Concurrent measurements of blood flow and transcapillary transport in avian sarcoma virus-induced experimental brain tumors: implications for chemotherapy.

A blood-to-tissue transfer constant, K, and tissue blood flow, F, were measured concurrently in seven rats with a total of 19 separate brain tumors induced by intracerebral inoculation of avian sarcoma virus. Regional and local measurements of K and F were obtained using double-label quantitative autoradiography with alpha-[14C]aminoisobutyric acid and [131I]iodoantipyrine, computerized microdensitometry and image analysis. Apparent tissue extraction fractions and capillary permeability-surface area products were calculated for different tumor regions, brain adjacent to tumor and tumor-free brain. The following observations were made: five histological categories of the tumors were found; significant local and regional variations of both K and F were typical in each group, resulting in marked regional variability of permeability-surface area products but more uniform values of apparent extraction fraction; the values of F, K, permeability-surface area products and apparent extraction fraction correlated poorly with morphological features of the tumors (necrosis, cellularity, cytology, location and size); the extraction fraction of alpha-aminoisobutyric acid was usually highest in tumor centers and then decreased in a gradient from tumor periphery through adjacent brain; and regardless of classification or histological features, capillary permeability and surface area, and not tissue perfusion or blood flow, seem to determine the blood-to-tissue transport processes (delivery of bloodborne materials) in most regions of these experimental brain tumors. An operational pharmacokinetic model of drug concentration in tumor tissue is developed and the results of our analysis indicate that increases in capillary permeability such as measured in these studies would not be sufficient to deliver adequate amounts of water-soluble drugs with short plasma half-lives to tumor tissue.