, B. C.) use a moving spot raster scan technique where the pion range is modulated in depth for each position of the moving spot. The spot scans in a stepwise fashion and can produce any desired field shape. This approach provides very good dose uniformity across the treatment field and allows maximum flexibility in shaping the treatment volume. Survival of cultured cells has been used as a biological dosimeter to test the isoeffectiveness of the pion dose distributions, which must be shaped in depth to compensate for the depth-dependent LET distribution. Isoeffectiveness across the treatment field has also been verified using this system, which involves irradiating cells supported in a gelatin matrix. The response of pig skin to pion irradiation at TRIUMF has provided a check on the in vivo RBE for acute effects derived from our earlier studies with mouse foot. In addition, the pig skin reactions have been followed for several months to assess the later dermal response. The RBE of our pion beam relative to 270 kVp X rays is approximately 1.5 for both the acute epidermal and the later dermal responses.

Animals↗
PubMed1985

Effects of glutathione depletion by buthionine sulfoximine on radiosensitization by oxygen and misonidazole in vitro.

Buthionine sulfoximine (BSO) has been used to deplete glutathione (GSH) in V79-379A cells in vitro, and the effect on the efficiency of oxygen and misonidazole (MISO) as radiosensitizers has been determined. Treatment with 50 or 500 microM BSO caused a rapid decline in GSH content to less than 5% of control values after 10 hr of exposure (t1/2 = 1.6 hr). Removal of BSO resulted in a rapid regeneration of GSH after 50 microM BSO, but little regeneration was observed over the subsequent 10-hr period after 500 microM. Treatment with either of these two concentrations of BSO for up to 14 hr did not affect cell growth or viability. Cells irradiated in monolayer on glass had an oxygen enhancement ratio (OER) of 3.1. After 10-14 hr pretreatment with 50 microM BSO, washed cells were radiosensitized by GSH depletion at all oxygen tensions tested. The OER was reduced to 2.6, due to greater radiosensitization of hypoxic cells than aerated ones by GSH depletion. GSH depletion had the effect of shifting the enhancement ratio vs pO2 curve to lower oxygen tensions, making oxygen appear more efficient by a factor of approximately 2, based on the pO2 required to give an OER of 2.0. In similar experiments performed with MISO, an enhancement ratio of 2.0 could be achieved with 0.2 mM MISO in anoxic BSO-pretreated cells, compared to 2.7 mM MISO in non-BSO-treated cells. Thus MISO appeared to be more efficient in GSH-depleted cells by a factor of 13.5. These apparent increases in radiosensitizer efficiency in GSH-depleted cells could be explained on the basis of radiosensitization of hypoxic cells by GSH depletion alone (ER = 1.29-1.41). The effect of GSH depletion was approximately equal at all sensitizer concentrations tested, except at high oxygen tensions, where the effect was insignificantly small. These results are consistent with hypoxic cell radiosensitization by GSH depletion and by MISO or oxygen acting by separate mechanisms.

Animals↗
PubMed1984

Lung radioprotection by WR-2721 at low X-ray doses per fraction.

The response of mouse lungs to single doses and ten fractionated irradiations has been tested using breathing rate and lethality as assays for damage. The radioprotective effect of 300 mg/kg WR-2721 has been determined for mice breathing air or 10% oxygen. The protection factor was assessed from dose response curves obtained at monthly intervals from 24 to 48 weeks. A low protection factor (1.2-1.4) was observed for single doses in air or 10% oxygen and also for ten fractions in air. Considerably more protection was seen with ten fractions in mice breathing the reduced oxygen concentration (protection factors of PF = 1.5-1.7). It is postulated that the low PF values normally reported for lung are due to the naturally high oxygen concentration in all cells in this tissue. A fraction of the cells becomes sufficiently hypoxic in 10% oxygen to be susceptible to WR-2721 radioprotection. This subpopulation can then be detected with small X-ray fractions (less than or equal to 5 Gy) but not with large single doses.

Amifostine↗
PubMed1984

The therapeutic advantage of combined X-rays and melphalan.

