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Publications and source records attributed to J F Fowler.
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Rubidium-86, 125I-human serum albumin and 51Cr-labelled red cells have been used to investigate the effects of the anaesthetics Nembutal (pentobarbitone sodium) and urethane on blood perfusion, blood volume and albumin leakage in 5 types of transplanted mouse tumour and in normal organs. Nembutal was found to increase the relative blood perfusion by a factor of 1-3 to 2-0 in tumours and by a factor of 1-7 to 3-0 in kidneys but muscle perfusion fell to 0-3-0-5 that of controls. The effects of urethane were found to be dose dependent, generally in the same direction as for Nembutal, and smaller. Both anaesthetics reduced the blood volume of tumours (except for the C3H mammary carcinoma) and of kidneys by factors of 0-2 to 0-8. The duration of anaesthesia had no effect on the plateau values of relative blood perfusion and blood volume in either tumours or normal organs, but Nembutal delayed slightly the 86Rb uptake and decreased the rate of albumin leakage.
First-generation transplants of spontaneous mouse mammary carcinomas have been used extensively for radiobiological investigations of fractionated irradiation schedules, r.b.e. of fast neutrons and effectiveness of radiosensitizers, as reported elsewhere. The present work investigates the growth characteristics of the tumours; the criteria for the choice of end-points used in the definition of 'local control' of irradiated tumours; the reason for a decrease of 30 per cent in X-ray dose required to control tumours in females as compared with male mice; the proportion of hypoxic cells and its variation with time (reoxygenation) after a single dose of 1500 rad of X-rays; and the repair capacity of tumour cells within 24 hours after a substantial first dose of X-rays. Evidence is presented that the male-female difference was due to a higher proportion of hypoxic cells in tumours in male than in female mice. The repair of sub-lethal injury in tumour cells made hypoxic was slightly less than in skin made hypoxic but not significantly so. In the two-dose experiments on clamped tumours, no evidence of induced synchrony was found.
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In previous experiments the highest proportions of tumours controlled for 150 days at a particular level of skin reaction were obtained with five or nine fractions of X rays in nine or ten days respectively. Poor results were obtained for the same numbers of fractions given in 4 or 18 days respectively. The present work reports results of three "non-standard" fractionation schedules: two with equal doses given at 12-hour intervals over four or nine days and one with eight decreasing doses given at decreasing intervals over 11 days. The two 12-hour interval schedules gave results which were equal to the best obtained by any other schedule tested. The 8F/11d non-uniform schedule, however, gave mediocre results in spite of being close to the previously optimum overall time. When these results are compared with previously published results from the same tumour system two, phases of optimum fractionation are demonstrated. At short overall times, up to four days, the situation is finely balanced, so that fraction size and interval matter greatly and results of the schedules vary from good to bad. At longer overall times, of nine days or more in these tumours, the response is no longer so variable. Eighteen days (two to three times the average volume doubling time) is too long for any successful treatment with this system, presumably because of proliferation in the tumour.
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The main differences between biologic effects of high and low LET irradiation are reviewed with special reference to multiple dose fractionation schedules. Some new results relating to RBE values of normal tissues (skin) at low doses per fraction are presented. Recent results of experiments to investigate optimum x-ray or fast neutron fractionation schedules are summarized. It is concluded that, until much more is known about the processes occurring inside tumors during treatment, high LET radiation is likely to be more reliable for eradicating tumors.
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C3H mice were implanted with pieces of spontaneous mammary carcinoma which were irradiated or removed surgically when they had grown to 6·5 mm mean diameter. The incidence of lung metastases was determined from samples taken at various times up to 6 months later. Single x-ray doses and fractionated schedules up to 15 fractions in 18 days were used, no significant difference being observed in the results for all these schedules.On the major question of whether radiation caused an increase in the number of lung metastases the study is inconclusive. The incidence of metastases was found to be 8% if the implanted tumour was cured by the radiation, whereas if the radiotherapy did not cure the tumours the incidence was 35%. This difference between the two groups was significant. If tumours recurred locally after radiotherapy and were then removed surgically, the incidence of lung metastases was significantly greater than that after surgery of unirradiated tumours. The incidence of metastases was similar after curative surgery and after curative radiotherapy.
Local tumour control has been determined at 150 days after single doses of 240 kV x-rays given with or without 1 mg/g body weight of the hypoxic cell radiosensitizer Ro-07-0582. The dose required to control 50% of the tumours (TCD50) was reduced from 4380 to 2410 rad, yielding an enhancement ratio of 1·82 ± 0·07 s.e.mean. This compares favourably with the corresponding single dose gain factor for fast neutrons, which was about 1·7.
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