Increases in brain tumor and cerebral blood flow by blood-perfluorochemical emulsion (Fluosol-DA) exchange.

It has been suggested that oxygen-carrying blood substitutes, perfluorochemical (PFC) emulsions, can increase blood flow and oxygen delivery to poorly perfused tumor regions. Local cerebral blood flow was measured in male Wistar rats bearing intracranial Walker 256 tumor with and without blood-PFC exchange using [14C]iodoantipyrine (IAP) and quantitative autoradiographic techniques. The exchange transfusion was performed in two groups of awake animals breathing 100% oxygen: (a) complete blood-PFC exchange, hematocrit 4%; and (b) partial blood-PFC exchange, hematocrit 20-25%. The tissue/blood partition coefficient for IAP was determined in a separate set of experiments under identical conditions and was used in calculating blood flow. Cerebral blood flow increased approximately 2-fold following complete blood-PFC exchange and 1.5-fold by the partial exchange. A similar 1.5-fold increase in flow was measured in intraparenchymal tumors following partial exchange; however, a flow increase was not identified in the meningeal extension of the tumors. The increase in cerebral blood flow is consistent with an autoregulatory response of the central nervous system vasculature to maintain an adequate supply of oxygen to central nervous system tissue. Presumably, the increase in blood flow to the intracerebral tumor reflects the autoregulatory response of the host tissue. The effect of blood-PFC exchange on blood flow and drug delivery to tumor may depend on the particular tumor and its site of growth (host tissue). The tissue/blood partition coefficient for IAP increased from 0.8 to 1.0 and 1.4 following partial and complete blood-PFC exchange, respectively. This change in the partition coefficient reflects the change in the intravascular fraction of IAP that is bound to plasma proteins. The enhanced therapeutic effect that has been reported in some experimental tumor models may result from a higher tissue/blood equilibrium distribution ratio (due to reduced plasma protein binding) resulting in a higher tissue exposure to certain drugs following PFC administration.

Dexamethasone effects on [125I]albumin distribution in experimental RG-2 gliomas and adjacent brain.

A total of 72 RG-2 transplanted gliomas were studied in 58 rats at three time points (1, 30, 240 min) after intravenous injection of [125I]radioiodinated serum albumin ([125I]RISA). The animals were divided into two groups: a control group that received no treatment and a second group that was treated with five doses of 1.5 mg/kg of dexamethasone over 2.5 days. Local tissue concentrations of [125I]RISA were measured with quantitative autoradiography based on morphological features of the tumors and used to calculate the tissue distribution space. Two models were used to analyze the data. A two compartment model yielded estimates of local blood-to-tissue influx constants (K1), lower limit extracellular volumes (Ve), and plasma vascular volumes (Vp) in different tumor regions. Treatment with dexamethasone consistently reduced the RISA distribution space in the RG-2 tumors; the reduction in Ve was statistically significant in almost all tumor regions: whole tumor Ve (mean +/- SE) was reduced from 0.14 +/- 0.02 ml g-1 in control animals to 0.08 +/- 0.01 ml g-1 in dexamethasone treated animals. K1 and Vp were also decreased in all tumor regions after treatment with dexamethasone (whole tumor K1 decreased from 2.36 +/- 0.89 to 0.83 +/- 0.29 microliter g-1 min-1 and Vp decreased slightly from 0.016 +/- 0.013 to 0.010 +/- 0.005 ml g-1 after dexamethasone treatment), but these changes were not statistically significant. A comparison of the tumor influx constants in control animals and the aqueous diffusion constants of two different size molecules (RISA and aminoisobutyric acid) suggests that the "pores" across RG-2 capillaries are large and may not restrict the free diffusion of RISA (estimated minimum pore diameter greater than 36 nm) and that the total pore area is approximately 6.2 X 10(-5) cm2 g-1 in RG-2 tumor tissue. The second model, which allows for diffusion and solvent drag of RISA across tumor capillaries and through the tissue, was used to analyze the distribution profiles of RISA in peripheral tumor and adjacent brain. This analysis was consistent with a small bulk flow of plasma-derived edema fluid (capillary filtration rate approximately equal to 0.8 microliter g-1 min-1) and a larger component of free diffusion of RISA (K approximately equal to 2 microliter g-1 min-1) through pores in the tumor vessels of control animals. Dexamethasone treatment markedly reduced or eliminated the filtration of plasma-derived fluid across tumor capillaries and the movement of RISA through the extracellular space by solvent drag.(ABSTRACT TRUNCATED AT 400 WORDS)

Comparison of iron-59, indium-111, and gallium-69 transferrin as a macromolecular tracer of vascular permeability and the transferrin receptor.