Early skin reactions on mouse feet and delay in growth of a mouse tumor (CA NT) were measured after combined treatments with X-rays and the cytotoxic drug Melphalan. The drug was given as a single dose (10 mg kg-1) with graded single doses of X-rays, either before or after irradiation with an interval of up to 4 days. In the mouse skin, addition of the drug increased the radiation response only slightly. The maximum Enhancement Ratio (ER) measured at a skin reaction of 1.5 (approximately 23 Gy) was 1.07 +/- 0.02 SEM for the schedule MEL 3 days before X-rays. ER's for all schedules tested were similar with a range of 1.00 to 1.07. For the tumor more enhancement was observed; the largest ER's were found when Melphalan was given before rather than after irradiation, with maximum ER's of 2.3 and 2.4 when the drug was given 3 days or 1 day before X-rays. This has been attributed to reoxygenation of hypoxic cells after drug treatment, rendering the tumor more radiosensitive. The range of ER over all schedules was 1.5-2.4. Since ER is greater for the tumor than skin for all schedules, a therapeutic advantage is indicated under these specific experimental conditions of single X-ray and drug doses.

Animals↗
PubMed1984

The influence of X ray dose levels on normal tissue radioprotection by WR-2721.

A variation in the degree of radioprotection by WR-2721 with X ray dose level is detectable in several normal tissue studies. A similar effect in tumors has been attributed to differential protection of oxic and hypoxic cells. For normal tissues it was previously postulated that it resulted from greater protection of 1 hit damage at low doses, with less protection of multihit damage. However, more extensive analysis of the normal tissue data, including both single dose and fractionated results show that it is not a universal effect in all normal tissues. It now seems more likely that varying PF values result from differential protection of cells at different oxygen tensions, even though the heterogeneity of oxygenation may not be detectable in the response to X rays alone.

Amifostine↗
PubMed1984

Radiation induced renal damage in mice: influence of fraction size.

Two functional assays (urine output and isotope clearance) have been used to assess the response of mouse kidneys to localized irradiation. The influence of the size of each X ray dose has been investigated by using single doses and two to 16 equal fractions. The X ray dose in each treatment ranged from 16 Gy as a single dose to 3.5 Gy (X 16 fractions). Three separate experiments were performed, one with and two without anesthetic for the irradiation. Sequential testing of the mice was used to determine the latent period before radiation damage became manifest. Latency was found to be dose dependent; functional defects appeared earlier after higher doses but there was a minimum period of 14-19 weeks before the onset of damage. The repair capacity of the kidney was assessed by comparing isoeffective doses from the dose-response curves. Within 24 hours a recovered dose of 5 Gy was obtained if 2 doses were used instead of one. The isoeffective dose increased with fractionation and a fraction number exponent of 0.42 was obtained. Analysis of the data using a linear quadratic model yielded a low alpha/beta ratio of 0-3.5 Gy. This is similar to values obtained for other late responding normal tissues and implies that the use of small dose fractions will spare the kidney relative to tumors and acutely reacting normal tissues. In conventional radiotherapy more effective sparing of the kidney should be achieved by using thin shielding with each fraction than by completely shielding the kidney for the latter part of the treatment course.

Animals↗
PubMed1984

Tumor sensitization and protection: influence of stromal injury on estimates of dose modification.

Tumor regrowth delay is an assay which reflects tumor cell kill but can be modified by growth rate changes resulting from damage to the stroma (tumor bed effects). If the stromal damage is modified by radiosensitizers and radioprotectors to a different degree from the tumor cells, the overall measurement of dose modifying factors may be influenced by the choice of a regrowth size for the growth delay analysis. We have studied the response of two mouse tumors; a fibrosarcoma which showed only a small TBE and a carcinoma which showed a very large TBE. Sensitizer enhancement ratios and protection factors have been obtained by assessing regrowth to a variety of endpoint sizes. The dose modifying effects on the stroma have then been determined by analyzing the regrowth rates of tumors after irradiation. The choice of endpoint size modified both the sensitizer enhancement ratio and the protection factor for both tumors. It appears that stromal damage may be the cause of the radioprotection observed in the carcinoma, whereas direct tumor cell radioprotection is indicated in the fibrosarcoma. Both direct tumor cell killing and cell death secondary to stromal damage will play an important role in determining the local control of irradiated tumors.

Amifostine↗
PubMed1984

Dose-response relationships for human tumors: implications for clinical trials of dose modifying agents.

