One of the problems facing clinical High-LET radiation is the late tissue changes associated with injury to the vascular system - in particular the capillaries - late effects associated with severe fibrosis. In vivo measurements of microvascular changes in the Sandison Clark ear chamber in the New Zealand rabbit and in vitro experiments using organ cultures of rabbit vascular cells are directed to provide pre-clinical information concerning the response of this tissue in vivo and in vitro. The effects on the microvasculature in vivo of graded single neutron doses (12.5-500 rads), fractionated neutron exposures, graded doses of x-rays and the interaction and possible potentiation of these two modalities will be evaluated. Early and intermediate vascular changes following single or combined treatment regimens will be scored and correlated by measuring the following parameters in vivo on capillaries, arterioles and venules: microvascular length, surface area and wall thickness. These parameters will be determined separately for capillaries, (less than or equal to 10Mu in diameter) larger vessels (greater than 10Mu dia.), and for the total microvasculature. From these measured parameters, microvascular volume, microvascular density/mm2 and a dilatation factor over time will be calculated. In vitro studies carried out in parallel will use comparable cultures of vascular endothelial and smooth muscle cells irradiated in vivo to further elucidate the role of these two most reactive cell populations in early and intermediate effects following radiation. Thus we will determine a) the neutron dose response (Do, Dq, LD-50) for microvasculature in vivo and its cellular components in vitro, b) the extent of early and intermediate injury and repair and c) the extent of differential sparing of capillaries by the use of fractionated regimens. Doses of neutron radiation and dose fractionation with this modality will be compared with already established observations made in these two systems with kilovoltage x-rays. The dynamics of RBE over dose and time in relation to these two clinically used modalities will be established. These quantitative experiments will provide valuable information to develop clinical strategies to minimize the late vascular changes in the use of High-L radiation in human cancer management.