Tracer amounts of [59Fe++]citrate, [111In+++]chloride, and [68Ga+++]chloride were complexed with autologous plasma transferrin. Each of these complexes were co-administered with [125I]albumin by i.v. injection and their biodistribution was studied in Wistar rats. The plasma clearance of 59Fe and [125I]albumin was monoexponential with half-times of 49-70 and 277 min, respectively. The plasma clearance of 68Ga and 111In was biexponential with second component half-times of 157 and 232 min, respectively. Indium-111 tissue distribution was similar to that of [125I]albumin in heart, lung, muscle, brain and Walker-256 allograft. Iron-59 distribution spaces were generally the highest of the metal complexes in all tissues except muscle, where the 68Ga space was highest. The effects of transferrin-specific receptor-mediated endocytosis can be avoided in many organs and Walker-256 allografts by using the indium-transferrin complex, and the radiolabeled complex may be a convenient macromolecular tracer to estimate vascular permeability and vessel pore size in tumor and systemic tissue. In contrast, the iron-transferrin complex may be useful for measuring and imaging transferrin-specific receptors in brain and tumor tissue.

Spinal subarachnoid perfusion of rhesus monkeys.

A technique of spinal subarachnoid perfusion is descirbed which effectively isolates the spinal cord from the remainder of the central nervous system. A method of obtaining and analyzing spinal cord tissue after subarachnoid perfusion is presented. The spinal subarachnoid space of 12 rhesus monkeys was perfused with [14C]sucrose, [14C]ethylenediaminetetraacetic acid-calcium complex (EDTA), and dextran blue as test substances. The sucrose and EDTA spinal cord distribution spaces are 13.6 +/- 0.9% in white matter and 18.1 +/- 1.4% in gray matter. The diffusion coefficient in tissue of sucrose is 1.7 x 10(-6) cm2/s and of EDTA is 1.55 x 10(-6) cm2/s. The spinal cord tortuosity factor is 2.0-2.1. Six rhesus monkeys were infused intravenously with [3H]sucrose and [14C]EDTA; the spinal capillary exchange half-time from blood to extracellular fluid was greater than 6 h for both sucrose and EDTA.

Initial studies on the penetration of spirohydantoin mustard into the cerebrospinal fluid of dogs.

A gas-chromatographic-mass-spectrometric method using selected ion monitoring has been developed to detect and quantitate levels of spirohydantoin mustard (SHM) as low as 1 ng per injected sample. The ions chosen for analysis of the drug were at m/e 154, 156, and 299. Using this procedure, the distribution of SHM in the blood and cerebrospinal fluid (CSF) of dogs following intravenous administration has been studied. The initial blood decay of SHM is rapid with a half-life of 1.78 and 1.85 min for 2 different dogs. SHM enters the CSF and, after reaching a peak value at approximately 10 min, exhibits a decay curve similar to that found in blood.

Attempts to increase intratumoral blood flow in the rat solid Walker 256 tumor by the use of the perfluorocarbon emulsion fluosol-DA.

We have examined the effect of the perfluorocarbon emulsion, Fluosol-DA 20% (FDA), on blood flow in rats bearing an advanced solid Walker 256 tumor implanted s.c. Blood-FDA exchange in unanesthetized rats maintained under 100% oxygen was accomplished by simultaneous arterial withdrawal and i.v. infusion until the hematocrit was less than 4%. Control rats were maintained under 100% oxygen but did not undergo any exchange. Regional blood flow studies in tumors of control and FDA-exchanged rats were performed using [14C]iodoantipyrine and quantitative autoradiography. FDA-blood exchange did not increase flow to the whole tumor. Similarly, the pattern of regional flow within the tumor, which was determined in histologically distinct areas--including dense and normocellular, necrotic and peripheral zones invading into muscle and connective tissue--was not substantially altered. Flow to cerebral tissue was increased two-fold, although flow to normal tissues including temporalis muscle, skin and diaphragm was not altered. These results show that FDA-blood exchange does not enhance vascular flow in solid Walker 256 tumor implanted s.c. in the rat.

Dexamethasone effects on vascular volume and tissue hematocrit in experimental RG-2 gliomas and adjacent brain.

We have studied the effects of dexamethasone, a corticosteroid commonly used to treat brain tumors, on vascular volume and tissue hematocrit in RG-2 experimental rat gliomas. 125I-RISA (radioiodinated serum albumin) was used to measure tissue plasma vascular volume (Vp) and 51Cr labeled red cells were used to measure tissue red cell volume (Vrbc). Quantitative autoradiography was used to obtain local measurements of Vp and Vrbc in different brain and tumor regions. From these experimentally measured values, we calculated the tissue vascular volume (Vv), tissue hematocrit (THct) and systemic arterial hematocrit (AHct). The value reported primarily reflect capillary and small vessel volumes since blood drained from larger vessels during tissue processing and large vascular structures were avoided during analysis of the autoradiographic images. A total of 110 tumors were studied in 29 animals. There was a consistent trend for Vp and Vv to be reduced in all tumor regions after dexamethasone treatment, although a significant decrease was seen only in tumor center. Dexamethasone did not affect Vp or Vv in tumor-free brain regions. Dexamethasone appeared to have little effect on Vrbc in any brain or tumor region. THct was consistently, although not significantly, higher in tumors after treatment with dexamethasone; THct in tumor-free brain regions was unaffected by dexamethasone treatment.