Clinical benefit from dose modifying agents depends upon the effectiveness of the agents and the steepness of dose response curves for the local control of human tumors by radiotherapy. We have analyzed the two prospective trials and the many retrospective analyses of clinical data from the literature to determine what dose increment is needed to increase local control from 40 to 60%. This increment ranges from 3 to greater than 35%. Thus a dose modifying factor of at least 1.03 (to greater than 1.35) will be necessary for clinical detection of the benefit of a new modality, even if 135 patients are included in each arm of a trial. Two dose levels in the new treatment arm would ensure that therapeutic advantage could be assessed, and would also generate prospective dose response information.

Animals↗
PubMed1984

Radiation induced renal damage in mice: influence of overall treatment time.

The influence of overall treatment time on the radiation response of the mouse kidney was studied by varying the time over which 2 or 5 fractions of X-rays were administered. Two functional assays (urine output and 51Cr-EDTA excretion), and renal weight at sacrifice were used to obtain dose-response curves and estimate isoeffective doses. Split dose experiments showed Elkind recovery of about 5 Gy in 24 h. With a 7-day interval between fractions a transitory increase in isoeffect dose was observed in the first experiment. In the second, more extensive, experiment the recovered dose did not increase significantly even if the interval between two fractions was prolonged up to 25 days. Therefore, if slow repair occurred it was not worth more than 1 Gy because this was the limit of resolution of the assays used. As overall time was prolonged to 60 days an additional 1-2 Gy were recovered: it is difficult to explain this delayed sparing effect on the basis of a compensatory proliferative response, because the labelling indices of the likely target cells in the kidney are so low. Whatever the mechanisms involved, an increase in overall time had only a slight effect on isoeffect dose in these experiments and values for the "T" exponent were low (0.0-0.09). Recovery from sublethal injury between fractions has a much larger effect.

Animals↗
PubMed1984

Effects of radiomodifiers on high and low LET responses in vivo.

The radioprotector WR-2721 and the radiosensitizer misonidazole have been studied for their influence on the response of mouse skin and tumours when irradiated with either single or fractionated doses of 240 kV X-rays or 3 MeV neutrons. The modification of radiosensitivity to neutrons was significantly less than that for X-rays, both for tumours and skin. When the two drugs were given in combination before single neutron doses, competitive interaction was observed.

Animals↗
PubMed1984

Enhancement of misonidazole radiosensitization by buthionine sulphoximine.

The influence of glutathione (GSH) depletion on the radiation response and on the radiosensitizing efficiency of misonidazole (miso) has been studied in two types of mouse tumour and in mouse skin. Buthionine sulphoximine (BSO) has been administered in a variety of regimes, leading to a maximal depletion of GSH to 37% of control values in one tumour (CA MT) and 61% in the other (SA FA). Pretreatment with BSO did not alter the radiosensitivity of either tumour when treated with X-rays. It had a slight effect on the sensitizing efficiency of miso, corresponding to a factor less than three, which was detectable only at the highest X-ray doses used. No enhancement of miso efficiency was seen with 5 daily fractions. Prolonged administration of BSO resulted in a slight radiosensitization of mouse skin. When combined with miso the effect was very small and was only detectable at high X-ray doses. BSO however produced a marked enhancement of the acute toxicity of miso, as judged by lethality after large single doses.

Animals↗
PubMed1984

Endothelial proliferation in tumours and normal tissues: continuous labelling studies.

The proliferation rate of vascular endothelium has been studied using repeated administrations of tritiated thymidine, given every 8 h for 1 week. Five experimental mouse tumours have been investigated and compared with placenta and with normal tissues. The large difference in labelling indices between tumour and normal endothelium that has previously been detected with single injections of ([3H]dT) is confirmed by these continuous labelling studies. The potential doubling time of the tumour endothelium is estimated to be between 2.4 and 13 days for the five tumours. Tpot for the placenta is at least as short. The turnover time of the normal tissue endothelium is estimated to be 20-2000 times longer (47-23,000 days) and does not seem to differ in slow turnover tissues e.g. lung and liver from that in tissues where the parenchymal cells are rapidly turning over e.g. jejunum or skin.

Adenocarcinoma↗