RESIDENCE TIME DISTRIBUTIONS OF VARIOUS TRACERS IN TUMORS - IMPLICATIONS FOR DRUG-DELIVERY AND BLOOD-FLOW MEASUREMENT

Background: The evaluation of rates of tumor blood now with small, rap idly diffusing tracers requires an accurate model for mass transport w ithin the tissue and tracer biodistribution. It is generally assumed t hat the whole tumor or several tumor regions act as well-mixed compart ments, an assumption that has never been evaluated in tumors. Purpose: The purpose of this study was to assess the accuracy of compartmental flow models in tissue-isolated tumors. Methods: We measured the resid ence time distributions of various tracers with the use of ex vivo per fusion of tissue-isolated rat R3230AC mammary tumors. This approach pe rmits simultaneous, independent measurements of total blood flow and t racer concentrations in afferent and efferent vessels. The isolated tu mors were perfused with Krebs-Henseleit solution, to which could be ad ded D2O saline and either 3% by volume F44-E (a perfluorocarbon emulsi on) or 1% by weight fluorescein isothiocyanate (FITC)-albumin. A pulse of D2O and one of the other tracers was added to the perfusing liquid , and the relative concentrations of both D2O and perfluorocarbon or F ITC-albumin were measured in the tumor effluent. D2O and the perfluoro carbon were measured with an imaging spectrometer tuned to either H-2 or F-19. FITC-albumin concentrations were measured by luminescence spe ctrometry. The results were analyzed using various compartmental model s. Results: The tracer residence time distribution deviated from that expected for a single well-mixed compartment. Only half of the D2O lef t the tumor with a time constant consistent with the known perfusate f low. The remainder exited the tumor more rapidly than expected, and ne ither vascular shunting nor macroscopic flow heterogeneity accounts fo r this component of the D2O flow. However, two-compartment models prov ide an improved fit to the data. Conclusions: Our experiments demonstr ate that the simple compartmental model used to estimate blood flow wi th diffusible tracers is not accurate. Implications: The nonideal bloo d flow found in our experiments reflects phenomena that may have impor tant effects in the development of pharmacokinetic models of drug deli very to tumors. The accuracy of blood flow measurements, made with suc h techniques as nuclear magnetic resonance, positron-emission tomograp hy, and computed tomography, may also be affected when they rely on th e assumption that the tumor is a collection of well-mixed compartments .