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Biomedical subjects

S B Field

Publications and source records attributed to S B Field.

At least 19 recordsLinked to original sources

Differences in vascular response between primary and transplanted tumours.

The vast majority of studies on tumour vasculature are performed on transplanted tumours in rodents. However, it is known that there may be differences between primary and transplanted lesions. The purpose of this study is to test whether a specific vascular response is similar in primary tumours and in transplanted tumours derived from them. The technique used was to give an intraperitoneal injection of 5 mg kg-1 hydralazine, which is known to result in hypoxia in transplanted tumours. Changes in perfusion were indicated by changes in metabolism, monitored using 31P Magnetic Resonance Spectroscopy. The primary tumours were induced by local irradiation many months previously and only 4/11 (36%) of these responded to hydralazine. One of the non responders was subsequently transplanted into isogeneic mice to produce a tumour line which was histologically very similar to the primary. Of these 16/17 (94%) responded. The difference is statistically significant (P = 0.001). The reasons for this difference are not known. A number of possibilities are discussed and in the authors' opinion, the most likely cause is that it results from an artefact of transplantation.

Animals

The potential for prazosin and calcitonin gene-related peptide (CGRP) in causing hypoxia in tumours.

Using 31P NMR spectroscopy, changes in tumour metabolic status were studied in a transplanted rat fibrosarcoma following the administration of vasodilators. Mean Arterial Blood Pressure (MABP) was monitored simultaneously. Two vasodilators were studied, prazosin and CGRP, which altered the NMR parameters Pi/sigma P, beta NTP,Pi, PCr/Pi and PME/Pi in a dose dependent manner. There was a good correlation between the various NMR parameters; for analysis, Pi/sigma P was used for convenience. With increasing doses of vasodilator, Pi/sigma P increased and the MABP decreased. Reduction in pHNMR showed a correlation with decreasing MABP following the administration of prazosin but not after CGRP. Both prazosin and CGRP produced changes in 31P NMR spectra consistent with a reduction in tumour blood flow. The results for prazosin and CGRP were comparable and showed a 15-20% increase in Pi/sigma P for a 20% reduction in MABP. These results were compared with those from hydralazine. With hydralazine an acceptable reduction in blood pressure (up to approximately 25%) has little effect and may even alter NMR parameters consistent with an increase in blood flow, a reduction of approximately 40% is required for a significant decrease in flow. Both prazosin and CGRP are shown to be far more effective than hydralazine in causing tumour hypoxia at a clinically acceptable reduction in blood pressure. CGRP may be the more suitable for clinical use because of its short half life, its capability to achieve controlled hypotension and the relatively few side effects associated with its use.

Animals

Treatment of functional menorrhagia by radiofrequency-induced thermal endometrial ablation.

42 patients were enrolled in a trial of radiofrequency-induced thermal endometrial ablation for the treatment of functional menorrhagia. The radiofrequency electromagnetic energy was delivered via a probe placed within the endometrial cavity. 10 patients received 330 kJ of energy, 10 received 445 kJ, and the other 22 received 660 kJ. 19 (87%) of those receiving the highest dose became amenorrheic or had a considerable reduction in menstrual flow. The procedure is simple and the heat induced in the endometrium does not penetrate much beyond the inner layers of the myometrium. There is no need for distension of the uterine cavity with flushing media.

Adult

The combined measurement of blood flow and metabolism in RIF-1 tumours in vivo. A study using H2 flow and 31P NMR spectroscopy.

Blood flow and phosphorus metabolites have been measured simultaneously in the murine RIF-1 tumour in vivo. Blood flow was measured using the H2 washout technique and 31P NMR spectroscopy was used to measure high energy phosphates, inorganic phosphate and intracellular pH within the tumour. Following NMR and flow measurements, hydralazine was administered and the measurements repeated. There was always a decrease in blood flow, and a fall in nucleoside triphosphate detected by NMR, after administration of hydralazine. At blood flows in excess of 15 mL 100 g-1 min-1, the nucleoside triphosphate/inorganic phosphate ratio was 1.0 or greater, whereas at flows in the range of 5-12 mL 100 g-1 min-1 the ratio fell to below 0.5, and at flows below 5 mL 100 g-1 min-1 there was no detectable resonance from nucleoside triphosphate.

Animals

Expression of dose in neutron therapy.

