Vascular permeability in the ears of rats after x-irradiation.

Late fibrosis in normal tissue is a complication which develops gradually after radiotherapy. It may be related to increase in vascular permeability induced by radiation. Plasma proteins leak into irradiated tissue where fibrinogen may be converted into fibrin which is gradually replaced by fibrous tissue. Vascular changes in the rat ear were investigated for six months after X-irradiation; Blood volume and vascular permeability were measured in vivo by monitoring the radioactivity in both irradiated and control ears after intravenous injection of phosphorus 32 labelled red cells and either iodinated (iodine 125) albumin or fibrinogen. After a single dose of 40 Gy there was an early increase in vascular permeability to both albumin and fibrinogen. After 20 Gy permeability to albumin was only increased during desquamation but extra-vascular fibrinogen accumulated at earlier times. Extravascular albumin was removed rapidly from irradiated ears, whereas some residual fibrinogen remained. Vascular permeability returned to normal but six weeks and showed no further changes up to six months after irradiation. Differences between the accumulation of extravascular albumin and fibrinogen at early times after irradiation could be due to some fibrinogen being fixed in the tissue. However, the rat ear showed no late changes comparable to the gradual development of late fibrosis seen in man.

Clinical testing of the radiosensitiser Ro-07-0582. III. Response of tumours.

The nitro-imidazole Ro-07-0582, a known radiosensitiser of hypoxic cells in animals, was administered orally to seven patients with metastatic tumour, before irradiation. The delay imposed on the growth of tumour treated in this way was compared to that of tumour in the same patient treated with radiation alone. Two patients died before any assessment of response could be made. Qualitative evidence from a further three patients suggested some enhancement of radiation effect in two patients but not in the third. Quantitative evidence was obtained from the remaining two patients. In one, a patient with multiple pulmonary metastases from a carcinoma of the breast, no enhancement was shown. In the other, a patient in whom 21 subcutaneous metastases from a carcinoms of the cervix of the uterus were measured, an enhancement ratio of 1-2 was found. This agrees with the value from the same patient's skin when rendered artificially hypoxic, as reported previously. The conditions under which quantitative information may best be obtained in this type of trial are described and various factors affecting the interpretation of results are discussed. Ro-07-0582 has thus been shown to have a radiosensitising effect in man and may therefore prove of value in radiotherapy.

Hypoxic cell sensitisers in radiotherapy.

Solid tumours contain poorly oxygenated cells, and these are disproportionately resistant to therapeutic radiation. Several methods of overcoming this problem have been used clinically, including the administration of hyperbaric oxygen during irradiation, radiotherapy with heavy nuclear particles such as neutrons from cyclotrons, optimum size and spacing of multiple doses of conventional radiation, and, most recently, chemical radiosensitisers. These radiosensitisers mimic the sensitising effect of oxygen and are active only against hypoxic cells. They do not, therefore, increase radiation response in well-oxygenated normal tissues. They are not rapidly metabollised and so can penetrate further than oxygen from the vascular capillaries and effectively reach the hypoxic cells in the tumour. Some of these drugs are of considerable clinical promise. The results of in vitro and in vivo studies with radiosensitisers are summarised and preliminary clinical work is described.

A marked dependence of the comparative effectiveness of neutrons on tumour line, and its implications for clinical trials.

The responses of five transplantable rat tumour lines to neutron and X irradiation have been compared by a method in which radiation-induced delay in tumour growth is used as a measure of effect. All the tumours were sarcomas and were irradiated at the same size, after growth in the same site, and under standard conditions. This group of similar tumours exhibited a large range in values of RBE in a dose range within which fractions of hypoxic cells did not detectably influence the result of X irradiation. Of the five tumour lines used, there were two pairs the members of which had a common origin and were histologically similar; the greatest differences in RBE values were between members of the pairs. These results suggest that the therapeutic use of high LET radiation cannot be expected uniformly to achieve local control better than conventional treatment of tumours at a given site, or even of a given histological type. Research is needed into methods that will have predictive value for the relative success of neutron therapy.