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Summary The regional distribution of blood flow to the LBDS, fibrosarcoma, transplanted into the subcutaneous site in rats, was investigated using the readily diffusible compound '4C-iodo-antipyrine ('4C-IAP). Quantitative autoradiography was used to establish absolute values of specific blood flow F for 100 x 100 x 20 1sm adjacent tissue volumes of the unperturbed tumour. Mean blood flow to whole tumours was found to decrease with increase in tumour size. This relationship was abolished if blood flow was only measured in sections cut from the periphery of the tumours. Detailed analysis of a sub-group of tumours showed that blood flow to individual tumours was heterogeneous. The range of blood flow was large, indicating that mean blood flow to a whole tumour is a poor reflection of the blood perfusion pattern of that tumour. Necrotic tumour regions were usually very poorly perfused. With the exception of the smallest tumours studied, blood flow was lower in the centre of tumours than in the periphery. Necrosis also tended to develop centrally. However, the peripheral to central gradient of blood flow was apparent even when densely cellular, viable tumour regions and necrotic regions were analysed separately. The decrease in blood flow with tumour size was also apparent in densely cellular, viable tumour regions when analysed separately. Qualitative comparison of tumour histology and regional blood flow showed that there were areas of very low blood flow associated with viable tumour regions. Less common were areas of rather high blood flow associated with necrotic tumour regions. A complicated relationship exists between tumour histology and blood flow. The quantitative autoradiography technique is suitable for investigating the most poorly perfused and the most well perfused viable fractions of animal tumours which may limit the efficacy of different types of therapy.The blood flow to tumours plays an important role in their treatment. In radiotherapy, the efficacy of treatment depends upon cellular oxygen concentration which is governed by respiration rate and local blood flow. In chemotherapy, blood flow determines the efficiency of drug delivery. In hyperthermia, the temperature elevation achieved and the sensitivity of cells to heat is influenced by blood flow. Blood flow is therefore a critical parameter to measure both experimentally and clinically.It is known that blood flow to both transplanted animal tumours and to human tumours is heterogeneous (Chaplin et al., 1987;Ito et al., 1982;Vaupel & Frinak, 1980). Therefore global measurements may not be the most pertinent means of describing tumour blood flow. For instance, global measurements will include blood flow to necrotic tumour regions which are not relevant for therapy. For hyperthermia, a knowledge of high blood flow in discrete tumour regions would be important because these regions are the ones most likely to limit efficacy of treatment.Blasberg and colleagues used the inert, readily diffusible compound iodo-antipyrine to measure blood flow to tr...

The primary effect of irradiation on self-renewing normal tissues is sterilisation of their proliferative cells, but how this translates into failure of tissue function depends on the mode of organisation of the tissue concerned. It has recently been suggested (Michalowski, 1981) that proliferative normal tissues may be classed as "hierarchical" (like haemopoietic tissues) or as "flexible" (like liver parenchyma) and that radiation injury to tissue function develops by different pathways in these tissues. Mathematical model studies confirm the different radiation responses of differently organized tissues. Tissues of the "flexible" or "F-type" category display a variety of novel radiobiological properties, different from those of the more familiar "hierarchical" or "H-type" tissues. The "F-type" responses are strongly influenced by radiation-sterilised ("doomed") cells, and it is suggested that the rôle of "doomed" cells has been undervalued relative to that of clonogenic survivors. Since "F-type" tissues have characteristically low rates of cell renewal, it is possible that these tissues are preferentially responsible for late effects of irradiation in clinical radiotherapy.

It is argued that proliferating normal tissues fall into two categories. In type H (for hierarchical) tissues, cells either multiply or perform tissue-specific functions. Sterilizing doses or radiation immediately initiate a gradual depopulation of irreversibly postmitotic, mature cells. The constant rate of functional cell depletion is given by physiological longevity of the cells. Consequently the onset of maximal depopulation is dose-independent and, after a range of radiation doses, the peak of milder damage is seen earlier than that of a more severe one. In type F (for flexible) tissues all cells are assumed to have the potential for proliferation and are also engaged in tissue-specific functions. Radiation leads to dose-dependent loss of the functional cells through their mitotic death, both immediately after exposure and during the next phase of increased compensatory proliferation resulting in accelerated expression of radiation damage ('avalanche'). Consequently the more severe damage following larger doses of radiation is seen earlier than the milder one produced with smaller doses. Assays of cell clonogenicity in vivo concern almost exclusively type H populations. The large radiation/drug/heat doses administered in these assays serve both to dilute the clonogenic cells by at least two orders of magnitude, and to produce a measurable response. When comparing two agents or interpreting their combined action it is advisable to ensure that the dilution step yields qualitatively comparable samples of clonogenic cells to be then characterized in terms of dose-survival curve parameters.

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Targeted radiotherapy with 211At-methylene blue (211At-MTB) is a systemic treatment selectively directed at melanoma due to a high affinity of MTB to melanin synthesized in the tumor cells. Since MTB forms a strong complex with melanin, it is an effective carrier for a number of radioisotopes to be addressed to the tumor deposits of any size including individually dispersed melanoma cells. Thus, appropriately radiolabeled MTB can be used for either diagnosis or therapy of the neoplasm. As predicted and found in animal experiments, 211At-MTB is most effective therapeutically. Histopathological investigations showed that the highly pigmented 211At-MTB-treated tumors were characterized initially by perivascular oedema and hydropic degeneration of tumor cells followed by gradual development of extensive areas of coagulative necrosis. The necrotic tumor areas contained microvessels occluded by thrombi and tended to undergo microfocal calcification. Although melanoma-bearing animals successfully treated with 211At-MTB did not reveal any adverse effects of the therapy, detailed toxicological studies were undertaken. No serious macro- or microscopic lesions were observed in normal organs of 211At-MTB treated mice. Only the relative number of small lymphocytes in the groin lymph nodes in a minority of animals was variably reduced, most often in conjunction with the treatment of highly, but not poorly, pigmented tumors.

The value of the radiobiological oxygen constant K has been found to depend on the concentration of non-protein sulphydryl (NPSH) within the cell. Cells in the exponential phase of growth have a higher concentration of NPSH and a higher value of K than cells in plateau phase. Binding NPSH with N-ethylmaleimide reduced the value of K and conversely, addition of NPSH as dithioerythritol increased the value of K. K also rises with the same time course as NPSH increases, when plateau phase cells are replated into fresh medium. These results support the hypothesis that free-SH groups within the cell compete with oxygen to react with radiation damaged molecules.