A pragmatic approach in neutron dosimetry is to consider the energy spectrum to consist of a neutron and a gamma component. The relationship between the two components of dose in neutron radiotherapy has been investigated for energies currently in clinical use. Changes in the neutron component itself are not dealt with. Because the two components are given simultaneously there is some interaction between them so that the gamma fraction is more effective than if the neutron and gamma doses were separated in time. This interaction has been accounted for using a well-proven extension of the linear-quadratic (LQ) equation. Using values of the LQ parameters alpha and beta measured recently in vivo, we have modelled the total effect from the neutron and gamma dose-contributions in terms of an equivalent neutron dose. This allows a comparison of different methods of expressing the measured physical dose with the biologically effective dose. The current practice in neutron therapy is to give the total (neutron plus gamma) dose, quoting also the gamma contamination. In all cases within the range of energies used for therapy, the total dose will give an overestimate of the biologically effective dose by approximately 4% for each 5% of gamma contamination. Expression of the neutron dose only (ignoring the gamma component) will give an underestimate of the biologically effective dose by approximately 1.5% for each 5% of gamma contamination, i.e. the error is approximately three times less for neutron dose than for total dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Gamma Rays

The energy metabolism of RIF-1 tumours following hydralazine.

Phosphorus-31 Magnetic Resonance Spectroscopy (MRS) was used to observe the effect of two doses of the vasodilator hydralazine on the energy status of RIF-1 tumours. An intravenous dose of 5 mg/kg hydralazine reduced the high energy phosphate metabolites PCr and ATP, lowered pHMRS and raised the levels of inorganic phosphate of tumours within 20 min of administering the drug. The levels of high energy metabolites continued to decrease for at least 24 h. Normal muscle spectra obtained up to 1 h after drug administration remained unchanged. An intravenous dose of 0.5 mg/kg hydralazine also reduced NTP/Pi and PCr/Pi levels of tumours up to at least 5 h after drug administration, but the effect was smaller than for the higher dose. Blood flow measurements and measurements of systemic blood pressure demonstrated that 5 mg/kg of hydralazine produced a reduction in both systemic blood pressure and tumour blood flow relative to most normal tissues investigated. It is concluded that the changes in the P-31 MRS spectra of tumours were due to a reduction in tumour vascular perfusion following administration of hydralazine.

Animals

Influence of hyperthermia on the oxygen enhancement ratio for x-rays, measured in vivo.

The skin of mouse tail has been used to study the effect of hyperthermia on the oxygen enhancement ratio (OER). Heating was by immersion of a portion of the tail in hot water. Radiation was given either immediately before or after hyperthermia. The average skin reaction between 15 and 50 days after treatment was taken as the end-point. The OER in the absence of hyperthermia was 1.77, suggesting significant hypoxia of the skin. When hyperthermia was given after irradiation the measured value for the OER was not significantly different, but with prior hyperthermia the OER was increased to an average value of 2.3. This increase in OER is probably due to a transient increase in blood circulation following hyperthermia and causing improved tissue oxygenation during irradiation. As a consequence we would expect a greater thermal enhancement ratio for heat given before irradiation than afterwards, and this has frequently been observed with other normal tissues. There was no evidence that heat reduces OER, as has been reported by some authors on the basis of experiments performed on cells in vitro.

Animals

Effects of hyperthermia on the mouse testis and its response to X-rays, as assayed by weight loss.

The effects of both hyperthermia alone and X-rays combined with hyperthermia on mouse testis have been investigated. Testis weight on heating time was observed for temperatures in the range 39.5 to 43.75 degrees C. The relationship between the reaction rate and the reciprocal of absolute temperature indicated that, over the temperature range considered, the activation energy associated with such thermal damage was (646 +/- 45) x 10(3) J mol-1. No evidence was obtained to indicate a change in slope of the Arrhenius plot over this temperature range. Finally, despite the high sensitivity of the testis to heat and X-rays, no thermal enhancement of the weight loss after irradiation was observed when thermal treatments which, if given alone would produce some observable damage, were administered immediately after irradiation.

Animals

A microwave heating system for improving temperature uniformity in heated tissue.

A microwave heating system, designed to improve temperature uniformity in heated tissue, is described. The system employs parallel-opposed waveguide applicators, operating in the TE10 mode at 2450 MHz with the tissue to be heated (i.e. mouse intestine) immersed in a liquid which is both biologically compatible with and dielectrically similar to the tissue. The liquid improves the microwave coupling and avoids shape and size dependent absorption characteristics of the irregularly shaped tissue. Also, by maintaining this liquid at a suitable temperature with respect to that required in the tissue, the thermal losses and hence temperature gradients in the tissue are reduced compared with heating in hot liquid alone.

Animals

Induced thermal resistance in the mouse ear.

The mouse ear (pinna) was used to investigate the effect of two hyperthermic treatments. Heating was by immersion in hot water at 43.5 degrees C. A single treatment of about 50 minutes was required to cause necrosis in 50% of the ears heated. When heat treatment was given in two equal fractions the total heating time had to be increased if the interval between fractions was greater than four hours. By 24 hours a total treatment of about 100 minutes was required, indicating almost complete recovery from the first heating. Priming treatments at 43.5 degrees C induced thermal resistance to a second heat treatment at 43.5 degrees C. Maximum resistance was observed one day after a 20 minute priming and two days after a 40 minute priming, when the heating time had to be increased to 120 minutes, an increase by a factor of 2.4. Shorter priming treatments induced less resistance, the minimum heating time to produce an effect being two minutes. In all cases the effect decreased during the next four to five days. These results indicate that the reduced response of tissues to fractionated hyperthermia is due both to the repair of sublethal heat damage and induction of thermal resistance.

Animals

The effect of prior heat treatment on the thermal enhancement of radiation damage in the mouse ear.

The effects of prior heat treatment on the skin reaction produced by a subsequent treatment with combined heat and X-rays were investigated in the mouse ear. Ears were heated by immersion in hot water. The priming heat treatment was always 43.5 degrees C for 40 minutes. Its effect was transient, beginning between 24 and 48 hours after the priming treatment and reaching a maximum at 48 to 96 hours when there was a reduction in the skin response to combined heat and X rays, i.e. it caused a reduction in the thermal enhancement ratio (TER). The effect was lost by 192 hours. At 96 hours after the priming treatment the TER for 30 minutes at 42.5 degrees C or at 43.5 degrees C was reduced by a value equivalent to decreasing the temperature by about 0.4 degrees C. This was equivalent to increasing the heating at 43.5 degrees C required to produce a given enhancement of radiation damage by a factor of 1.4 relative to that required without prior heating. The effect was smaller than induced resistance to damage caused by severe heat treatment alone (i.e. necrosis) and it occurred later. These differences support the concept that two separate mechanisms underlie direct heat necrosis and thermal enhancement of radiation damage.

Animals

The effect of local hyperthermia on the small intestine of the mouse.

Small loops of mouse jejunum were exteriorized and heated by immersion in a bath of Krebs-Ringer salt solution. Crypts were lost in the heated regions with a half-time of approximately six hours and reached a steady level of damage by 10--16 hours. There was no recovery in crypt number for one week after hyperthermia. Using a 24 hour assay, crypt survival curves were obtained using various heating times in the temperature range 37.5 degrees C--44.5 degrees C. These curves were qualitatively similar to those resulting from radiation damage, showing a shoulder followed by exponential killing. As the temperature was increased, progressive changes in shape of the curves indicated a proportional inhibition of accumulation of sublethal heat damage combined with increased rate of expression of lethal damage. Over the temperature range 42.3 degrees C--44.5 degrees C, a linear relationship was found between the rate of crypt loss and the reciprocal of the absolute temperature. An activation energy of 600 +/- 70 kJ mole-1 was calculated using the Arrhenius equation. In this temperature range, doubling the heating time had the same effect as increasing the temperature by 1 degree C. At temperatures below about 42.3 degrees C, the tissue became relatively less sensitive to increasing the treatment time.

Animals

Two qualitatively different effects of hyperthermia on acid phosphatase staining in mouse spleen, dependent on the severity of the treatment.

Heating the lower body of the mouse for up to 1.5 hours at temperatures above 41.0 degrees C causes an increase in splenic lysosomal acid phosphatase activity. For mouse temperatures up to 42.3 degrees C the change is probably due to enzyme activation, which reaches a maximum 1.5 hours after heating and then decays in a way which may be related to the transient ability of moderate hyperthermia to potentiate X-ray damage. At temperatures above about 42.5 degrees C hyperthermia results in a qualitatively different lysomal response, probably due to an increased lysosomal membrane permeability. The change is observed immediately after heating and remains high for at least 4 hours. The resultant release of hydrolases into the cytoplasm may be involved in the irreversible cell damage caused by severe hyperthermia.

Animals